Herpes Simplex Virus 1 Interaction with Myeloid CellsIn Vivo

Abstract

Herpes simplex virus 1 (HSV-1) enters mice via olfactory epithelial cells and then colonizes the trigeminal ganglia (TG). Most TG nerve endings are subepithelial, so this colonization implies subepithelial viral spread, where myeloid cells provide an important line of defense. The outcome of infection of myeloid cells by HSV-1 in vitro depends on their differentiation state; the outcome in vivo is unknown. Epithelial HSV-1 commonly infected myeloid cells, and Cre-Lox virus marking showed nose and lung infections passing through LysM-positive (LysM ؉ ) and CD11c ؉ cells. In contrast, subcapsular sinus macrophages (SSMs) exposed to lymph-borne HSV-1 were permissive only when type I interferon (IFN-I) signaling was blocked; normally, their infection was suppressed. Thus, the outcome of myeloid cell infection helped to determine the HSV-1 distribution: subepithelial myeloid cells provided a route of spread from the olfactory epithelium to TG neurons, while SSMs blocked systemic spread. IMPORTANCEHerpes simplex virus 1 (HSV-1) infects most people and can cause severe disease. This reflects its persistence in nerve cells that connect to the mouth, nose, eye, and face. Established infection seems impossible to clear. Therefore, we must understand how it starts. This is difficult in humans, but mice show HSV-1 entry via the nose and then spread to its preferred nerve cells. We show that this spread proceeds in part via myeloid cells, which normally function in host defense. Myeloid infection was productive in some settings but was efficiently suppressed by interferon in others. Therefore, interferon acting on myeloid cells can stop HSV-1 spread, and enhancing this defense offers a way to improve infection control.T he alpha-, beta-, and gammaherpesviruses establish broadly neuro-, myelo-, and lymphotropic persistent infections (1). Less is known about acute infection, as sporadic transmission and late clinical presentation make it difficult to analyze. Acutely adaptive immunity exerts little restraint on viral tropism, so common themes are likely. The difficulty in clearing established infections makes these themes important to understand. Genomic comparisons indicate that herpesvirus infections long predate human speciation (2). Therefore, related mammalian herpesviruses are likely to share mechanisms of host colonization, allowing those of experimentally tractable hosts to provide new insights. Murid herpesviruses have particular value in this regard, as their hosts provide the main in vivo experimental model of mammalian biology.Murid herpesvirus 4 (MuHV-4) (a gammaherpesvirus), murine cytomegalovirus (MCMV) (a betaherpesvirus), and herpes simplex virus 1 (HSV-1) (an alphaherpesvirus) all enter mice via olfactory neurons (3-5). MuHV-4 and MCMV spread from there to lymph nodes (LNs) (4, 6), while HSV-1 spreads to trigeminal ganglia (TG) (5). Nonetheless, each virus penetrates the epithelium and so will encounter subepithelial myeloid cells. While these cells normally provide an early defense against invading p...

Type 1 Interferons and NK Cells Limit Murine Cytomegalovirus Escape from the Lymph Node Subcapsular Sinus

“…Infecting CD11c-cre mice gave similar results (Fig 9d-9f), confirming the low virus productivity of SSM and ruling out LysM -CD11c + DC as the source of unswitched virus in IFNAR-blocked lysM-cre mice. Whereas floxed MuHV-4 [40] and Herpes simplex virus type 1 [41] show substantial switching in lysM-cre and CD11c-cre mice after IFNAR blockade, unswitched MCMV from crecells such as FRC seemed to dilute out switched SSM virus regardless of IFNAR blockade.…”

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“…As a major cause of human herpetic diseases, herpes simplex virus type 1 (HSV1) not only results in significant herpes labialis with very high morbidity in populations worldwide, as shown by epidemic studies [ 1 ], but it is also an important cause of painful genital herpes and herpetic encephalitis [ 2 , 3 ]. For decades, multiple studies on viral pathogenesis have formed a systematic network of knowledge of HSV1 infection in the host [ 4 , 5 ]. Based on these studies, further investigation into viral pathogenesis in humans requires an animal model to properly mimic whole pathological processes [ 6 ].…”

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