A systemic macrophage response is required to contain a peripheral poxvirus infection

Abstract

The goal of the innate immune system is to reduce pathogen spread prior to the initiation of an effective adaptive immune response. Following an infection at a peripheral site, virus typically drains through the lymph to the lymph node prior to entering the blood stream and being systemically disseminated. Therefore, there are three distinct spatial checkpoints at which intervention to prevent systemic spread of virus can occur, namely: 1) the site of infection, 2) the draining lymph node via filtration of lymph or 3) the systemic level via organs that filter the blood. We have previously shown that systemic depletion of phagocytic cells allows viral spread after dermal infection with Vaccinia virus (VACV), which infects naturally through the skin. Here we use multiple depletion methodologies to define both the spatial checkpoint and the identity of the cells that prevent systemic spread of VACV. Subcapsular sinus macrophages of the draining lymph node have been implicated as critical effectors in clearance of lymph borne viruses following peripheral infection. We find that monocyte populations recruited to the site of VACV infection play a critical role in control of local pathogenesis and tissue damage, but do not prevent dissemination of virus. Following infection with virulent VACV, the subcapsular sinus macrophages within the draining lymph node become infected, but are not exclusively required to prevent systemic spread. Rather, small doses of VACV enter the bloodstream and the function of systemic macrophages, but not dendritic cells, is required to prevent further spread. The results illustrate that a systemic innate response to a peripheral virus infection may be required to prevent widespread infection and pathology following infection with virulent viruses, such as poxviruses.

Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden

“…Local depletion of either inflammatory monocytes [53] or the tissue-protective Ly6G + cells [50] produces tissue pathology similar to that observed in cGAS -/or IFNaR -/mice. However, depletion of T cells does not affect local pathology or systemic spread of virus following dermal VACV infection [50,53]. Because the recruitment of classical inflammatory monocytes occurs concurrently with the induction of T1-IFN gene transcripts (Fig.…”

“…Both classical inflammatory monocytes and the non-classical tissue-protective Ly6G + cell population home to foci of VACV infection, although only classical inflammatory monocytes are infected within the lesion [19]. Local depletion of either inflammatory monocytes [53] or the tissue-protective Ly6G + cells [50] produces tissue pathology similar to that observed in cGAS -/or IFNaR -/mice. However, depletion of T cells does not affect local pathology or systemic spread of virus following dermal VACV infection [50,53].…”

“…Here, the action of T1-IFN is mediated through the CCL4-dependent recruitment of inflammatory monocytes, rather than through the direct inhibition of virus replication via the action of intracellular ISGs, a process that can be subverted by viral proteins within infected cells. In a number of viral infections, including the VACV system used here, tissue-resident macrophage populations in secondary lymphoid organs are required to prevent systemic dissemination of viruses [53,[56][57][58]72]. After infection with some viruses, infection of macrophage populations is required in order to facilitate development of an effective adaptive immune response [55].…”

“…After infection with some viruses, infection of macrophage populations is required in order to facilitate development of an effective adaptive immune response [55]. However, the role of recruited inflammatory monocyte populations after infection differs from that of macrophages resident in systemic organs [53]. Although inflammatory monocyte recruitment has been indirectly implicated in the response to virus infection [73][74][75], the mechanisms employed by recruited inflammatory monocyte populations are unknown.…”

“…Following infection with some viruses, macrophage populations are preferentially infected in order to facilitate initiation of an adaptive immune response [54][55][56] or otherwise restrict virus spread [53,57,58]. However, primary macrophage populations do not typically support VACV replication, restricting gene expression at a point prior to DNA replication [59].…”