Control Tools

• Crohn’s disease is an idiopathic syndrome, i.e. the aetiology is not known. The severity of the clinical symptoms is likely to be correlated with the level of reporting.

  A common aetiology for all cases of Crohn’s disease seems unlikely.

  Misclassifications (false-positive and false-negative) are likely to occur for Crohn’s disease, because it is a syndrome, not a specific diagnosis.

  Some cases of Inflammatory Bowel Disease may not be reported as Crohn’s.

  GAPS

  The cause(s) of Crohn’s disease remains to be identified.

  The role of MAP in human disease complexes remains to be identified.

  If MAP is involved in some cases of “Crohn’s disease”, the proportion of humans infected with and affected by MAP is not known.

  The full gap analyses for cattle, small ruminants, other domestic species, and terrestrial wildlife for Paratuberculosis can be downloaded here

• Diagnostics availability

• Commercial diagnostic kits available worldwide

  There are many commercially available ELISA kits for detecting antibodies, interferon gamma kits for detecting cellular immune response and culture and PCR kits for detecting the organism and bacterial DNA. Culture is used less because of the long incubation time required. However, both liquid and solid ready-to-use media are commercially available. Liquid media is advantageous since it can also be used in specific automated instruments that allow indirect monitoring of growth and MAP´s growth in liquid media is generally faster than in solid media. In addition, new media formulations have speeded up growth (Bull et al., 2017)

  List of commercially available diagnostics (Diagnostics for Animals)

  GAPS

  Characteristics of tests in a population that reflects the target population.

  Reliable on-farm tests.

• Diagnostic kits validated by International, European or National Standards

  There is an in house developed PCR validated according to the OIE (Validation of IS900- qPCR assay to assess the presence of Mycobacterium avium subs. paratuberculosis in faecal samples according to the OIE procedure by Russo et al., 2022. Similarly, the Australian and New Zealand diagnostic standards includes a validated faecal PCR method (the High-throughout-Johne’s (HT-J) test) used for diagnostic and export testing (Plain et al, 2014).

  GAPS

  There are no globally accepted standards for validating diagnostic tests.

• Diagnostic method(s) described by International, European or National standards

  Routine methods are described in the OIE Manual of Diagnostic Tests and Vaccines

  Identification of the agent

  • Necropsy
  • Bacterial culture
  • Bacterial microscopy
  • DNA probes and PCR

  Serological Tests

  • CFT
  • ELISA
  • AGID

  Cell mediated immunity

  • Gamma interferon
  • Delayed hypersensitivity

  GAPS

  The sensitivity of necropsy and bacterial tissue culture in sub-clinically infected cattle has not been well established.

  Models for evaluation of the test results on individual as well as herd level should be improved.

• Commercial potential for diagnostic kits worldwide

  There is potential for use in Europe as part of industry control measures to reduce the level of MAP infected herds.

• DIVA tests required and/or available

  A DIVA test will be required if vaccination becomes widely used to control disease with the added requirement to ensure that cross reactions and interference with the tests for bovine TB are avoided.

• Opportunities for new developments

  Test to differentiate young animals on the basis of how successfully their immune system is managing/eliminating Map infection so that animals of higher resistance are retained in the herd and population.

• Vaccines availability

• Commercial vaccines availability (globally)

  Currently, there is only a commercial killed vaccine in two formats: for sheep (Gudair™) and for cattle (Silirum™). Only a commercial whole cell killed vaccine is registered in the EU (France) for cattle although by mutual recognition it can be applied in other countries with animal health authority special permits. Vaccination is illegal in some animal species in some countries (e.g. Denmark, The Netherlands). Currently, the only internationally commercial registered vaccine is a water-in-oil killed Map 316F vaccine that is presented in two slightly different formulations for cattle (Silirum™) and small ruminants (Gudair™), both produced by CZ Vaccines. Gudair™is licensed for use in small ruminants, in Spain, Portugal, Norway, Iceland, France, Greece and Netherlands. The vaccine for cattle (Silirum™) is licensed for use in France and is not to be used in cattle (or in small ruminants) in areas where tuberculosis is endemic because of interference with the M. bovis skin test. Both vaccines are effective in preventing clinical disease and retarding development of the disease and of faecal excretion, but they do not confer sterile protection.

• Marker vaccines available worldwide

  No.

  GAPS

  No marker vaccine is available.

  Several vaccines have been designed and only some have DIVA potential (preliminary studies with subunit, GMO).

• Effectiveness of vaccines / Main shortcomings of current vaccines

  Vaccination of young animals does not completely prevent infection and shedding of MAP can continue although there is a reduction in Map shedding and clinical disease incidence. Management practices combined with vaccination can reduce transmission and as a result may reduce the amount of disease occurring in infected herds and the level of environmental contamination. Current vaccines may interfere with the interpretation of the tuberculin test. Oil adjuvant vaccines can cause severe inflammation if accidentally inoculated into operators. Vaccination can completely clear shedders if applied to young replacers in less time than testing and culling alone. It is the most economically efficient method when combined with faecal PCR testing.

  GAPS

  Development of a cattle vaccine that completely limits infection and/or shedding and does not interfere with diagnostics for other mycobacterial infections is needed

  A DIVA (Differentiating Infected from Vaccinated Animals) vaccine is required.

  Appropriate level of attenuation of vaccine strains to elicit immune response without causing disease.

  More studies on the long-term effectiveness of vaccines, considering factors such as the prolonged lifespan of infected animals and extended faecal shedding over time are needed.

  More effective antigens requiring less inflammatory adjuvants or development of more secure devices or administration routes to protect the operator during the administration process.

• Commercial potential for vaccines

  Depends on demand and price. There is a demand to reduce the level of disease caused by MAP in herds especially with the uncertainty about potential links to Crohn’s disease in humans.

• Regulatory and/or policy challenges to approval

  Use of genetically modified vaccines might be problematic in some countries. The field trials may need specific regulation regarding the release of GMOs into the environment.

• Commercial feasibility (e.g manufacturing)

  Feasible.

• Opportunity for barrier protection

  Could be used to protect herds.

• Opportunity for new developments

  Development of DIVA vaccine.

• Pharmaceutical availability

• Current therapy (curative and preventive)

  None.

  GAP

  Further work on potential preventive effect of monensin in young animals

• Future therapy

  Therapy to treat Map infections could have a potential but it is currently unlikely that any therapy could eliminate the organisms once infection has occurred.

  Pre/post exposure therapeutic interventions to prevent infection in calves may be more feasible provided it does not lead to AMR.

  Studies on bacterial strains with probiotic effect have been carried out but need further validation.

  Antimycobacterial phage therapy may be a future therapy specially to limit the infection of young calves according to recent studies (Harman-McKenna et al 2024).

  GAPS

  Further work on the use of probiotics and phages in young animals.

  Probiotics with antibiotic resistance genes capable of horizontal transfer exist.

  AMR profile of MAP strains not well described probably due to slow growth, but genetic prediction studies could fule this area.

• Commercial potential for pharmaceuticals

  High if effective.

• Regulatory and/or policy challenges to approval

  If the pharmaceutical is an antibiotic, challenges like those for other diseases will arise, including rules regarding limited use, prevention of AMR and the presence of residues in milk and meat. Probiotics are licensed as food additives with certain distinctive attributes, not as pharmaceuticals. Phage therapy is not a licensed medicine for humans in many countries. Regarding their use in animals, phage therapy does not easily fit into currently existing EU regulations. 

• Commercial feasibility (e.g manufacturing)

  Depends on the type of pharmaceutical, demand and price.

• New developments for diagnostic tests

• Requirements for diagnostics development

  WOAH provide guidelines for the validation of diagnostic tests. Test (SNPs profiling assays) to differentiate young animals on the basis of how successfully their immune system is managing/eliminating MAP infection so that animals of higher resistance are retained in the herd and population. dPCR kits and novel biomarker (protein and microRNA)-based diagnostic methods are being commercially produced. Mycobacteriophage-based methods to rapidly detect viable MAP are showing promise for diagnosis of Paratuberculosis (Grant 2021; Foddai and Grant 2021) but require further validation before commercialisation. Methods for measuring and interpretation of environmental DNA of MAP for herd diagnostic, evaluation of within herd transmission and research purposes should be developed.

  GAP

  Cost-effective and specific immuno-diagnostics that can discriminate between “non-infected”, “exposed”, “MAP infected” and “infectious”.

• Time to develop new or improved diagnostics

  In general the development of tests is much faster and less expensive than developing vaccines. However, from development through validation to commercial availability is time consuming and can take years.

• Cost of developing new or improved diagnostics and their validation

  The development and validation of new tests is time consuming and labour intensive which is costly. Costs cannot be specified as they will depend on the nature of the test and the cost of producing reagents and supplying reading or processing machines if necessary Once validated a commercial company willing to market the test will be needed.

• Research requirements for new or improved diagnostics

  Identification of cocktails of specific and sensitive antigens, which can be used in either cell-mediated or humoral immuno-diagnostics.

  Evaluation of these tests in longitudinal field studies.

• Technology to determine virus freedom in animals

  This would be difficult with current technologies and would need a method of detecting Map in the animals.

• New developments for vaccines

• Requirements for vaccines development / main characteristics for improved vaccines

  Improved vaccines which do not interfere with statutory TB eradication and control program (skin test) as well as PTB (Map) control programs (DIVA vaccine).

  Improved vaccines which can limit or block transmission of infection as well as prevent progression to clinical disease.

  GAPS

  Limited knowledge of mycobacterial (proteins) antigens critical to causing infection, carriership and disease.

  Virtually no knowledge on complex lipid-, glycol-, glycolipid-, lipoprotein antigens.

• Time to develop new or improved vaccines

  Depending on when a candidate vaccine could be identified the timescale will be 5-10 years. This will involve development, clinical trials and licensing. Potential vaccines need to be identified and subjected to initial trials and the time to commercial availability will depend on the outcome.

  GAPS

  There is an urgent need for screening methods through which vaccine candidates can be evaluated in a time of 1-2 years. This means a workable definition of when a vaccine can be considered an effective vaccine, such a definition which is currently missing. Research on correlates of protection or correlates of transmission is essential.

• Cost of developing new or improved vaccines and their validation

  Expensive with the need to develop and undertake all the relevant tests to provide data to enable the product to be authorised. Field trial will be difficult as will evaluating the results.

  GAP

  See. section “Time to develop new or improved vaccines”.

• Research requirements for new or improved vaccines

  Better understanding of the mechanism of bacterial replication and shedding (host-pathogen interaction).

  GAP

  The correlates of infection and (immune) protection are not defined as they are poorly understood.

• New developments for pharmaceuticals

• Time to develop new or improved pharmaceuticals

  Time to develop would depend on the product and the trials necessary to validate the efficacy and safety. Commercial production would then take further time. Five to 10 years seems a realistic timeframe

• Cost of developing new or improved pharmaceuticals and their validation

  Expensive with the need to develop and undertake all the relevant tests to provide data to enable the product to be authorised. Field trial will be difficult as will evaluating the results.

  GAP

  See. section “Time to develop new or improved vaccines”

• Research requirements for new or improved pharmaceuticals

  Better understanding of the mechanism of bacterial replication and shedding (host-pathogen interaction).

  GAP

  The correlates of infection and (immune) protection are not defined as they are poorly understood.

Disease details

• Description and characteristics

• Pathogen

  Paratuberculosis (or Johne’s disease) is caused by Mycobacterium avium subsp paratuberculosis (MAP).

• Variability of the disease

  Disease associated with MAP is primarily apparent in adult cattle, sheep, goats and deer. Cattle and sheep are usually infected with strains adapted to those species although most strains appear to be able to infect a variety of different species to a certain extent. Clinical signs vary significantly between species (Mackintosh et al., 2004), and the course of infection can vary greatly within species. Investigations have determined phenotypic differences among MAP subtypes for a variety of traits, including growth rates and invasion efficiencies, immunogenicity, virulence as measured by macrophage invasion efficiencies and kinomic responses. There are differences among MAP strains in the immune response that they stimulate, as well as differences in host tropism, disease phenotypes and ability to evade control by vaccines.

  GAPS

  Although the distribution of MAP genotypes has been explored by WGS in the last ten years, specific databases are lacking.

  Differences in virulence, pathogenicity, immunogenicity, persistence, transmission, survival outside the host and host specificity between genotypes.

  Effect of mixed genotype infections and superinfections.

  Not all calves are equally susceptible to (experimental) infection. It is unknown which genetic factors modulate immunocompetence, and entry of the bacteria through the gut wall and if variation in these factors explains variation in susceptibility or resistance to MAP infection.

  There could be a role for host genetic factors in immunocompetence in response to MAP infection. Although genetics of PTB susceptibility have been largely investigated, only a few studies on genetic resistance to MAP infection exist.

• Stability of the agent/pathogen in the environment

  MAP is resistant to cold temperatures and desiccation. MAP bacilli can survive for extended periods in soil (greater than a year) and even longer in water. There is a suggestion of prolonged survival in biofilms (Cook et al., 2010).MAP bacteria remain in grassland soil after application of contaminated slurry being able to infect amoeba increasing MAP’s persistence (Salgado et al.,2015>). When exposed directly to summer temperatures and sunlight, the number of MAP bacteria decreases under most conditions.

  MAP's ability to form spore-like structures remains a debate, as phylogenetic studies show no clustering with endosporulator sequences, indicating a lack of sporulation-related genes (Abecasis et al., 2013). However, the existence of spore-like structures has been reported in certain culture medium conditions (Lamont et al., 2012).

  Eisenberg et al. (2011) demonstrated survival in settled dust in cattle barns. Recovery was lower after environmental washing and absent after disinfection and removal of animals for 2 weeks.

  GAPS

  Typical survival times for different environments is poorly described, e.g. survival on different types of pasture, with and without application of manure or slurry, and at different temperatures should be further explored.

  The role of biofilms needs to be further elucidated. MAP´s survival during bio digestive processes has been investigated but remains uncertain.

  More studies on MAP sporulation should be carried out.

• Species involved

• Animal infected/carrier/disease

  MAP can affect domestic cattle, sheep goats, camelids and deer. Wildlife, including deer and rabbits are also susceptible. Animals in zoological collections are also frequently infected (Witte et al., 2009). Pathological lesions or occurrence of bacteria have also been reported in horses, pigs, alpaca, llama, stoat, fox, weasel and crow, and other multiple other animals (e.g. Beard et al., 1999; Beard et al., 2001a; 2001b; Larsen et al., 1971; 1972; Köhler et al., 2024 ).

  The characteristic inflammatory intestinal and lymphatic lesions are shared across different host species (Balseiro et al., 2019).

  GAPS

  Although production stresses are believed to be an inducer of the onset of clinical disease, there is a lack of knowledge of why some infected animals do not develop the disease and what mechanisms are involved in clinical disease development (host genetics, multiplicity of infection, MAP strains, etc).

• Human infected/disease

  Crohn's disease, which is a chronic inflammatory disorder of the gastrointestinal tract of humans, has been associated with MAP. The main theory is that the lesions seen in Crohn's Disease (CD) patients are due to an immune-dysregulation leading to an inflammatory syndrome. Many microorganisms have been proposed to play a role in the pathogenesis including MAP. Their role is more related to initiation of an allergic type (IV) hyperactivation of cellular immunity and subsequent inflammatory response in humans (genetically) prone to this type of local immune hyperactivation. The immune dysregulation hypothesis is also favoured over an infectious agent hypothesis as a result of the success of anti-inflammatory and immunsuppressive therapies such as anti-TNF treatments. Antibiotic treatments have been far less successful.

  High IgA or IgM response to MAP antigens was associated with increased use of biologic therapy in CD and ulcerative colitis (van der Sloot et al., 2021).

  MAP can be detected in blood of healthy individuals at a relatively high frequency suggesting other (host) factors play an important role (Elguezabal et al. 2012; Kuenstner et al. 2020). The findings of the study by Kuenstner et al. (2020) strongly suggest that successful detection of MAP in human blood is very much dependent on employing the appropriate methods. There are some similarities between MAP associated disease in ruminants and CD in humans. On occasions MAP has been isolated from tissues of patients suffering from CD. This has led to speculation that MAP may be associated with CD in some patients.

  Additionally, anti-mycobacterial antibiotics can induce remission of paediatric CD (Agrawal et al., 2020). Graham et al. (2024) reported that antibiotics directed against MAP, specifically RHB-104 triple antibiotic cocktail, resulted in significantly greater improvement in clinical and laboratory (Faecal calprotectin) measures of active Crohn's disease. Although a link has been suggested, the scientific evidence is insufficient to confirm or refute the link still.

  GAPS

  The cause(s) of CD remains to be proven.

  Many studies have demonstrated an association between the occurrence of MAP and CD, but the causal link has not been demonstrated.

  A hypothesis is that there could be regional differences in involvement of MAP in CD. MAP and other pathogens could also play a role as initiators of an allergic hyperinflammatory response in subjects prone to this form of chronic inflammation.

  Furthermore, the origin of MAP in some CD patients has not been determined, i.e. is it from agricultural products such as meat and milk, or from other sources?

  A possible role for MAP in other human diseases has been suggested but needs further research.

  Exposure to close human contacts (CD patients) has not been investigated in depth.

• Vector cyclical/non-cyclical

  MAP can survive in water between 9 and 12 months, either in a slow metabolism state or inside protozoa (Whittington et al., 2005; Whan et al., 2006).

  GAP

  A possible role for some amoeba species has been postulated, especially for contaminations linked to water but this should be further investigated.

• Reservoir (animal, environment)

  Primarily cattle, sheep, deer and goats with possible involvement of wildlife and feral animals, especially deer and rabbits in the epidemiology.

  MAP has also been detected in monogastric animals such as marsupials, rabbits, foxes, stoats, badgers, mice, rats, birds like rooks and crows, and invertebrates such as cockroaches and earthworms (Fox et al., 2020). The presence of MAP in these species is relevant, as it could be a source of infection for cattle and humans.

  GAPS

  The main limitation in considering the role of wildlife species is understanding the circulation of MAP at the livestock–wildlife interface and identifying elements that allow certain wildlife populations to maintain MAP infection and potentially act as a reservoir for livestock. 

  More data needed on the distribution of MAP among free-ranging wildlife populations, impacts of infection on the health of these populations, potential for these populations to act as reservoirs for MAP and the extent of MAP transmission between wildlife and livestock in various environments.

• Description of infection & disease in natural hosts

• Transmissibility

  Most infected animals may excrete no MAP or shed amounts below the infectious dose in their early years. Some infected animals may excrete large numbers of organisms in their faeces which contaminate food, water and the environment. MAP can also be excreted in milk and colostrum. Transmission is mainly via the ingestion of contaminated material, but MAP can also be transferred in utero. Other proposed transmission sources by the same route are contact with other susceptible domestic and wild species, as well as insects (Fischer et al., 2005), from scavenging behaviour or consumption of preys infected by MAP (Fox et al., 2020) or bio-aerosol transmission (Eisenberg et al., 2010). Herd/flock transmission is typically via purchase of live infected animals (Conde et al., 2022), although transmission via transfer of infected material might also be possible.

  GAPS

  Minimal infectious dose for animals of all ages and the importance of single vs. repeated exposures. Role of contact structure in groups of calves on transmission and minimal infectious dose (high intensity contacts within age groups as opposed to sporadic contacts between calves – cows (e.g. at birth)) has yet to be determined. Epidemiological importance of MAP shedding in calves for transmission between calves has only partly been investigated. The relative importance of various transmission routes (including transmission in utero, through bio-aerosols, dust, drinking water and via contaminated run-off from farms) needs further attention. Advice to cull offspring of infected cows is often given, despite the absence of quantification of the in-utero route and can become very costly in selection herds.

• Pathogenic life cycle stages

  Not applicable.

• Signs/Morbidity

  Paratuberculosis is characterised by a slow progressive wasting of the animal with or without (small ruminants) increasingly severe diarrhoea. It is an untreatable, intestinal disease of ruminants characterised by three stages. 1. Calves are particularly susceptible and often ingest MAP from the first days of life. Some calves may be infectious in the first months of life (Corbett eta al., 2017). This is followed by a long latent period during which the animals are not clinically affected. 2. During the latent period, animals remain clinically normal but then become infectious by intermittently excreting MAP in low numbers in their faeces. These asymptomatic carrier animals may be important sources of transmission. Animals in the subclinical stage of MAP infection show slightly lower milk production, feed efficiency and reproductive capabilities, and slightly higher susceptibility to other infectious diseases such as mastitis than uninfected cattle. 3. Finally, clinical disease may occur. In cattle, this may be characterised by a profuse and persistent diarrhoea and weight loss, but often the clinical stage includes a slowly progressing drop in milk production. In sheep and goats, the only clinical signs may be weight loss. Large numbers of MAP are then excreted in the faeces and possibly also in the milk and colostrum. Generally, there is a period of reduced milk output well before the animals begin to show signs of advanced disease which is inevitably fatal. In deer, the animals usually lose weight over a period of several months and mostly develop diarrhoea and eventually die.

  GAP

  Early clinical stage can be reverted or significantly slowed by lowering an animals’ metabolic demands, e.g. by drying off cows. The relation between metabolic status and pathogenesis has been largely unexplored.

• Incubation period

  Animals are usually infected very early life, but signs of the disease are rarely seen before two years of age in cattle (this can be earlier in other species, such as sheep and deer). There is huge variation in the incubation period, with onset of clinical signs ranging from a few months to a lifetime (15 years or older).

  Infection mainly occurs in young animals, though older ones may also get infected.

  GAPS

  It is unknown if the outcome of youth vs. adult infection is similar or different.

  The role of the HPA axis (hypothalamic-pituitary-adrenal axis) is unknown.

  Various stressors appear to influence disease progression.

  Ratios of progression versus latency at different ages needs to be investigated.

  Factors linking bacterial burden with intestinal inflammation and disease need to be investigated.

• Mortality

  Affected animals eventually die but clinical disease usually only affects one or two percent of animals at any one time in the herd. Since one of the first symptoms of advanced infection is a drop in milk yield, affected animals in dairy herds are often removed from the herd in early stages of clinical disease. In some circumstances, high producing cows are affected and although there is decrease in their production, farmers may not be convinced to cull. In deer herds losses due to clinical disease can be quite dramatic and result in the loss of a whole “generation”.

  GAP

  Raising awareness among farmers on culling PTB positive although high producing cows when diagnosed.

• Shedding kinetic patterns

  The faeces of infected animals may contain large numbers of the bacteria, and the usual route of infection is the faecal-oral route with the ingestion of food (including milk and colostrum) or water contaminated by the organism. A single diseased animal can pose a high risk to susceptible animals and particularly to the young calves in the herd. Removing super-shedder animals greatly reduces the number of positive animals or positive environmental samples. Priority should be focused on removing these animals from the herds.

  Two distinct shedding patterns among infected cows have been observed; so-called ‘progressors’, characterised by continuous and progressive shedders, and ‘non-progressors’, characterised by intermittent and low shedding of MAP bacteria and a virtual absence of a humoral immune response (Schukken et al., 2015).

  GAPS

  The mechanism of how bacteria are shed is unknown. It is not known if infected macrophages migrate into the lumen or if only free bacteria translocate to the lumen (and if so actively or passively?).

  Shedding pattern of MAP-infected animals, including the role of super-shedders.

  The role peri-parturient stress may play in precipitating shedding or clinical disease is not understood.

• Mechanism of pathogenicity

  The infection progressively damages the intestinal tissue of affected animals. As the disease progresses, gross inflammatory lesions occur in the ileum, jejunum, terminal small intestine, caecum and colon, and in the mesenteric lymph nodes. The organism induces a host inflammatory response that causes the intestinal walls to become thickened by a cellular infiltrate. Damage to the intestinal wall allows the leakage of proteins and makes the intestine less able to absorb nutrients. New omic approaches have revealed that different pathways of pathogenicity can exist and enhance understanding of PTB pathogenicity and offer biomarkers for diagnosing or predicting MAP infection. Key molecules such as cathepsin G (Canive et al., 2022) and EGR4 (Navarro et al., 2025) have been identified to play a role in controlling MAP infection. Preliminary studies have shown that MAP-specific antibodies limit MAP invasion in an ileal loop model (Jolly et al., 2022). In sheep MAP-specific faecal IgG and IgA were elevated in resilient sheep and proposed to have a protective role against environmental MAP exposure (Begg et al. 2015).

  GAPS

  The mechanisms responsible for loss of immunological control of the infection are not well understood. Furthermore, pro-inflammatory immune responses may be able to clear the infection in some animals, but what characterises the animals that cannot develop cell-mediated immune responses that cope with the infection is unknown. The role of antibodies in infection has been understudied, so is not well understood. The role of innate immunity induction of inflammatory changes or control of the infection has not been investigated in depth.

• Zoonotic potential

• Reported incidence in humans

  The role of MAP in the development of CD is not known (see Section “Species involved > Human infected/diseased”).

  The incidence of CD in developed countries is approximately 4-12 /100.000 people annually.

  GAPS

  The proportion of CD patients with MAP is not known, and the causal relationship between MAP and CD remains to be proven.

  The proportion of all people with MAP is unknown.

• Risk of occurence in humans, populations at risk, specific risk factors

  The cause of CD is not yet known. Current opinions differ on whether MAP causes CD, some cases of CD or is isolated as a secondary organism from individuals with the disease. Host genetic factors, i.e. mutations in genes of the innate immune system are associated with CD. Several food safety authorities have reviewed evidence for a causal link between MAP and CD and conclude that the current evidence does not support a causal relationship (Anon., 2004; Anon., 2009; European Commission, 2000; Rubery, 2001). A more recent report from EFSA (EFSA report adopted 2017) stated how with the current information available, it is not possible to support or dismiss the role of MAP as a potential zoonotic agent. However, current Regulation (EU) 2016/429 of the European Parliament and of the Council reported paratuberculosis among the list of category E diseases (Diseases that require monitoring).

  GAP

  The cause(s) of CD remains to be identified. If MAP is a component cause of CD, where do the human patients get exposed to MAP – is it of animal origin?

• Symptoms described in humans

  CD can affect any part of the digestive tract from the mouth to the terminal rectum. The ileum and the colon are the most commonly affected areas. The symptoms include abdominal pain, fever and weight loss. It is a long-term chronic illness

• Likelihood of spread in humans

  MAP has not been reported to spread between humans.

  However, there is contradictory evidence on the presence of MAP DNA in blood and tissues of humans, since many studies find MAP only in IBD patients (Aitken et al., 2021; Amirizadehfard et al., 2020; Mendoza et al., 2010) and other studies find MAP in both in IBD patients and healthy controls (Elguezabal et al., 2012; Nazareth et al., 2015; Kuenstner et a. 2020). The latter suggests that MAP could be widespread in healthy humans also.

  GAPS

  The shedding of MAP in the faeces of infected or colonized humans has not been studied.

  Possible transmission between humans should be further explored.

  Frequency of MAP in blood of healthy humans.

• Impact on animal welfare and biodiversity

• Both disease and prevention/control measures related

  There are welfare implications for affected animals since they are weakened, have lost weight and probably have inflammation associated pain over long periods from months to years until death.

  GAP

  Stress and pain in the different forms of paratuberculosis has not been investigated.

• Endangered wild species affected or not (estimation for Europe / worldwide)

  Some wildlife species are endangered. There is no evidence of wild populations being severely affected by paratuberculosis. However, there are numerous reports of losses in zoo collections. There is no extensive list as diagnostics are not carried out and reported routinely, but the following species can either be infected or affected (infection, but not disease, has been reported in some species) according to the IUCN Red List of Threatened Species. Version 2009.2 and Witte et al. (2009):
  • Addax /screwhorn antelope (Addax nasomaculatus) (critically endangered)
  • Lowland Anoa (Bubalus depressicornis, ante-mortem evidence only)
  • Mountain Anoa (Bubalus quarlesi, ante-mortem evidence only)
  • Black Rhinoceros (Diceros bicornis) (Critically endangered)
  • Hog deer (Axis porcinus)
  • East Caucasian tur, West Caucasian tur (Capra caucasica)
  • Turkomen markhor (Capra falconeri)
  • Père David's Deer (Elaphurus davidianus) (extinct in the wild)
  • Slender-horned Gazelle (Gazella leptoceros)
  • Nilgiri Tahr (Nilgiritragus hylocrius)
  • Dama Gazelle (Nanger dama) (critically endangered)
  A number of other species which have tested positive by faecal or tissue culture are listed as “vulnerable” or “near endangered”.

• Slaughter necessity according to EU rules or other regions

  In case of significant losses, the more widespread recommendation in cattle is to kill the affected animals to prevent spread of the infection. In small ruminants and zoo animals vaccination makes slaughter unnecessary.

  GAP

  The optimal age for culling is not known due to the unpredictable incubation period. However, it is recommended that cows that are detected as infected during lactation are at least culled at the end of that lactation.

• Geographical distribution and spread

• Current occurence/distribution

  Paratuberculosis has been recognised as a widespread problem throughout the world. It is a problem in developed countries in temperate zones and those with well –developed dairy industries. Very low levels of infection may exist in some areas such as northern and western Australia and Scandinavian countries.

  The disease is probably under-reported to the WOAH, with Spain, Japan and Germany being the countries with higher reporting rates and other countries that have devoted huge efforts to the study of the disease not reporting at all.

  GAPS

  Prevalence in most regions is currently unknown, and prevalence studies have low design uniformity, making comparisons among regions unreliable due to different sampling strategies and case definitions. Harmonized and multi-country prevalence studies using the same methodology are needed.

  Identification of cost-effective methods to reliably classify herds or regions free of infection or as having low within and among herd prevalence is needed.

  Genomic epidemiology of MAP is new but has already provided important insights into transmission dynamics.

  More data are needed on the distribution of different MAP genotypes and how these are linked to virulence and pathogenicity.

  Accurate reporting is a necessary step towards effective control and justification of potential zoonotic risks.

• Epizootic/endemic- if epidemic frequency of outbreaks

  Usually endemic but with single or multiple cases within a herd or flock.

  GAP

  For extensively managed animals on pasture, there is a need for research into the rate of faecal-oral transmission under various stocking densities and in various ages of animals.

• Speed of spatial spread during an outbreak

  With the long latent period the speed of spread is difficult to assess but high numbers of calves can be infected at any one point in time if hygiene and husbandry are unsatisfactory.

  Spread as distinct from transmission can be rapid with transport of affected animals from one farm to another – we can send it from one side of a country to the other in 48 hours, but it can then take 7 years to be detected!

  Recent studies with simulation models indicate that MAP spread between farms can be decreased if MAP-free farms do not purchase animals from low to high level prevalence farms. Trade should be done always in direction from less-risk to higher risk farms (Ezanno et al., 2022).

  GAP

  Simulation models could be generated to understand disease spread for a country, based on the degree of movement of infective animals and given the prevalence of disease.

• Transboundary potential of the disease

  Spread by subclinically or latently affected animals, which are very difficult to detect, occurs frequently.

  GAP

  Improved export-import protocols required that commensurate with the risk of animals being infected and infectious Certification of free of disease status could be given to those farms that have participated in control plans for more than 10 years and are free of the disease.

• Route of Transmission

• Usual mode of transmission (introduction, means of spread)

  MAP is usually introduced into a herd or flock by purchase of infected animals (see above).

  Transmission is by either direct or indirect contact with infected animals and occurs mainly, but not exclusively, through the faecal–oral route. A source of infection in calves is milk from infected cows or milk that is contaminated with the faeces of infected cows. Contaminated land and housing and in utero infection are also considered as sources of infection.

  Environmental persistence of mycobacteria by forming pellicle biofilms, which can stick and grow on different surfaces allowing the bacteria to maintain their infective capacity can contribute to transmission and spread.

  Use of contaminated susceptible species manure for crop fertilization is one of the routes of transmission and maintenance in a farm.

  Between-herd transmission is typically via purchase of live infected animals (Conde et al., 2022).

  GAPS

  We need to know what the percent attribution to the various modes of transmission is to prioritize control strategies.

  Digital droplet PCR should enable a determination of the exact number of organisms associated with the different modes of transmission (faeces, milk, colostrum) for all different stages of infection (susceptible/uninfected, transiently infectious, latently infected, infectious, resistant stages). This knowledge would be especially meaningful if in parallel the corresponding infectious dose and the corresponding infection risk associated with the various transmission routes were determined for animals of all ages.

  Survival in dust and spread in dust and aerosols raises the possibility of pharyngeal infection via the respiratory route (or oral infection following ingestion of contaminated sputum) this could account for long term low dose exposure in young animals.

• Occasional mode of transmission

  Congenital infection can occur. Semen from animals in the advanced stages of infection can be infected with the organism.

  Intra-uterine (transplacental) transmission can occur.

  Other proposed transmission sources by the same route are contact with other susceptible domestic and wild species, as well as insects (Fischer et al., 2005), from scavenging behaviour or consumption of preys infected by MAP (Fox et al., 2020) or bio-aerosol transmission (Eisenberg et al., 2010).

  GAPS

  The epidemiological significance of congenital infection and other proposed transmission routes is not known.

  The role of faecal-contaminated water needs to be better described.

• Conditions that favour spread

  Poor hygiene leading to increased contact with (MAP contaminated) faeces, pooling of milk/colostrum to feed young calves, close contact with adult animals and high stocking densities.

• Detection and Immune response to infection

• Mechanism of host response

  Passage through (intestinal) mucosal barriers followed by uptake by (tissue resident) macrophages. MAP is able to survive and replicate inside some if not all macrophages and dendritic cells. MAP has a large array of mechanisms to manipulate the macrophage to survive and manipulate the adaptative immune response. T cell mediated immune responses are believed to be able to contain MAP replication and transmission however this apparent control is limited leading to progressive infection. T cell response measured in blood reflects the severity of infection, not the level of control. In late stages of disease MAP specific T cell immunity appears to wane. Humoral (antibody mediated) immunity is slow to develop (lagging behind T cell responses) based on serological measurements and reflects severity of infection. Also wanes in late stages of the disease when symptoms (weight loss, emaciation) become apparent.

  Granuloma formation is thought to limit bacterial spread but fails to eliminate MAP, resulting in persistent infection. MAP eventually leaves the granuloma, spreading via the lymphatic system to other tissues including the mammary glands where it contaminates milk and colostrum. Stressors like labour, immunodepression, genetics, or their combination are thought to trigger MAP release. Finally, host genetics seem to influence disease progression.

  There is growing evidence indicating that the presence of MAP-specific antibodies can been associated with protection against infection by MAP in macrophages in vitro and in in vivo in cattle (Jolly et al., 2022) and sheep (Pooley et al., 2022).

  GAPS

  There is a huge variability in both the temporal development of immune responses and the responses observed between different animals (even under controlled conditions) suggesting an important role of host genetics in MAP infection

  The fact that macrophages predominate, and neutrophils are scarce in intestinal granulomatous lesions albeit IL-8 levels are high is intriguing. Many recent transcriptomic studies have reported that in cows with PTB, the pathways involving neutrophils are altered. Despite all this data the role of neutrophils in both the initial and advanced stages PTB has not been deeply studied.

  There are massive knowledge gaps about protective immune responses – we know very little. The assumption that cell mediated immunity is protective and antibodies may not be valid and should be further studied in much more detail with relevant antigens in relevant host tissues besides blood.

  Further research on the role of neutrophils and other important cells of the immune system in PTB pathogenesis is needed.

  Immunogenetics of disease susceptibility / resistance may aid understanding of pathogenesis and host response. New tools (i.e. SNPs profiling assays) to identify and select susceptible and resistant animals are needed. Genetic variants associated with PTB resistance or immunocompetence. could be used in breeding programs to improve immune responses against MAP infection and likely against other pathogens as well. SNPs associated with susceptibility/resistance to MAP infection could allow the development of novel PTB control strategies based on gene editing

  Limited knowledge of mycobacterial (protein) antigens critical in causing infection, carrier status and disease. (virulence factors) Virtually no knowledge on complex lipid-, glycol-, glycolipid-, lipoprotein antigens.

  Better understanding of immune evasion and immune modulation strategies of MAP.

  Better understanding of gene expression regulation of the immune response mediated by micro-RNAs, alternative splicing and long-non-coding RNAs in distinct stages of MAP infection is needed for the development of novel diagnostic and therapeutic tools.

  We need to better categorize the CMI response to MAP so that it might be used as part of a diagnostic strategy in young animals.

  Limited knowledge on the role of B cells and antibodies.

  Kinetic patterns of sequences in T and B responses may vary between animals and depending on the antigen studied. This has to be further documented and better understood.

• Immunological basis of diagnosis

  Diagnostic tests based on detection of cell-mediated immune responses may be used for early diagnosis of the infection.

  There is a serological response to infection, but this can be variable and appears to depend on the stage of infection, extent of the lesions and the amount of MAP present. Antibody detection can be useful in diagnosis but has important limitations. As antibody is produced relatively late in the disease process, the ability of these tests to identify latent infections is low. However, they can often detect the infectious and affected animals. Most of these remarks are also valid for cell mediated immune responses, but they have been studied less frequently.

  Other immunological markers and biomarkers with improved sensitivity and specificity have been recently proposed but these approaches require a more extensive validation.

  GAPS

  Immuno-diagnostics cannot discriminate between “exposure”, “infection” and “diseased”, thus limiting their use. Furthermore, specific and sensitive antigens are lacking.

  The ability of immuno-diagnostics to predict whether an animal is infectious or not remains to be characterised. Some animals shedding minor amounts of bacteria may be non-infectious and therefore, some antibody tests may be sufficient for control, but the correlation between “infectivity” and “antibody-production” or “infectivity” and cell-mediated responses needs further characterisation.

• Main means of prevention, detection and control

• Sanitary measures

  National control programmes for PTB have been developed in at least 22 countries including Australia, Japan and several countries in Europe. A survey of 48 countries showed that 46% had PTB control programs from 2012–2018, mostly in Europe, while many in South/Central America, Asia, and Africa did not (Whittington et al., 2019). The key measure is preventing infection in herds via purchase of undetected infected animals.

  GAP

  Apart from depopulation of infected herds and flocks, there are relatively few descriptions of strategies which have successfully controlled or eradicated MAP from herds or regions.

• Mechanical and biological control

  If MAP are present in the herd good sanitation and effective husbandry practices are critical to reduce the level of infection. Measures to prevent the transfer of infection from excreting animals to young stock in particular should be introduced. This includes:

  • Culling of highly infectious animals
  • Animals should be born in areas free of manure
  • Neonates should be removed from the dam immediately after birth and fed colostrum from non-infectious animals
  • Avoid feeding pooled colostrum in infected herds
  • Ensure discarded milk is not fed to calves unless it has been effectively pasteurised to kill MAP.
  • Calves and young cattle to be reared away from adult faecal contamination.
  • Ensure good hygiene in the calving areas
  • Do not breed from the offspring of diseased animals.
  • Do not graze young stock on pasture where adults have grazed or where slurry has been applied in the past three months and ideally in the past year.

  GAPS

  Bio-aerosol spreading of life bacteria may severely limit effects of sanitary measures, relevance for transmission of infection should be studied.

  Temporal and spatial dynamics of with-in farm endemic spread are poorly understood. Observational combined with simulation model studies to quantify role of bio-aerosols, and population contact structure effects for calf shedders, young stock shedders, adult low/intermittent shedders and super shedders in endemic spread and stability are needed.

  The relative importance of each of the sanitary measures is not known.

  Our ability to complete clinical trials or cohort studies to examine each of these control points is limited by funding and the time needed to complete such studies. Therefore, there is limited evidence which control methods are the best.

  Further validation on genetic selection in field conditions is needed.

• Diagnostic tools

  Diagnostic tools are required for multiple purposes.

  • to confirm MAP in clinically affected animals
  • to detect infectious animals
  • to certify herds test-negative herds
  • to describe the prevalence of a population
  • to provide historical test-information to derive information on the probability that a population is infection.

  Existing tools cover a wide range of tests detecting viable MAP (culture), MAP DNA (PCR,), antibody reactions (antibody ELISA) and cell-mediated immune responses (interferon-gamma detection with ELISA), and histopathology. None of the existing tests are sensitive enough to detect all infected animals, and all tests may result in low rates of false-positive reactions under field conditionsTests based on presence of MAP in faeces can occasionally be false-positive regarding infection because they can detect transient passive digestive carriers and not infected shedders only.

  GAPS

  There is a need to increase the sensitivity of our diagnostic and screening tools, especially when applied to early infected animals.

  Combinations and/or variations or improvements of existing tests may be helpful (IgG2/PPA ELISA combined with IgG/PPA ELISA can improve disease stage differentiation).

  Development and validation of novel biomarkers-based diagnostic tools in field conditions are needed

  Multicenter studies with a high number of samples are required to validate the use of the blood digital PCR for the diagnosis of cattle in subclinical stages of MAP infection

• Vaccines

  There are a number of vaccines against MAP infections. These are either live attenuated or killed bacteria either incorporated with an adjuvant or lyophilised and adjuvanted on reconstitution. Vaccines may be prepared from one strain of Map 316F or 2E (Weybridge) or Map 3 and 5 or II (Canadian strains), or as many as three strains may be used.

  Currently, the only internationally commercial registered vaccine is a water-in-oil killed Map 316F vaccine that is presented in two slightly different formulations for cattle (Silirum™) and small ruminants (Gudair™), both produced by CZ Vaccines. Gudair™is licensed for use in small ruminants in Spain, Portugal, Norway, Iceland, France, Greece, Netherlands, Australia and NZ. The vaccine for cattle (Silirum™) is licensed for use in France and Australia and is not to be used in cattle (or in small ruminants) in areas where Bovine Tuberculosis is endemic because of interference with the M. bovis skin test. Both vaccines are effective in preventing clinical disease and retarding development of the disease and of faecal excretion, but they do not confer sterile protection.

  Current developments are aiming at subunit vaccines to be used with skin test for M. bovis diagnosis or whole cell attenuated strains to be used with alternative M. bovis testing e.g. interferon gamma assay in combination with specific antigens.

  Modelling and simulation studies have predicted vaccination as the most promising type of JD control practice (Juste and Casal, 1993; Rasmussen et al.,2021).

  GAPS

  Development of a cattle vaccine that limits infection and/or shedding and does not interfere with diagnostics for other mycobacterial infections.

  More effective protective vaccines and DIVA (Differentiating Infected from Vaccinated Animals) are required

  Appropriate level of attenuation of vaccine strains to elicit immune response without causing disease.

  Cost-effectiveness of vaccination strategies need to be further documented.

  The effect of host genetics on vaccine response has not been fully evaluated.

• Therapeutics

  No treatment is available, but there is evidence that monensin decreases shedding, and may therefore be useful as a component of a control strategy. Monensin is labeled in Canada as a controlled-release capsule for the reduction of faecal MAP shedding in mature cattle from high-risk herds as part of a multicomponent JD control program. The effect of oral administration of monensin to calves prior to infection with MAP is inconclusive and needs further research. Due to its toxicity to mammalian cells, the use of monensin in feed additives has been forbidden by the EU since 2006 (Regulation EC No. 1831/2003, article 11).

  GAPS

  It is possible that pharmaceuticals could be produced that would reduce the shedding of viable MAP organisms from infected animals, but such a strategy is unlikely to be cost-effective as an intervention in production animals.

  How can feeding of monensin be used in a control program?

  Alternative treatments including mycobacteriophages or probiotics have been proposed and evaluated but need further validation studies. Would there be side effects on other gut bacteria with alternative treatments? Would there be development of resistance?

• Biosecurity measures effective as a preventive measure

  General biosecurity measures to prevent the introduction of MAP or in the case of infected herds/flocks to limit the spread of infection within the herd/flock.

  GAP

  There is a need to understand the relative importance of the various biosecurity practices so that they can be appropriately prioritized. The reasons for lack of compliance with biosecurity protocols, even simple ones, need to be investigated.

• Border/trade/movement control sufficient for control

  Some national rules but no international standards to ensure that animals being moved for restocking purposes are from herds/flocks in which there is a low risk of MAP being present.

  GAP

  Tools to identify herds/flocks where there is a low risk that MAP are present are required in a form that is universally accepted.

• Prevention tools

  Preventing the introduction of MAP infection through purchase of infected animals.Ensuring in infected herds/flocks that animals do not become infected by ingesting:

  • contaminated colostrum;
  • dung that may be present on unclean teats;
  • contaminated feed; and
  • contaminated environment or water supplies
  • being born to an infectious dam

  GAP

  Identification of host genetic factors contributing to resistance or selection markers to identify highly susceptible animals may aid control strategies.

• Surveillance

  Surveys have been carried out in many countries to estimate the herd level prevalence of MAP infections, but the studies vary greatly in quality and are often non-comparable. In many European countries, a herd-level prevalence of >50% is likely in cattle, whereas there is limited information on sheep and goats. There is likely great variation depending on the type (beef, dairy, other) of herd and herd-size.

  There are specific control programmes in several countries. Within these programmes, surveillance of herds or flocks are carried out to reduce the prevalence of infection.

  GAP

  Reliable prevalence estimates are not available for most European countries (and the rest of the world).

• Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

  Some farmers have been successful in controlling or eradicating MAP from their herd, and others have not been so successful. However, documentation for these successes and failures are few, and the reasons for success or failure are also poorly described.

  GAP

  Long-term efficacy of control programmes reporting.

• Costs of above measures

  There are costs associated with serological tests, vaccines, hygienic measures and culling affected animals. The costs vary greatly from country to country and herd to herd and particularly vary with purpose of intervention and test-strategy used to achieve the goal.

• Disease information from the WOAH

• Disease notifiable to the WOAH

  Yes.

  GAP

  There is underreporting

• WOAH disease card available

  Not available.

• WOAH Terrestrial Animal Health Code

  Available here.

• WOAH Terrestrial Manual

  Available here.

• Socio-economic impact

• Zoonosis: impact on affected individuals and/or aggregated DALY figures

  Unknown as the link between MAP and Crohn’s diseases is not known.

• Zoonosis: cost of treatment and control of the disease in humans

  Treatment of Crohn’s disease is expensive and takes place over a long period as the condition is chronic, often affecting young people. Relapses are common.

• Direct impact (a) on production

  Production losses result from reduced milk output (10-12% in last lactation), deaths, increased involuntary culling, reduced weight at slaughter (10-50% for antibody-positive animals, depending on stage of infection), continued spread of MAP, and loss of genetic potential. Substantial losses due to MAP infection were reported, which escalate as the within-herd MAP prevalence and incidence of clinical JD cases increase. In Canada, the economic damage caused by JD was estimated at $50 CAN per cow per year in MAP-infected herds, resulting in an average loss per infected farm of nearly $3,000 CAN annually (Tiwari et al., 2008). Raizman et al. (2009) estimated the income over feed cost losses at $366 per MAP-shedding cow per lactation. Bhattarai et al. (2014) estimated a loss of $1,644 US per 100 cows in a herd with a true prevalence of 7%. The cost of the disease to the US cattle industry was estimated at $250M US per year (Ott, 1999).

  In a recent study, Rasmussen et al. (2021) estimated the 10-year average annual loss due to PTB using available reported prevalences with a single methodological framework, and estimated the losses per cow at 53.30 US$ in USA, 34.40 US$ in Great Britain, 33.45 US$ in Italy, 48.91 US$ in Canada, 31.25 US$ in Australia, 45.99 US$ in Spain and 21.72 US$ in Belgium. These losses represent between 0.72 and 1.41% of the annual milk revenue. Estimates of global annual losses due to PTB nowadays reach up to 4-5 billion US$ (Rasmussen et al., 2024).

  GAP

  Some reproductive measures may also be affected, but documentation is limited and vague.

• Direct impact (b) cost of private and public control measures

  There are huge differences between countries in the involvement of public funding for control measures. Private costs link to testing, vaccinating and culling of affected animals, loss of access to markets.

• Indirect impact

  Low.

• Trade implications

• Impact on international trade/exports from the EU

  The trade and economic implications are limited, although some countries require assurances on MAP freedom or disease freedom as part of their import health certification, both with regards to export of live animals and export of milk. Studies on the epidemiology of paratuberculosis analysing local MAP isolates by WGS have reported that the trade market is the main driver of MAP diversity found in these studies at both national and international levels.

  There has been some controversy regarding international trade of susceptible species, as countries claiming freedom from paratuberculosis wanted to restrict trade according to paratuberculosis status in cattle. However, as most countries are aware of its widespread endemic and relatively low clinical impact characteristics, they prefer to treat the problem as an individual farm issue to be controlled by the owners without administration interference.

  GAPS

  A unique and universally accepted definition of the infection in animals and occurrence of MAP in animal-derived products does not exist. This result in trade barriers which make little sense in respect of risk assessment and management.

  Ineffective tests are prescribed by some countries for animal imports (e.g. CFT).

• Impact on EU intra-community trade

  The disease is listed as category E (429/2016), but this gives the member states flexibility in disease control. This can lead to inconsistencies, regional disparities, and trade barriers within the EU, as some countries may impose stricter controls than others, impacting the smooth flow of animals within the region.

• Impact on national trade

  No specific controls in many countries with no specific movement controls from infected herds or flocks. This may not impact trade, but to a higher extent impact diagnosis, because many infections are not diagnosed, so that farmers will avoid having to notify authorities.

  GAP

  The effects on spread of MAP of making PTB notifiable is not known but can be assumed to be negative where owners are subject to subsequent regulatory or market discrimination.

• Links to climate

  Seasonal cycle linked to climate

  No information available.

• Distribution of disease or vector linked to climate

  Not apparent.

• Outbreaks linked to extreme weather

  No.

• Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

  Not known although hotter conditions and decreased stocking densities of grazing animals in drying regions would be expected to reduce the incidence.

Conclusion

• Conclusion summary (s)

  Despite nearly a century of JD control efforts, progress has remained insufficient. Apart from Norwegian goat herds, there are no documented cases of MAP infection being fully eradicated, and in many regions, herd- and animal-level prevalence has not declined. Consequently, JD continues to inflict substantial economic losses on the livestock sector. The lack of progress is originated by the incomplete understanding of this complex disease. Research has primarily focused on developing and evaluating tests, creating vaccines, and designing strategies to manage MAP infection. Many of the identified knowledge gaps fall within these areas.
  The introduction of a JD vaccine has significantly impacted the Australian sheep industry. A JD Vaccine for cattle is also licensed in certain countries that meet the requirements for tuberculosis-free status or low prevalence. In this sense, one of the most critical challenges for the livestock sector remains to be the development of a vaccine that not only prevents infection and pathogen shedding but also does not interfere with tuberculosis diagnostics. Another priority is the early identification of infected animals likely to shed MAP, potentially through biomarkers and digital PCR (dPCR). Susceptibility to MAP infection varies across breeds, and pinpointing genetic markers that differentiate highly susceptible animals from more resistant ones is underway but further validation on genetic selection in field conditions is needed. Additionally, understanding calf-to-calf transmission will be key to refining cattle management programmes.
  The uptake of JD control initiatives is expected to improve as these knowledge gaps are successfully addressed. However, since participation in JD programmes is voluntary, identifying the factors that encourage farmers to enroll will remain essential.

Sources of information

• Expert group composition

  N. Elguezabal, NEIKER-Basque Institute for Agricultural Research and Development, Spain – (Leader)

  M. Alonso-Hearn, NEIKER-Basque Institute for Agricultural Research and Development, Spain

  R. Arrazuria, NEIKER-Basque Institute for Agricultural Research and Development, Spain

  RA Juste, NEIKER-Basque Institute for Agricultural Research and Development, Spain

  A. Facciuolo, University of Saskatchewan, Canada

  A.P. Koets, Utrecht University and Wageningen Bioveterinary Research, The Netherlands

  H. Kohler, Friedrich-Loeffler-Institut, Germany

  R. Guatteo, Nantes Veterinary Faculty, France

  I. Grant, Queens University Belfast, UK

  K. Plain, Elizabeth Macarthur Agricultural Institute, Australia

  C. McAloon, University College Dublin, Ireland

  M. Ricci, Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna, Italy

  S. Mundo, Universidad de Buenos Aires, Argentina.

• Reviewed by

  Project Management Board.

• Date of submission by expert group

  16th May 2025

• References

  The information in this analysis was provided by experts, in some cases supplemented by selected references. The information could in some cases be affected by the opinions of experts. The information should therefore be considered as such, and the reader is urged to seek further information if specific information is used.

  Please cite this chapter as: "Elguezabal N., Alonso-Hearn M., Arrazuria R., Juste R.A., Facciuolo A., Koets A.P., Kohler H., Guatteo R., Grant I., Plain K., McAloon C., Ricci M., Mundo S., 2025. DISCONTOOLS chapter on paratuberculosis.https://www.discontools.eu/database/53-paratuberculosis.html."

  Selected references

  Abecasis AB, Serrano M, Alves R, Quintais L, Pereira-Leal JB, Henriques AO. A Genomic Signature and the Identification of New Sporulation Genes. J Bacteriol 2013;195(9):2101-15.

  Amirizadehfard S, Mahzounieh M, Safarpour A, Nejabat M, Nazari N. Genomic Detection of Mycobacterium

  avium subspecies paratuberculosis in Blood Samples of Patients with Inflammatory Bowel Disease in Southern Iran. Iran J Med Sci 2020;45(3):214-219.

  Aitken JM, Phan K, Bodman SE, Sharma S, Watt A, George PM, Agrawal G, Tie ABM. A Mycobacterium species for Crohn's disease? Pathology 2021;53(7):818-823.

  Alonso-Hearn M, Badia-Bringué G, Canive M. Genome-wide association studies for the identification of cattle susceptible and resilient to paratuberculosis. Front Vet Sci. 2022;9:935133.

  Anon., 2004. Association between Johne's disease and Crohn's disease. A microbiological review. Food Standards Australia New Zealand, Technical Report series no. 35. Available at: http://www.foodstandards.govt.nz/_srcfiles/edit_Report_JD%20and%20CD-%20Final%20Dec%202004.pdf.

  Anon., 2009. Mycobacterium avium subsp. paratuberculosis and the possible links to Crohn's disease. Report of the Scientific Committee of the Food Safety Authority of Ireland. Available at: http://www.foodauthority.nsw.gov.au/_Documents/corporate_pdf/FSAI_Report_on_MpTB_May_2009.pdf

  Agrawal G, Hamblin H, Clancy A, Borody T. Anti-Mycobacterial Antibiotic Therapy Induces Remission in Active Paediatric Crohn's Disease. Microorganisms 2020;8(8):1112

  Balseiro, A., Perez, V., & Juste, R. A. Chronic regional intestinal inflammatory disease: A trans-species slow infection? Comparative Immunology, Microbiology and Infectious Diseases 2019;62, 88–100.

  Badia-Bringué G, Canive M, Casais R, Blanco-Vázquez C, Amado J, Iglesias N, González A, Bascones M, Juste RA, Alonso-Hearn M. Evaluation of a droplet digital PCR assay for quantification of Mycobacterium avium subsp. paratuberculosis DNA in whole-blood and fecal samples from MAP-infected Holstein cattle. Front Vet Sci 2022;9:944189.

  Beard PM, Henderson D, Daniels MJ, Pirie A, Buxton D, Greig A, Hutchings MR, McKendrick I, Rhind S, Stevenson K, Sharp JM. Evidence of paratuberculosis in fox (Vulpes vulpes) and stoat (Mustela erminea). Vet Rec 1999;145: 612-613.

  Beard PM, Rhind SM, Buxton D, Daniels MJ, Henderson D, Pirie A, Rudge K, Greig A, Hutchings MR, Stevenson K, Sharp JM. Natural paratuberculosis infection in rabbits in Scotland. J Comp Pathol 2001;124:290-299.

  Beard PM, Daniels MJ, Henderson D, Pirie A, Rudge K, Buxton D, Rhind S, Greig A, Hutchings MR, McKendrick I, Stevenson K, Sharp JM. Paratuberculosis infection of nonruminant wildlife in Scotland. J Clin Microbiol 2001;39:1517-1521.

  Begg DJ, de Silva K, Plain KM, Purdie AC, Dhand N, Whittington RJ. Specific faecal antibody responses in sheep infected with Mycobacterium avium subspecies paratuberculosis. Vet Immunol Immunopathol. 2015 Aug 15;166(3-4):125-31.

  Bhattarai B, Fosgate GT, Osterstock JB, Fossler CP, Park SC, Roussel AJ. Comparison of calf weaning weight and associated economic variables between beef cows with and without serum antibodies against or isolation from feces of Mycobacterium avium subsp paratuberculosis. J Am Vet Med Ass 2014;243:1609–1615.

  Bull TJ, Munshi T, Mikkelsen H, Hartmann SB, Sørensen MR, Garcia JS, Lopez-Perez PM, Hofmann S, Hilpert K, Jungersen G. Improved Culture Medium (TiKa) for Mycobacterium avium subspecies paratuberculosis (MAP) Matches qPCR Sensitivity and Reveals Significant Proportions of Non-viable MAP in Lymphoid Tissue of Vaccinated MAP Challenged Animals. Front Microbiol 2017;7:2112.

  Canive M, Badia-Bringué G, Alonso-Hearn M. The Upregulation of Cathepsin G Is Associated with Resistance to Bovine Paratuberculosis. Animals 2022;12(21):3038.

  Cook KL, Britt JS, Bolster CH. Survival of Mycobacterium avium subsp. paratuberculosis in biofilms on livestock watering trough materials. Vet Microbiol 2010;141:103-109.

  Comper JR, Hand KJ, Poljak Z, Kelton D, Greer AL. Within-herd mathematical modeling of Mycobacterium avium subspecies paratuberculosis to assess the effectiveness of alternative intervention methods Prev Vet Med. 2025;239:106496.

  Conde C, Thézé J, Cochard T, Rossignol MN, Fourichon C, Delafosse A, Joly A, Guatteo R, Schibler L, Bannantine JP, Biet F. Genetic Features of Mycobacterium avium subsp. paratuberculosis Strains Circulating in the West of France Deciphered by Whole-Genome Sequencing. Microbiol Spectr 2022;10(6):e0339222.

  Corbett CS, De Buck J, Orsel K, Barkema HW. Fecal shedding and tissue infections demonstrate transmission of Mycobacterium avium subsp. paratuberculosis in group-housed dairy calves. Vet Res 2017;48:1-10.

  De Silva KR, Eda S, Lenhart S. Modeling environmental transmission of MAP infection in dairy cows. Math Biosci Eng. 2017;14(4):1001-1017.

  Eisenberg SW, Nielen M, Santema W, Houwers DJ, Heederik D, Koets AP. Detection of spatial and temporal spread of Mycobacterium avium subsp. paratuberculosis in the environment of a cattle farm through bio-aerosols. Vet Microbiol 2010;143(2-4):284-92.

  Eisenberg S, Nielen M, Hoeboer J, Bouman M, Heederik D, Koets A. Mycobacterium avium subspecies paratuberculosis in bioaerosols after depopulation and cleaning of two cattle barns. Vet Rec 2011;168(22):587.

  Elguezabal N, Chamorro S, Molina E, Garrido JM, Izeta A, Rodrigo L, Juste, RA. Lactase persistence, NOD2 status and Mycobacterium avium subsp. paratuberculosis infection associations to Inflammatory Bowel Disease. Gut Pathogens 2012;4(1):6.

  European Commission, 2000. Possible links between Crohn's disease and paratuberculosis. Report of the Scientific Committee on Animal Health and Welfare, European Commission. Directorate-General Health and Consumer Protection, SANCO/B3/R16/2000, pp. 76.

  Ezanno P, Arnoux S, Joly A, Vermesse R. Rewiring cattle trade movements helps to control bovine paratuberculosis at a regional scale. Prev Vet Med 2022;198:105529.

  Fischer OA, Matlova L, Dvorska L, Svastova P, Bartos M, Weston RT, Kopecna M, Trcka I, Pavlik I. Potential risk of Mycobacterium avium subspecies paratuberculosis spread by syrphid flies in infected cattle farms. Med Vet Entomol 2005; 19(4):360-6.

  Foddai ACG, Watson G, McAloon CG, Grant IR. Phagomagnetic separation-quantitative PCR: A rapid, sensitive and specific surveillance tool for viable Mycobacterium avium ssp. paratuberculosis in bulk tank and individual cow milk samples. J Dairy Sci. 2021; 104(5):5218-5228.

  Fox NJ, Caldow GL, Liebeschuetz H, Stevenson K, Hutchings MR. Counterintuitive increase in observed Mycobacterium avium subspecies paratuberculosis prevalence in sympatric rabbits following the introduction of paratuberculosis control measures in cattle. Vet Rec 2018;182(22):634.

  Graham DY, Naser SA, Borody T, Hebzda Z, Sarles H, Levenson S, Hardi R, Arłukowicz T, Svorcan P, Fathi R, Bibliowicz A, Anderson P, McLean P, Fehrmann C, Harris MS, Zhao S, Kalfus IN. Randomized, Double-Blind, Placebo-Controlled Study of Anti-Mycobacterial Therapy (RHB-104) in Active Crohn's Disease. Antibiotics (Basel). 2024; 13(8):694.

  Grant IR. Bacteriophage-Based Methods for Detection of Viable Mycobacterium avium subsp. paratuberculosis and Their Potential for Diagnosis of Johne's Disease. Front Vet Sci. 2021; 8:632498.

  Harman-McKenna VK, Eshraghisamani R, Shafer N, De Buck J. Lining the small intestine with mycobacteriophages protects from Mycobacterium avium subsp. paratuberculosis and eliminates fecal shedding. Proc Natl Acad Sci U S A. 2024 Aug 13;121(33):e2318627121.

  Jolly A, Fernández B, Stempler A, Ingratta G, Postma G, Boviez J, Lombardo D, Hajos S, Mundo SL. Antibodies from healthy or paratuberculosis infected cows have different effects on Mycobacterium avium subspecies paratuberculosis invasion in a calf ileal loop model. Vet Immunol Immunopathol 2022; 245:110381.

  Juste RA, & Casal J. An economic and epidemiologic simulation of different control strategies for ovine paratuberculosis. Preventive Veterinary Medicine 1993:15(2–3):101–115.

  Kirkpatrick BW, Cooke ME, Frie M, Sporer KRB, Lett B, Wells SJ, Coussens PM. Genome-wide association analysis for susceptibility to infection by Mycobacterium avium ssp. paratuberculosis in US Holsteins. J Dairy Sci. 2022;105(5):4301-4313.

  Koets AP, Gröhn YT. Within- and between-host mathematical modeling of Mycobacterium avium subspecies paratuberculosis (MAP) infections as a tool to study the dynamics of host-pathogen interactions in bovine paratuberculosis. Vet Res. 2015;46(1):60.

  Köhler H, Müller J, Kloß E, Möbius P, Barth SA, Sickinger M, Gies N, Heydel C, Peters M. Paratuberculosis in South American camelids: two independent cases in alpacas in Germany. BMC Vet Res 2024 20:550.

  Kuenstner JT, Potula R, Bull TJ, Grant IR, Foddai A, Naser SA, Bach H, Zhang P, Yu D, Lu X, Shafran I. Presence of Infection by Mycobacterium avium subsp. paratuberculosis in the Blood of Patients with Crohn's Disease and Control Subjects Shown by Multiple Laboratory Culture and Antibody Methods. Microorganisms 2020; 8(12):2054.

  Lamont EA, Bannantine JP, Armién A, Ariyakumar DS, Sreevatsan S. Identification and characterization of a spore-like morphotype in chronically starved Mycobacterium avium subsp. paratuberculosis cultures. PLoS One. 2012;7(1):e30648.

  Larsen AB, Moon HW, Merkal RS. Susceptibility of horses to Mycobacterium paratuberculosis. Am J Vet Res 1972;33:2185-2189.

  Larsen AB, Moon HW, Merkal RS. Susceptibility of swine to Mycobacterium paratuberculosis. Am J Vet Res 1971;32:589-595.

  Mackintosh CG, de Lisle GW, Collins DM, Griffin JF. Mycobacterial diseases of deer. N Z Vet J 2004;52:163-174.

  McAloon CG, Doherty ML, Whyte P, More SJ, O'Grady L, Citer L, Green MJ. Relative importance of herd-level risk factors for probability of infection with paratuberculosis in Irish dairy herds. J Dairy Sci 2017:100(11):9245-9257.

  Mendoza JL, San-Pedro A, Culebras E, Cíes R, Taxonera C, Lana R, Urcelay E, de laTorre F, Picazo JJ, Díaz-Rubio M. High prevalence of viable Mycobacterium avium subspecies paratuberculosis in Crohn’s disease. World Journal of Gastroenterology : WJG 2010;16(36), 4558.

  Navarro León AI, Alonso-Hearn M, Muñoz M, Iglesias N, Badia-Bringué G, Iglesias T, Balseiro A, Casais R. The Upregulation of Cathepsin G Is Associated with Resistance to Bovine Paratuberculosis. Animals; 2025 Mar 31;15(7):1012.

  Nazareth N, Magro F, Machado E, Ribeiro TG, Martinho A, Rodrigues P, Alves R, Macedo GN, Gracio D, Coelho R, Abreu C, Appelberg R, Dias C, Macedo G, Bull T, Sarmento A. Prevalence of Mycobacterium avium subsp. paratuberculosis and Escherichia coli in blood samples from patients with inflammatory bowel disease. Medical Microbiology and Immunology 2015;204(6), 681–692.

  Plain KM, Marsh IB, Waldron AM, Galea F, Whittington AM, Saunders VF, Begg DJ, de Silva K, Purdie AC, Whittington RJ. High-throughput direct fecal PCR assay for detection of Mycobacterium avium subsp. paratuberculosis in sheep ancattle. J Clin Microbiol. 2014 Mar;52(3):745-57.

  Pooley HB, Begg DJ, Plain KM, Whittington RJ, Purdie AC, de Silva K. The humoral immune response is essential for successful vaccine protection against paratuberculosis in sheep. BMC Vet Res. 2019;15(1):223.

  Raizman EA, Fetrow J., Wells SJ. Loss of income from cows shedding Mycobacterium avium subspecies paratuberculosis prior to calving compared with cows not shedding the organism on two Minnesota dairy farms. J Dairy Sci 2009;92:4929–4936.

  Rasmussen P, Barkema HW, Hall DC. Effectiveness and Economic Viability of Johne's Disease (Paratuberculosis) Control Practices in Dairy Herds. Front Vet Sci 2021;7:61472.

  Rasmussen P, Barkema HW, Osei PP, Taylor J, Shaw AP, Conrady B, Chaters G, Muñoz V, Hall DC, Apenteng OO, Rushton J, Torgerson PR. Global losses due to dairy cattle diseases: A comorbidity-adjusted economic analysis. J Dairy Sci 2024;107(9):6945-6970.

  Russo S, Galletti G, Leo S, Arrigoni N, Garbarino C, Ricchi M. Validation of IS900- qPCR assay to assess the presence of Mycobacterium avium subs. paratuberculosis in faecal samples according to the OIE procedure. Prev Vet Med. 2022;208:105732.

  Salgado M, Alfaro M, Salazar F, Badilla X, Troncoso E, Zambrano A, González M, Mitchell RM, Collins MT. Application of cattle slurry containing Mycobacterium avium subsp. paratuberculosis (MAP) to grassland soil and its effect on the relationship between MAP and free-living amoeba. Vet Microbiol 2015;30;175(1):26-34.

  Sanchez MP, Tribout T, Fritz S, Guatteo R, Fourichon C, Schibler L, Delafosse A, Boichard D. New insights into the genetic resistance to paratuberculosis in Holstein cattle via single-step genomic evaluation. Genet Sel Evol 2022;54(1):67.

  Serrano M, Elguezabal N, Sevilla IA, Geijo MV, Molina E, Arrazuria R, Urkitza A, Jones GJ, Vordermeier M, Garrido JM, Juste RA. Tuberculosis Detection in Paratuberculosis Vaccinated Calves: New Alternatives against Interference. PLoS One 2017;12(1):e0169735.

  Schukken YH, Whitlock RH, Wolfgang D, Grohn Y, Beaver A, VanKessel J, Zurakowski M, Mitchell R. Longitudinal data collection of Mycobacterium avium subspecies paratuberculosis infections in dairy herds: the value of precise field data. Vet Res. 2015;46(1):65.

  Sullivan J & Behr MA. Drug susceptibility testing and antimicrobial resistance in Mycobacterium avium subsp. paratuberculosis. In: Paratuberculosis: Organism, Disease, Control. 2nd edition. MA Behr, K Stevenson, V Kapur. CABI 2020.

  Tiwari A, VanLeeuwen JA, Dohoo IR, Keefe GP, Weersink A. Estimate of the direct production losses in Canadian dairy herds with subclinical Mycobacterium avium subspecies paratuberculosis infection. Can Vet J 2008;49, 569–576.

  van der Sloot KWJ, Voskuil MD, Blokzijl T, Dinkla A, Ravesloot L, Visschedijk MC, van Dullemen HM, Festen EAM, Alizadeh BZ, van Leer-Buter C, Weersma RK, van Goor H, Koets AP, Dijkstra G. Isotype-specific Antibody Responses to Mycobacterium avium paratuberculosis Antigens Are Associated With the Use of Biologic Therapy in Inflammatory Bowel Disease. J Crohns Colitis. 2021 Aug 2;15(8):1253-1263.

  Weber MF, Kelton D, Eisenberg SWF, Donat K. Progress in Paratuberculosis Control Programmes for Dairy Herds. Animals 2024;14(7):1127.

  Whan L, Grant IR, Rowe MT. Interaction between Mycobacterium avium subsp. paratuberculosis and environmental protozoa. BMC Microbiol 2006;6:63.

  Whittington RJ, Marsh IB, Reddacliff LA. Survival of Mycobacterium avium subsp. paratuberculosis in dam water and sediment. Appl Environ Microbiol 2005;71(9):5304-8.

  Whittington R, Donat K, Weber MF, Kelton D, Nielsen SS, Eisenberg S, Arrigoni N, Juste R, Sáez JL, Dhand N, Santi A, Michel A, Barkema H, Kralik P, Kostoulas P, Citer L, Griffin F, Barwell R, Moreira MAS, Slana I, Koehler H, Singh SV, Yoo HS, Chávez-Gris G, Goodridge A, Ocepek M, Garrido J, Stevenson K, Collins M, Alonso B, Cirone K, Paolicchi F, Gavey L, Rahman MT, de Marchin E, Van Praet W, Bauman C, Fecteau G, McKenna S, Salgado M, Fernández-Silva J, Dziedzinska R, Echeverría G, Seppänen J, Thibault V, Fridriksdottir V, Derakhshandeh A, Haghkhah M, Ruocco L, Kawaji S, Momotani E, Heuer C, Norton S, Cadmus S, Agdestein A, Kampen A, Szteyn J, Frössling J, Schwan E, Caldow G, Strain S, Carter M, Wells S, Munyeme M, Wolf R, Gurung R, Verdugo C, Fourichon C, Yamamoto T, Thapaliya S, Di Labio E, Ekgatat M, Gil A, Alesandre AN, Piaggio J, Suanes A, de Waard JH. Control of paratuberculosis: who, why and how. A review of 48 countries. BMC Vet Res 2019;13;15(1):198.

  Witte CL, Hungerford LL, Rideout BA. Association between Mycobacterium avium subsp. paratuberculosis infection among offspring and their dams in nondomestic ruminant species housed in a zoo. J Vet Diagn Invest 2009;21:40-47. Erratum in: J Vet Diagn Invest. 21:288.