IL-4 receptor signaling regulates lung macrophages during helminth coinfection resulting in enhanced gammaherpesvirus permissiveness

Helminth infection conditions lung macrophages in the long term, but little is known about how helminths affect the lung macrophage responses to respiratory viral coinfection. While comparing BALB/c and C57BL/6 mice, we found that helminth infection in C57BL/6 mice resulted in enhanced permissiveness to a subsequent infection with murid gammaherpesvirus 4 (MuHV-4), and that viral early tropism was mainly restricted to lung macrophages. Helminth infection resulted in enhanced type 2 airway inflammation and M(IL-4) polarization of interstitial macrophages (IntMs) in C57BL/6 mice, associated with an IL-4Rα-dependent disappearance reaction of alveolar macrophages (AlvMs) and enriched monocyte-derived IntMs proportions. Competent IL-4Rα responsiveness or intra-tracheal instillation of recombinant IL-4 or IL-13 significantly resulted in reduced numbers of AlvMs and enriched IntMs as well as increased permissiveness to MuHV-4 infection, which was restricted to AlvMs. Thus, direct IL-4Rα signaling during helminth infection affects macrophage permissiveness to gammaherpesvirus infection.