Coinfection with Intestinal Parasite Expands Resident Macrophages and Impairs Control of Chronic Herpesvirus Infection

Abstract

In addition to a range of homeostatic functions, resident macrophages are essential for immune surveillance in tissues. Therefore, anything that alters the phenotype or function of these cells potentially impacts their response to infectious challenges. Parasite infections cause proliferation of large peritoneal macrophages (LPMs), which are the resident macrophages of the peritoneal cavity. However, the functional consequences of LPM expansion on the control of secondary infectious challenge is unknown. Using a coinfection model with the intestinal parasite Heligmosomoides polygyrus (HP) and the virus, murine gammaherpesvirus-68 (MHV68), we investigated the impact of LPM expansion on viral infection. We determined that LPM expansion induced by HP required retinoic acid signaling. When we challenged HP-infected mice with MHV68, we observed increased herpesvirus infection and latency. Coinfection of mice with macrophage-specific deletion of GATA6, the retinoic acid-responsive transcription factor that drives LPM transcriptional programming, eradicated the increase in viral infection. In addition to increased MHV68 infection, parasite coinfected mice displayed increased herpesvirus reactivation from latency, indicating impaired control of chronic herpesvirus infection. Elimination of dietary vitamin A, which depletes retinoic acid and LPMs, abolished the increased MHV68 reactivation in parasite coinfected mice. These results indicate that parasite- and retinoic acid-mediated resident macrophage expansion drives increased herpesvirus infection, latency, and reactivation.

Murine Gammaherpesvirus 68 Efficiently Infects Myeloid Cells Resulting In An Atypical, Restricted Form Of Infection

“…This is particularly relevant in the context of in vivo infection, where IFN constrains MHV68 reactivation from latency within peritoneal macrophages (44) and CD4 T cells constrain chronic macrophage infection in the lung (17). Recent studies of parasitic infection have further revealed that parasite-dependent expansion of the large peritoneal macrophage compartment, a primary target of MHV68 infection (36), can dramatically enhance the pool of MHV68-infected macrophages (45) indicating that MHV68 infection of macrophages is subject to multiple positive and negative regulatory pathways.…”