Macrophage mediated recognition and clearance of Borrelia burgdorferinelicits MyD88-dependent and -independent phagosomal signals that contribute to phagocytosis and inflammation

Abstract

Macrophages play prominent roles in bacteria recognition and clearance, including Borrelia burgdorferi (Bb), the Lyme disease spirochete. To elucidate mechanisms by which MyD88/TLR signaling enhances clearance of Bb by macrophages, we studied Bb-infected wildtype (WT) and MyD88−/− mice and Bb-stimulated bone marrow-derived macrophages (BMDMs). Bb-infected MyD88−/− mice show increased bacterial burdens, macrophage infiltration and altered gene expression in inflamed heart tissue. MyD88−/− BMDMs exhibit impaired uptake of spirochetes but comparable maturation of phagosomes following internalization of spirochetes. RNA-sequencing of infected WT and MyD88−/− BMDMs identified a large cohort of differentially expressed MyD88-dependent genes involved in re-organization of actin and cytoskeleton during phagocytosis along with several MyD88-independent chemokines involved in inflammatory cell recruitment. We computationally generated networks which identified several MyD88-independent master regulators (Cxcl2 and Vcam1) and MyD88-dependent intermediate proteins (Rhoq and Cyfip1) that are known to mediate inflammation and phagocytosis respectively. These results provide mechanistic insights into MyD88-mediated phagosomal signaling enhancing Bb uptake and clearance.

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