Alternative Host Response to MAP Infection

Although later stages of paratuberculosis ap­pear to be associated with a classical Th2-like humoral immune response (Ganusov et al., 2015; Koets et al., 2015), the innate or early re­sponse is not as well understood.

Traditionally, classical Th1 responses are thought to be a major early reaction to MAP infection, via the elevated expression of inflammatory cytokines IFNγ and TNF α (Begg et al., 2011; Dudemaine et al., 2014; Roussey et al., 2014). In later stage infections, a simultaneous decrease of Th1 cy­tokines appears to be coupled to an increase in Th2 cytokines (Roussey et al., 2014; Ganusov et al., 2015; Roussey et al., 2016). Recent work has also highlighted the potential importance of alternative Th17-like responses in early M. tuberculosis and M. bovis infections (Khader et al., 2011; Steinbach et al., 2016). The no­tion that MAP may also be activating this pat­tern of response is supported by macrophage and epithelial cell upregulation of mRNA en­coding the Th17-driving cytokines IL-23, IL-6 and TGFβ (Dudemaine et al., 2014; Everman et al., 2015). Our own research has shown a mean relative percentage increase of CD4, CD8 and γδ T cells expressing the receptor for IL-23 (IL-23R) in peripheral blood mononuclear cells of MAP test-positive cows relative to cells from MAP test-negative cows. This response was in­ducible by MAP in vitro with cells from both MAP test-positive and test-negative cows, sug­gesting that IL-23R upregulation is a general feature of MAP-immune cell interactions. With M. bovis and M. tuberculosis, CD4+ and γδ T cells are the primary producers of the Th17 specific cytokines IL-17a and IL-22 (Steinbach et al., 2016; Basile etal., 2017). Th17 cell activation is a specific and early immune response to M. bovis and M. tuberculosis (Dhiman et al., 2009, 2012; Tzu, 19 71; Waters et al., 2016). Our work has shown that while early lesions from MAP infect­ed tissues express elevated mRNA encoding IL- 17a, tissues exhibiting more advanced infection stages do not (Roussey et al., 2016). Preliminary experimentation with isolated CD3+ T cells from cows also demonstrated a robust innate Th 17 response, with production of enhanced levels of IL-17a following exposure to two strains of MAP or to purified protein derivative of MAP (PPDj). Th17 cells can exhibit a certain plasticity and may also produce IL-10 and IFNγ and be a source of these cytokines during some phases of MAP infection (Zielinski et al., 2012). Finally, the Th17 driving cytokine IL-23 can be highly pro- inflammatory and prolonged expression of IL-23 can limit the effect of regulatory T cells (Ahern etal., 2010; Petermann etal., 2010). To this end, we are exploring the possibility that IL-23 may be one source of the continued inflammation observed in later stages of paratuberculosis.

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