Competition for Antigen between Th1 and Th2 Responses Determines the Timing of the Immune Response Switch during Mycobaterium avium Subspecies paratuberulosis Infection in Ruminants

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.

Gene Expression Profiles of Th1-type Chemokines in Whole Blood of Mycobacterium avium subsp. paratuberculosis-Infected Cattle

“…Additionally, the progression of mycobacterial infection has been thought to be related to Th1 / Th2 migration of the host (13). In the early stage of infection, the cell-mediated CD4 + T cell response (Th1 response) to MAP is displayed (13). Th1 response decreases as the disease progresses, but the antibody response (Th2 response) to MAP increases (13).…”

“…In the early stage of infection, the cell-mediated CD4 + T cell response (Th1 response) to MAP is displayed (13). Th1 response decreases as the disease progresses, but the antibody response (Th2 response) to MAP increases (13). Thus, since the Th1 / Th2 shift is related to disease progression and bacterial excretion, many studies have determined the MAP infection stage based on detection of MAP and MAP-specific antibody in specimen such as feces, milk, and sera (12,14,15).…”

The within host dynamics of Mycobacterium avium ssp. paratuberculosis infection in cattle: where time and place matter

“…Ultimately it is still unclear what is driving the shift in this model. A recent mathematical modeling study on the Th1/Th2 paradigm indicated that initial dose and bursting size control the timing of the switch [ 73 ]. Most of the data underlying these models were derived from PBMC and serum derived from animals in cross sectional studies usually in a setting of optimizing diagnosis of paratuberculosis.…”

Computational modeling of heterogeneity and function of CD4+ T cells

“…Computational methods have also been applied to study the plasticity of CD4+ T cells. Magombedze et al considered a population plasticity mechanism between Th1 and Th2 during Mycobacterium avium infection by using a reduced ODE-based model where the phenotype change of MAP-specific T cells occurred due to differences in the rates of differentiation, proliferation, and death at the site of infection (Magombedze et al, 2014 ). However, the cellular plasticity involving several intracellular pathways was not represented.…”