Recovery from viral encephalomyelitis: immune-mediated noncytolytic virus clearance from neurons

Griffin, Diane E.

doi:10.1007/s12026-009-8143-4

Cited by 61 publications

(72 citation statements)

References 83 publications

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“…45,46 The age-dependent virulence of ONNV is typical of alphaviruses and has been described in numerous rodent models of alphavirus infection and pathogenesis. 28,42,[47][48][49][50][51][52][53][54][55] Our results also represent progress in developing a murine model to represent human disease after ONNV infection. The STAT1 KO and A129 mice inoculated s.c. do recapitulate the myositis and tenosynovitis that are probably present in humans, as suggested by findings from human infections with the closely related CHIKV.…”

Section: Discussionmentioning

confidence: 80%

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

Seymour

Rossi

Bergren

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. O'nyong-nyong virus (ONNV), an alphavirus closely related to chikungunya virus (CHIKV), has caused three major epidemics in Africa since 1959. Both ONNV and CHIKV produce similar syndromes with fever, rash, and debilitating arthralgia. To determine the roles of the innate and adaptive immune responses, we infected different knockout mice with two strains of ONNV (SG650 and MP30). Wild-type, RAG1 KO, and IFNγR KO mice showed no signs of illness or viremia. The STAT1 KO and A129 mice exhibited 50-55% mortality when infected with SG650. Strain SG650 was more virulent in the STAT1 KO and A129 than MP30. Deficiency in interferon α/β signaling (A129 and STAT1 KO) leaves mice susceptible to lethal disease; whereas a deficiency of interferon γ signaling alone had no effect on survival. Our findings highlight the importance of type I interferon in protection against ONNV infection, whereas the adaptive immune system is relatively unimportant in the acute infection.

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Section: Discussionmentioning

confidence: 80%

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

Seymour

Rossi

Bergren

et al. 2013

The American Society of Tropical Medicine and Hygiene

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“…CD8 ϩ T cells play a critical role in clearance of viruses from the CNS (10,89,90). CD8 ϩ T cells can control viral infection directly by inducing apoptosis of virus-infected cells via perforin, granzyme, or Fas-FasL interactions (63,91) or indirectly by immunemediated noncytolytic clearance of viruses from neurons by producing cytokines, such as TNF-␣ and IFN-␥ (89,90).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Acharya

Wang

Paul

et al. 2017

J Virol

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CD8 ϩ T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8 ϩ T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a Ϫ/Ϫ ) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8 ϩ T cells isolated from Il17a Ϫ/Ϫ mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo. Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8 ϩ T cell cytotoxicity, which may have broad implications in other microbial infections and cancers.IMPORTANCE Interleukin-17A (IL-17A) and CD8 ϩ T cells regulate diverse immune functions in microbial infections, malignancies, and autoimmune diseases. IL-17A is a proinflammatory cytokine produced by diverse cell types, while CD8 ϩ T cells (known as cytotoxic T cells) are major cells that provide immunity against intracellular pathogens. Previous studies have demonstrated a crucial role of CD8 ϩ T cells in recovery from West Nile virus (WNV) infection. However, the role of IL-17A during WNV infection remains unclear. Here, we demonstrate that IL-17A protects mice from lethal WNV infection by promoting CD8 ϩ T cell-mediated clearance of WNV. In addition, treatment of WNV-infected mice with recombinant IL-17A reduces the viral burden and increases survival of mice, suggesting a potential therapeutic. This novel IL-17A-CD8 ϩ T cell axis may also have broad implications for immunity to other microbial infections and cancers, where CD8 ϩ T cell functions are crucial.

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“…Although perforin-mediated cell killing is a primary strategy to eliminate virus from rapidly dividing and renewable cell types, neurons are generally nonrenewable, and thus it has been proposed that these cytolytic strategies may be more harmful than beneficial within the brain. For a number of viral model systems, it has been shown that cytokine-mediated, noncytolytic strategies control many neurotropic infections (40)(41)(42)(43)(44)(45)(46)(47). These data suggest that the mechanisms by which viral infections are resolved are exquisitely cell type specific and may reflect evolutionary pressures to restrict an infection while minimizing cytopathology and tissue damage.…”

Section: Discussionmentioning

confidence: 99%

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

Holmgren

Miller

Cavanaugh

et al. 2015

J Virol

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In permissive mouse central nervous system (CNS) neurons, measles virus (MV) spreads in the absence of hallmark viral budding or neuronal death, with transmission occurring efficiently and exclusively via the synapse. MV infection also initiates a robust type I interferon (IFN) response, resulting in the synthesis of a large number of genes, including bone marrow stromal antigen 2 (Bst2)/tetherin/CD317. Bst2 restricts the release of some enveloped viruses, but to date, its role in viral infection of neurons has not been assessed. Consequently, we investigated how Bst2 was induced and what role it played in MV neuronal infection. The magnitude of induction of neuronal Bst2 RNA and protein following IFN exposure and viral infection was notably higher than in similarly treated mouse embryo fibroblasts (MEFs). Bst2 synthesis was both IFN and Stat1 dependent. Although Bst2 prevented MV release from nonneuronal cells, its deletion had no effect on viral pathogenesis in MV-challenged mice. Our findings underscore how cell-type-specific differences impact viral infection and pathogenesis. IMPORTANCE Viral infections of the central nervous system can lead to debilitating disease and death. Moreover, it is becoming increasingly clear that nonrenewable cells, including most central nervous system neurons, combat neurotropic viral infections in fundamen-tally different ways than other rapidly dividing and renewable cell populations. Here we identify type I interferon signaling as a key inducer of a known antiviral protein (Bst2) in neurons. Unexpectedly, the gene is dispensable for clearance of neurotropic viral infection despite its well-defined contribution to limiting the spread of enveloped viruses in proliferating cells. A deeper appreciation of the importance of cell type heterogeneity in antiviral immunity will aid in the identification of unique therapeutic targets for life-threatening viral infections. Many of the foundational principles in immunology have resulted from basic observations of virus-cell interactions, including the induction and antiviral function of both type I and type II interferons (IFNs) (reviewed in references 1, 2, and 3). Viral infection of a cell typically results in cellular production and secretion of type I IFNs, which can then bind to cell surface receptors in a paracrine and autocrine fashion, leading to synthesis of interferon-stimulated genes (ISGs). These ISGs, in turn, aid in clearing the viral infection by directly cleaving viral nucleic acids, triggering cellular apoptosis, inducing autophagy, upregulating major histocompatibility complex (MHC) class I expression to aid in CD8 ϩ T cell-mediated cytotoxicity, and preventing viral egress. Moreover, the induction of type I IFN contributes to the recruitment of adaptive immune effectors to infected sites, which further promotes viral clearance.One ISG that is highly induced following infection by many viruses, and in response to both type I and II IFN signaling, is the gene for bone marrow stromal antigen 2 (Bst2; also known a...

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Recovery from viral encephalomyelitis: immune-mediated noncytolytic virus clearance from neurons

Cited by 61 publications

References 83 publications

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

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Recovery from viral encephalomyelitis: immune-mediated noncytolytic virus clearance from neurons

Cited by 61 publications

References 83 publications

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

The Role of Innate versus Adaptive Immune Responses in a Mouse Model of O'Nyong-Nyong Virus Infection

Interleukin-17A Promotes CD8+T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Bst2/Tetherin Is Induced in Neurons by Type I Interferon and Viral Infection but Is Dispensable for Protection against Neurotropic Viral Challenge

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Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance