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

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.Author Summary: Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne's disease, a chronic enteric disease of ruminants such as sheep and cows. Due to early culling and reduction in milk production of affected animals, MAP inflicts high economic cost to diary farms. MAP infection has a long incubation period of several years, and during the asymptomatic stage a strong cellular (T helper 1) immune response is thought to control MAP replication. Over time, Th1 response is lost and ineffective antibody response driven by Th2 cells becomes predominant. We develop the first mathematical model of helper T cell response to MAP infection to understand impact of various mechanisms on the dynamics of the switch from Th1 to Th2 response. Our results suggest that in contrast to the generally held belief, Th1/Th2 switch may be driven by the accumulation of long-lived extracellular bacteria, and therefore, may be the consequence of the disease progression of MAP-infected animals and not its cause. Our model highlights limitations of our current understanding of regulation of helper T cell responses during MAP infection and identifies areas for future experimental research.