Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination

Frederico, Bruno; Chao, Brittany; Lawler, Clara; May, Janet S.; Stevenson, Philip G.

doi:10.1099/vir.0.000140

Cited by 33 publications

(52 citation statements)

References 57 publications

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“…Natural MuHV-4 entry is probably via the upper respiratory tract (22), but i.f. infection is also productive (16) and allows comparison with data from other SSM studies. Both intranasal (i.n.)…”

Section: Human Gammaherpesviruses Cause Cancers By Infecting B Cellsmentioning

confidence: 89%

“…Viral exploitation of endocytic scavenging pathways (13,14) makes myeloid cell entry difficult to block, but virus production by myeloid cells might be susceptible. Of note, not all myeloid infection is productive: subcapsular sinus macrophages (SSM) communicate with B cells (15) and are infected by MuHV-4 yet restrict its spread (16). To reveal mechanisms capable of in vivo infection control, we sought to understand how SSM restrict MuHV-4 replication.…”

Section: Human Gammaherpesviruses Cause Cancers By Infecting B Cellsmentioning

confidence: 99%

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Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection

Lawler

Tan

Simas

et al. 2016

J Virol

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Gammaherpesviruses establish persistent, systemic infections and cause cancers. Murid herpesvirus 4 (MuHV-4) provides a unique window into the early events of host colonization. It spreads via lymph nodes. While dendritic cells (DC) pass MuHV-4 to lymph node B cells, subcapsular sinus macrophages (SSM), which capture virions from the afferent lymph, restrict its spread. Understanding how this restriction works offers potential clues to a more comprehensive defense. Type I interferon (IFN-I) blocked SSM lytic infection and reduced lytic cycle-independent viral reporter gene expression. Plasmacytoid DC were not required, but neither were SSM the only source of IFN-I, as IFN-I blockade increased infection in both intact and SSM-depleted mice. NK cells restricted lytic SSM infection independently of IFN-I, and SSM-derived virions spread to the spleen only when both IFN-I responses and NK cells were lacking. Thus, multiple innate defenses allowed SSM to adsorb virions from the afferent lymph with relative impunity. Enhancing IFN-I and NK cell recruitment could potentially also restrict DC infection and thus improve infection control. IMPORTANCE Human gammaherpesviruses cause cancers by infecting B cells. However, vaccines designed to block virus binding to B cells have not stopped infection. Using a related gammaherpesvirus of mice, we have shown that B cells are infected not via cell-free virus but via infected myeloid cells. This suggests a different strategy to stop B cell infection: stop virus production by myeloid cells. Not all myeloid infection is productive. We show that subcapsular sinus macrophages, which do not pass infection to B cells, restrict gammaherpesvirus production by recruiting type I interferons and natural killer cells. Therefore, a vaccine that speeds the recruitment of these defenses might stop B cell infection.E pstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) persist in B cells and cause cancers (1). Reducing their B cell infections is therefore an important therapeutic goal. Limited viral gene expression (2) makes established infections difficult to clear. The early events of host colonization may provide better targets. However, control mechanisms must be defined in vivo: inferring mechanisms from in vitro studies has proven problematic because immune function and its evasion are context dependent. Thus, EBV gp350-specific antibodies block B cell infection, and CD8 ϩ T cells kill infected B cells in vitro, but vaccinations to induce these effectors have not reduced infection rates (3).The early events of human infections are difficult to analyze because they predate clinical presentation (4). However, gammaherpesviruses long predate human speciation (5), and peak viral diversity in genes that interact with host-diverse functions suggests that viral coevolution has since acted to counter host divergence. Therefore, human and other mammalian gammaherpesviruses should colonize their hosts in similar ways. Murid herpesvirus 4 (MuHV-4) realistically infects la...

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Section: Human Gammaherpesviruses Cause Cancers By Infecting B Cellsmentioning

confidence: 89%

Section: Human Gammaherpesviruses Cause Cancers By Infecting B Cellsmentioning

confidence: 99%

Type I Interferons and NK Cells Restrict Gammaherpesvirus Lymph Node Infection

Lawler

Tan

Simas

et al. 2016

J Virol

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“…SSMs also limit the spread of MuHV-4 and MCMV (39,43). MuHV-4 bypasses this restriction by entering LNs in DCs.…”

Section: Discussionmentioning

confidence: 99%

“…Virus tagging tells us what proportion of productive paths traversed a Cre ϩ cell. LysMcre mice express Cre mainly in neutrophils, mature macrophages (28,38,39), and type 2 alveolar epithelial cells (40). HSV-RG accordingly showed fluorochrome switching in peritoneal macro- phages but not embryonic fibroblasts of LysM-cre mice (Fig.…”

Section: Hsv-1 Infects Myeloid Cells At Its Likely Natural Entry Sitementioning

confidence: 99%

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Herpes Simplex Virus 1 Interaction with Myeloid CellsIn Vivo

Shivkumar

Lawler

Milho

et al. 2016

J Virol

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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...

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