Interference with Dendritic Cell Populations Limits Early Antigen Presentation in Chronic γ-Herpesvirus-68 Infection

Mount, Adele M.; Masson, Frédérick; Kupresanin, Fiona; Smith, Christopher M.; May, Janet S.; Rooijen, Nico van; Stevenson, Philip G.; Belz, Gabrielle T.

doi:10.4049/jimmunol.1001079

Cited by 4 publications

(3 citation statements)

References 34 publications

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“…MHV-RG in CD11c-Cre LNs argued that peripheral replication promotes DC infection. This may also be important for early immune priming by mucosal MuHV-4 ( Mount et al , 2010 ). SSM infection should reinforce DC-driven responses, but a more important SSM function may be to contain locally the large amounts of virus produced by peripheral replication.…”

Section: Discussionmentioning

confidence: 99%

Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination

Frederico

Chao

Lawler

et al. 2015

Journal of General Virology

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Lymphocyte proliferation, mobility and longevity make them prime targets for virus infection. Myeloid cells that process and present environmental antigens to lymphocytes are consequently an important line of defence. Subcapsular sinus macrophages (SSMs) filter the afferent lymph and communicate with B-cells. How they interact with B-cell-tropic viruses is unknown. We analysed their encounter with murid herpesvirus-4 (MuHV-4), an experimentally accessible gammaherpesvirus related to Kaposi's sarcoma-associated herpesvirus. MuHV-4 disseminated via lymph nodes, and intranasally or subcutaneously inoculated virions readily infected SSMs. However, this infection was poorly productive. SSM depletion with clodronate-loaded liposomes or with diphtheria toxin in CD169–diphtheria toxin receptor transgenic mice increased B-cell infection and hastened virus spread to the spleen. Dendritic cells provided the main route to B-cells, and SSMs slowed host colonization, apparently by absorbing virions non-productively from the afferent lymph.

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Section: Discussionmentioning

confidence: 99%

Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination

Frederico

Chao

Lawler

et al. 2015

Journal of General Virology

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“…In both this setting and that of virus transfer, the B cell latency defects of MuHV-4 lacking its MHC class I down-regulation gene K3 [51] or its bcl-2 homolog M11 [52] could reflect that these genes function in DCs [74], [75]. Exploiting DCs presumably brings gamma-herpesviruses advantages of efficiency and stealth.…”

Section: Discussionmentioning

confidence: 99%

Murid Herpesvirus-4 Exploits Dendritic Cells to Infect B Cells

et al. 2011

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Dendritic cells (DCs) play a central role in initiating immune responses. Some persistent viruses infect DCs and can disrupt their functions in vitro. However, these viruses remain strongly immunogenic in vivo. Thus what role DC infection plays in the pathogenesis of persistent infections is unclear. Here we show that a persistent, B cell-tropic gamma-herpesvirus, Murid Herpesvirus-4 (MuHV-4), infects DCs early after host entry, before it establishes a substantial infection of B cells. DC-specific virus marking by cre-lox recombination revealed that a significant fraction of the virus latent in B cells had passed through a DC, and a virus attenuated for replication in DCs was impaired in B cell colonization. In vitro MuHV-4 dramatically altered the DC cytoskeleton, suggesting that it manipulates DC migration and shape in order to spread. MuHV-4 therefore uses DCs to colonize B cells.

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“…Herpesvirus infections remain immunogenic because uninfected cells can engage in cross-priming. Therefore, the purpose of viral evasion in infected myeloid cells is probably to delay their recognition (20,21). For MCMV and MuHV-4, this makes sense, as they use infection of myeloid cells to reach other cell types.…”

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confidence: 99%

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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Interference with Dendritic Cell Populations Limits Early Antigen Presentation in Chronic γ-Herpesvirus-68 Infection

Abstract: Material

Cited by 4 publications

References 34 publications

Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination

Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination

Murid Herpesvirus-4 Exploits Dendritic Cells to Infect B Cells

Herpes Simplex Virus 1 Interaction with Myeloid CellsIn Vivo

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