Paratuberculosis (PTB) is a chronic disease of ruminant animals caused by Mycobacterium avium subspecies paratuberculosis (MAP). It is distributed worldwide and has a substantial economic impact on milk production and the dairy industry. It is more burdensome in low—and middle-income countries with high livestock population density and low productivity, but it has received low priority for surveillance, prevention, and control. MAP is an epidemiologically complex disease problem due to its subclinical manifestation in infected animals, continuous shedding of MAP contaminating pasture and water sources, and environmental persistence. In recent years, MAP has been implicated as a trigger for various chronic human diseases and conditions such as Crohn’s disease. Since the human population with autoimmune disorders and immunocompromised status is increasing and susceptible to Crohn’s disease and other chronic diseases, an epidemiological study and meta-analysis have to be carried out to establish an association of MAP with Crohn’s disease and other chronic human diseases. Paratuberculosis surveillance, prevention, and control may be candidates for applying the One Health approach since it involves animals (domestic and wild), humans, and the environment, demanding a holistic, multidisciplinary, and multidimensional approach.

• Paratuberculosis; Mycobacterium Avium Subspecies Paratuberculosis (MAP); Johne’s Disease; Crohn’s Disease; livestock; Human

MAP: Mycobacterium Avium Subspecies Paratuber culosis; PTB: Paratuberculosis; JD: Johne’s Disease; CD: Crohn’s Disease

Many livestock diseases, including paratuberculosis, infect small and large ruminants and are hidden and underappreciated. Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of paratuberculosis in ruminants, belongs to the M. avium complex, a heterogeneous group of slow-growing mycobacteria [1,2]. MAP infection results in the chronic inflammatory condition of the intestines commonly known as paratuberculosis or Johne’s disease (JD) in domestic and wild ruminants [3]. It is a debilitating disease, and a clinical condition characterized by poor body condition, progressive weight loss with or without diarrhea, and emaciation [4]. The cardinal symptom of the disease is intermittent or continuous, leading to progressive emaciation and death [5]. MAP could infect many different animal species, which has implications for disease control. It appears that an infection can persist in certain populations without causing overt disease, which is critical from epidemiological points of view [6]. MAP has not only economic importance in the livestock industry but is also considered a potential trigger for various chronic human diseases and conditions, which may help to draw attention of policymakers and decision-makers to give due priority to surveillance of paratuberculosis to make an economic case for investment for prevention and control of neglected livestock disease.

Risk Factors and Persistence of Infection

The faecal-oral route mainly transmits MAP in livestock, including via faecal contamination of the udder, pasture, or water. Newborn animals acquire infection from infected parents through semen during pregnancy, consumption of colostrum and milk, and the oral-faecal route from a contaminated environment [7,8].

MAP is a relatively resistant organism to environmental, physical, and chemical stressors [9,10], that can persist in the environment and survive up to 120 weeks in soil or water [11]. The contaminated soil and water may be a significant reservoir of MAP due to biofilm formation [12,13]. Published reports indicate that MAP may not be entirely inactivated by pasteurizing milk at 72°C for 15 seconds [14]. Products from pasteurized milk constitute a consumption risk as pasteurization only reduces the actual MAP load in milk [15,16]. MAP can survive the chlorine disinfection treatment used for treating municipal water sources and has been detected in drinking water systems [17,18].

Newborn ruminants are more susceptible than adults, presumably due to their relatively undeveloped immune systems [19]. After ingestion, MAP may persist in the intestines and other tissues for years without causing clinical disease, and subclinical infection can develop into clinical disease under stress conditions [20]. After infection, disease progression follows four distinct stages: latent, subclinical, clinical, and advanced [21,22]. Most calves exposed to MAP develop persistent infection; only 10 to 15% will develop fatal clinical disease [23,24]. The introduction of MAP into a herd is often recognized only after spread has occurred [25]. The finding of a clinically infected animal is the ‘‘tip of the iceberg,’’ alluding to the high background prevalence of undiagnosed, subclinical infection of animals [26].

Burden of Disease: Paratuberculosis is distributed worldwide and is highly endemic in the dairy cattle herds of the developed countries [27,28]. In a survey of 48 countries, paratuberculosis, more than 20% of herds and flocks were infected with MAP in about half the countries [29]. According to the United States Department of Agriculture, the herd-level prevalence of MAP infection in US dairy herds increased from 21.6% in 1996 to 91.1% in 2007 [30]. India extensively tested ruminant animals for MAP burden and reported an increasing MAP ‘‘bio-load’’ in cattle (43%), buffalo (36%), goats (23%), and sheep (41%). Moreover, in this same geographic area, 30.8% of 28,291 humans tested positive for MAP [31]. Numerous species of free-living wildlife, including monogastric species and carnivores, were reported to be exposed to and infected with MAP [29].

Decreased milk production is a significant economic consequence of this infection and has been documented for both subclinical and clinical MAP infection [22]. Each year, an estimated US$198 million is lost due to JD in the United States, US$75 million in Germany, US$56 million in France, and US$54 million in New Zealand [32].

Control measures: Since MAP is insidious within an animal population, good hygienic practices and herd health management are the most helpful tools for controlling paratuberculosis within domestic livestock herds. Epidemiological Models in dairy cattle suggest that test and cull, or actions targeting infection routes, are effective strategies to decrease MAP prevalence [33]. The effectiveness and repetition of diagnostic techniques are considered the main issue for test and cull strategies to identify the early infection of MAP in animals, particularly before the onset of faecal shedding [34]. The combination of vaccination with ‘test and cull’ was economical and a more effective strategy for controlling PTB in various herds of goats, buffaloes, and cattle [35].

However, the highly recommended test and cull policy as a part of the bovine tuberculosis, brucellosis, or paratuberculosis control programme may not be socially acceptable and economically feasible in South Asian countries due to sociocultural reasons.

Paratuberculosis is not notifiable, and surveillance and control programmes may not get due attention, particularly in low and middle-income countries. The 26 out of 48 countries that did not have a control programme for PTB had several reasons, such as low priority, insufficient animal health resources and capacities, and lack of feasibility due to inadequate control tools, such as poor diagnostic tests and poor vaccines [29].

Protective immunity against mycobacterial diseases, especially PTB in ruminants, is poorly understood. Vaccines for PTB have been commercially available for many years, but unfortunately, they are not entirely effective in preventing the disease [3]. Presently, no drugs are approved for treating Johne’s disease in livestock, and the rare instances where antibiotic therapy is attempted are limited to the off-label use of standard antimicrobial agents [3].

Human Health Concern: In 1984, Mycobacterium paratuberculosis was first reported from a Crohn’s disease patient and was isolated [36]. Due to the similarities between Crohn’s disease (CD) and Johne’s disease, MAP has long been considered a potential cause of Crohn’s disease [37]. The fact that MAP can cause disease in several mammal species, including primates, is an argument favouring the link between MAP and CD in humans [38,39]. Genetic evidence for zoonotic transmission comes from whole genome sequence comparisons of MAP isolates from humans with inflammatory bowel disease and animals [40], and adaptations of strains between sheep and camels [41]. A comprehensive review of paediatric inflammatory bowel disease in thirty-eight countries between 1985 and 2018 found a steadily increasing incidence of Crohn’s disease [42]. Although MAP is not easy to detect and even more difficult to culture, it is significantly associated with CD and, if appropriate culture and PCR tests are done correctly, nearly every individual with chronic inflammation of the gut from Crohn’s disease is found to be infected with MAP [43-45]. On the other hand, it has been suggested that the presence of MAP in Crohn’s disease is not causal but reflects that MAP colonizes and invades an already inflamed bowel [46]. MAP is now linked to an increasing list of inflammatory and autoimmune diseases [47,48]. MAP acts as a risk factor or a triggering agent of multiple sclerosis in some Japanese patients with genetic susceptibility to the mycobacterium [49].

Humans can be exposed to the MAP by consuming raw milk of the infected dairy animals, ground beef from the infected buffalo, and the domestic water supply originating from the surface source near the runoff from infected farms [50]. Milk and dairy products are considered the primary source of MAP infection in humans [15]. In recent years, MAP has also been causing considerable concern to the dairy industry worldwide because of unresolved issues regarding its potential role in CD in humans [14-51]. It is interesting to observe that in South Asian countries, people have a tradition of drinking hot milk. As a result, even pasteurized milk is boiled before consumption. This may be one of the factors that human mycobacterial infection due to bovine tuberculosis is less common in Asian countries than in African countries. The cultural culinary practice of vegetarianism would reduce exposure to MAP, as would the common practice of boiling milk before consumption [52].

Research Needs: There is a knowledge gap in understanding JD’s role and importance in the development or progression of human disease and its impact on public health, which needs to be addressed [53]. Since the human population with autoimmune disorders and immunocompromised status is increasing and susceptible to CD and other chronic diseases, an epidemiological study and meta-analysis have to be carried out to establish an association of MAP with CD and other chronic human diseases.

MAP is an epidemiologically complex disease problem due to its subclinical manifestation in infected animals, continuous shedding of MAP contaminating pasture and water sources, and environmental persistence. As a result, prevention and control are not straightforward, and they will require considerable changes in economic, policy, regulatory, and farming practices through public-private partnerships.

MAP is a neglected livestock disease hidden on farms with poor hygienic conditions. It is not part of the surveillance and herd health management programme, as the diagnosis of MAP infection is challenging due to the chronic and subclinical nature of the disease, and its economic impact is underappreciated. Consequently, low priority has been given to surveillance, prevention, and control of paratuberculosis in animals due to a lack of disease burden data at the national level. It is more burdensome in low- and middle- income countries with high livestock population density and low productivity. Without a policy to control paratuberculosis in animals, the human population is at a continued risk of exposure to MAP [4]. Animal health authorities have a social responsibility and a significant role in controlling MAP in livestock to prevent environmental contamination and reduce human exposure to MAP. Hence, research and development should be prioritized to develop cost effective, user-friendly, and robust molecular diagnostic tools for MAP, including effective vaccines.

Paratuberculosis surveillance, prevention, and control may be candidates for applying the One Health approach since it involves animals (domestic and wild), humans, and the environment, demanding a holistic, multidisciplinary, and multidimensional approach. Recognizing the impact MAP has on animal and human health and the environment, it is time for One Health and other global regulatory agencies to acknowledge that MAP is causing an insidious, slow-motion tsunami of zoonosis and implement public health mitigation [50].

The author acknowledges Ms. Citra Prasetyawati’s contribution and support in formatting, editing, and validating references.

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