Abstract
Johne's disease (JD), a persistent and slow progressing infection of ruminants such as cows and sheep, is caused by slow replicating bacilli Mycobacterium avium subspecies paratuberculosis (MAP) infecting macrophages in the gut. Infected animals initially mount a cell-mediated CD4 T cell response against MAP which is characterized by the production of interferon (Th1 response). Over time, Th1 response diminishes in most animals and antibody response to MAP antigens becomes dominant (Th2 response). The switch from Th1 to Th2 response occurs concomitantly with disease progression and shedding of the bacteria in feces. Mechanisms controlling this Th1/Th2 switch remain poorly understood. Because Th1 and Th2 responses are known to cross-inhibit each other, it is unclear why initially strong Th1 response is lost over time. Using a novel mathematical model of the immune response to MAP infection we show that the ability of extracellular bacteria to persist outside of macrophages naturally leads to switch of the cellular response to antibody production. Several additional mechanisms may also contribute to the timing of the Th1/Th2 switch including the rate of proliferation of Th1/Th2 responses at the site of infection, efficiency at which immune responses cross-inhibit each other, and the rate at which Th1 response becomes exhausted over time. Our basic model reasonably well explains four different kinetic patterns of the Th1/Th2 responses in MAP-infected sheep by variability in the initial bacterial dose and the efficiency of the MAP-specific T cell responses. Taken together, our novel mathematical model identifies factors of bacterial and host origin that drive kinetics of the immune response to MAP and provides the basis for testing the impact of vaccination or early treatment on the duration of infection.
Highlights
Mycobacterium avim subsp. paratuberculosis (MAP) infects intestine of ruminants and causes a chronic inflammatory disease called Johne’s disease (JD) [1,2]
We show that the following factors strongly influence Th1/ Th2 switching dynamics: the mechanism by which MAP-specific Th cells are maintained at the site of infection, rate at which Th1 response is exhausted, longevity of extracellular bacteria, and the efficiency at which immune responses cross regulate each other
The two assumptions are sufficient to drive the switch of the initially dominant cellular (Th1) response to antibody (Th2) production. These assumptions are 1) the generation of Th1 response is driven by density of infected macrophages while the generation of the Th2 response is driven by free bacteria (see Eqns. (1)–(6)), and 2) extracellular bacteria are long lived
Summary
Mycobacterium avim subsp. paratuberculosis (MAP) infects intestine of ruminants (e.g., cattle and sheep) and causes a chronic inflammatory disease called Johne’s disease (JD) [1,2]. At late stages of JD, MAP-infected animals shed bacilli in their feces thereby completing the infection cycle. The lack of progress in vaccine development is in part due to poor understanding of the nature of the protective immune response against MAP infection [18]. In this respect, experimental infections of animals with MAP have been carried out in several studies examining the kinetics of MAP-specific immune responses [18,19,20]. These studies demonstrated that animals with paucibacillary lesions (at early stages of the infection) are likely to express a
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