Innate Response to MAP Infection
Upon transcytosis across the intestinal epithelium, MAP is taken up by macrophages and DCs in the subepithelium. In general, these cells will then traffic to the lamina propria of the small intestine, the mesenteric lymph nodes and the peripheral circulation, thereby initiating an immune response to clear or control the infection (Lugton, 1999).
Survivability of MAP within the macrophage is dependent upon the host, as MAP can thwart degradation by blocking maturation and preventing acidification of phagosomes (Sturgill-Koszycki et al., 1994; Hostetter et al., 2003). Hostetter et al. (2003) found that phagosomes within macrophages infected with live MAP expressed higher levels of transferrin, an early phagosome marker and lower levels of lysosome-associated membrane protein one, a late maturation marker, compared with phagosomes within macrophages infected with heat-killed MAP or M. avium subsp. avium. The arrestment of phagosome maturation has been correlated with inhibition of phagosome acidification, a process that produces bactericidal agents such as nitric oxide, reactive oxygen species (H2O2 and OH-) and lysosomal hydrolases (Akaki et al., 199 7). The mechanism by which MAP is taken up by phagocytes can affect the subsequent ability of the phagocyte to effectively destroy the pathogen. The engagement of complement receptors (CR1, CR3 and CR4) for MAP uptake can limit macrophage activation (Hostetter et al., 2005). Blocking bovine CR3 receptor by incubating activated macrophages with anti-CD18∕CD11b reduced uptake of opsonized MAP (Hostetter et al., 2005). Opsonization of MAP with heat-treated serum limited uptake, further demonstrating that CR is a primary means of MAP entry into macrophage. Perhaps even more interesting was the observation that opsonization of MAP lowered levels of phagosome acidification, suggestive of decreased ability to kill the pathogen (Hostetter et al., 2005). More recently, pre-incubation of bovine monocyte-derived macrophages with mannosylated-lipoarabinomannan (Man-LAM) derived from MAP was shown to reduce killing of live M. avium subsp. avium (Souza et al., 2013). Reduced killing was directly associated with lower phagosome acidification and fusion of the phagosome-lysosome, along with increased IL-10 expression. IL-10 is induced via a MAPK-p38 pathway in macrophages, a signalling pathway that has been shown to negatively impact acidification of the phagosome and killing of MAP within the macrophage (Souza et al., 2006). Activation of the MAPK pathway in bovine monocytes upon infection with MAP is mediated through TLR 2 (Weiss et al., 2008). Blocking TLR2 on bovine monocytes resulted in increased phagosome acidification, phagosome-lysosome fusion and MAP survival, suggesting that TLR2 signalling is critical to macrophage bactericidal activities (Weiss et al., 2008). It is clear that IL-10 plays a substantial role in the ability of the macrophages to arrest the infectious process (Hussain et al., 2016). IL-10 is a negative regulator of IL-12 production by antigen-presenting cells, thereby influencing the cross-talk between macrophages and T cells and retarding the amplification of the adaptive immune response (Rahim et al., 2005). Although IL-10 plays an essential role in controlling inflammatory responses of the host during infection, one contrary aspect may be a weaponization by the intracellular pathogen to defeat the macrophage. A recent review outlines a critical role for regulation of IL-10 by mycobacteria, suggesting that it is a key effector in survival of the pathogen (Abdalla et al.,2016). Another cytokine that controls macrophage responses to intracellular infection is IL-1β (Lamont et al., 2012). The infection of MAC-T-bovine monocyte-derived macrophages with live MAP demonstrated that phagosome acidification was calcium-dependent and linked to IL-1β processing by the cells. It was suggested that IL-1β plays a critical role in the recruitment of other monocyte-derived macrophages to the site of infection and that MAP has the ability to exploit this by inducing calcium influx in the cell. A comprehensive RNA-seq analysis of genes expressed by monocyte-derived macrophages infected with MAP complemented those results as they found upregulation of IL-1 and other proinflammatory genes in early infection, concomitant with expression of IL-10 and other proinflammatory mediators (Casey et al., 2015). It is clear that macrophage-mycobacteria interactions have to be balanced between protection and pathology and this is not always successful in the infected host (Divangahi et al., 2018). Participation of other cell types involved in adaptive immunity may be required to skew the host response to a more protective nature.
17.4
More on the topic Innate Response to MAP Infection:
- Alternative Host Response to MAP Infection
- Alfano Massimo (ed.). Soluble Factors Mediating Innate Immune Responses to HIV Infection. Bentham Books,2010. — 159 p., 2010
- Pathogenesis and Stages of MAP Infection in Cattle
- The Effect of Immunosuppressive Therapy on MAP Infection
- INNATE IMMUNITY
- Chapter 46 No Innate Principles in the Mind John Locke
- Chapter 50 What Is Innate and Why: Comments on the Debate Hilary Putnam
- HMGB1: An Active “Go-Between” Linking Innate and Adaptive Immunity
- Immune Response
- Genomic Epidemiology of MAP
- MAP Antigens
- GENOMIC AND RAPID RESPONSE PATHWAY TO VITAMIN D
- Enumeration of MAP
- Comparison of the Virulence and Pathogenicity of MAP Strains
- Drug Susceptibility Testing for MAP, Why Bother?
- The Ukrainian Response
- Study of MAP Proteins
- Cultural Requirements of Different Strains of MAP
- Survival of MAP During Dairy Processing
- Genomic Comparison of MAP Strains