title: The long subclinical phase of Mycobacterium avium ssp. paratuberculosis infections explained without adaptive immunity.
abstract: Mycobacterium avium ssp. paratuberculosis (MAP) is an infection of the ruminant intestine. In cows, a long subclinical phase with no or low intermittent shedding precedes the clinical phase with high shedding. It is generally considered that an adaptive cell-mediated immune response controls the infection during the subclinical phase, followed by unprotective antibodies later in life. Based on recent observations, we challenge the importance of adaptive immunity and instead suggest a role of the structural organization of infected macrophages in localized granulomatous lesions. We investigated this hypothesis by mathematical modelling. Our first model describes infection in a villus, assuming a constant lesion volume. This model shows the existence of two threshold parameters, the MAP reproduction ratio R MAP determining if a lesion can develop, and the macrophage replacement ratio R MF determining if recruitment of macrophages is sufficient for unlimited growth. We show that changes in R MF during a cow's life - i.e. changes in the innate immune response - can cause intermittent shedding. Our second model describes infection in a granuloma, assuming a growing lesion volume. This model confirms the results of the villus model, and can explain early slow granuloma development: small granulomas grow slower because bacteria leave the granuloma quickly through the relatively large surface area. In conclusion, our models show that the long subclinical period of MAP infection can result from the structural organization of the infection in granulomatous lesions with an important role for innate rather than adaptive immunity. It thus provides a reasonable hypothesis that needs further investigation.
authors.affiliation: Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 7, 3584 CL, Utrecht, The Netherlands. don.klinkenberg@rivm.nl.|Present address: Centre for Infectious Disease Control, National Institute for Public Health and the Environment, PO Box 1, 3720, AB Bilthoven, The Netherlands. don.klinkenberg@rivm.nl.
authors.forename: Don
authors.initials: D
authors.lastname: Klinkenberg
authors.affiliation: Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 7, 3584 CL, Utrecht, The Netherlands. a.p.koets@uu.nl.|Department of Bacteriology and TSE, Central Veterinary Institute of Wageningen UR, Lelystad, The Netherlands. a.p.koets@uu.nl.
authors.forename: Ad
authors.initials: A
authors.lastname: Koets
mesh_terms: D000818:Animals; D058345:Asymptomatic Infections; D002417:Cattle; D002418:Cattle Diseases / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D006099:Granuloma / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology*; D008962:Models, Theoretical; D016927:Mycobacterium avium subsp. paratuberculosis / Q000502:physiology*; D010283:Paratuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology