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
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