Mouse hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein expression and immunopathology

Rempel, Julia D.; Murray, Shannon J.; Meisner, Jeffrey; Buchmeier, Michael J.

doi:10.1016/j.virol.2003.08.041

Cited by 30 publications

(56 citation statements)

References 34 publications

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“…In CNS autoimmune diseases, such as multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE), alterations in CXCL12 expression at the BBB contributes to the inappropriate entry of leukocytes, which is associated with significant glial cell activation and CNS injury (5,8). Whereas immunopathology is an established consequence of CNS lymphocyte entry during noncytopathic viral infections (9), the effects of enhanced lymphocyte migration into the CNS parenchyma during cytopathic viral infections are less clear. Studies of CNS infections with cytopathic viruses, such as West Nile virus (WNV), suggest that lymphocyte presence promotes pathogen clearance but may also lead to immunopathology (10,11).…”

mentioning

confidence: 99%

CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis

McCandless¹,

Zhang²,

Diamond

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

127

144

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The migration of lymphocytes into the CNS during viral encephalitis is hindered by the blood-brain barrier (BBB) such that most infiltrating cells remain localized to perivascular spaces. This sequestration of leukocytes away from the parenchyma is believed to protect the CNS from immunopathologic injury. Infections of the CNS with highly cytopathic neurotropic viruses, such as West Nile virus (WNV), however, require the parenchymal penetration of T lymphocytes for virus clearance and survival, suggesting that perivascular localization might hinder antiviral immune responses during WNV encephalitis. Using human and murine brain specimens from individuals with WNV encephalitis, we evaluated the expression of CXCL12 and its receptor, CXCR4, at the BBB and tested the hypothesis that inhibition of CXCR4 would promote T lymphocyte entry into the CNS parenchyma and increase viral clearance. Antagonism of CXCR4 significantly improved survival from lethal infection through enhanced intraparenchymal migration of WNV-specific CD8 ؉ T cells within the brain, leading to reduced viral loads and, surprisingly, decreased immunopathology at this site. The benefits of enhanced CD8 ؉ T cell infiltration suggest that pharmacologic targeting of CXCR4 may have therapeutic utility for the treatment of acute viral infections of the CNS.CD8 T cell ͉ CNS ͉ CXCL12 ͉ chemokine ͉ neuropathology U nder normal, uninflamed conditions, the CNS is an immuneprivileged site with minimal infiltration by inflammatory cells (1). The limited trafficking of leukocytes is the result of restriction at the blood-brain barrier (BBB); the specialized microvasculature of the CNS that prevents the entry of cells through mechanisms that are incompletely understood. Although immune cell restriction may protect the brain from inappropriate immune activation and neuropathology (2), it may also act as a barrier to successful pathogen clearance during acute infections of the CNS (3). Indeed, one of the hallmarks of viral encephalitis is the development of perivascular infiltrates comprised of virus-specific T cells with minimal invasion of the CNS parenchyma (4). Thus, BBB restriction may limit CNS antiviral immune responses at the expense of delayed clearance of microbial agents.Studies in mice suggest that polarized expression of the chemokine CXCL12 at the BBB localizes infiltrating mononuclear cells to the perivascular spaces of the CNS microvasculature, therefore limiting their entry into the CNS parenchyma (5). CXCL12 expression is present along the basolateral surfaces of CNS endothelial cells where leukocytes, which ubiquitously express its receptor CXCR4, engage CXCL12 when attempting to enter the CNS. This subcompartment retention, which is analogous to the role of CXCL12 in lymphoid compartments (6), could be an integral component of CNS protection from the pathologic consequences of immune cell activation (7). In CNS autoimmune diseases, such as multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE), alterations in...

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mentioning

confidence: 99%

CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis

McCandless¹,

Zhang²,

Diamond

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

127

144

View full text Add to dashboard Cite

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“…A59 induces a strong protective interferon-g (IFN-g) response (Rempel et al, 2004a;Scott et al 2008). Additionally, JHM.SD induces more macrophage chemoattractants, such as macrophage inflammatory protein-1a and -1b (MIP-1a and MIP-1b) and MIP-2, consistent with the greater number of macrophages recruited into the CNS during JHM.SD infection (Iacono et al, 2006;Rempel et al, 2004b). SD infection (Rempel et al, 2004a).…”

Section: Innate Immune Responsementioning

confidence: 87%

“…JHM.SD, on the other hand, induces a weaker IFN-g response (Rempel et al, 2004a;Scott et al, 2008) and there is one report of a stronger IFN-b response early in JHM. The robust macrophage infiltration induced by JHM.SD partially maps to the JHM.SD spike gene, as evidenced by the greater level of macrophage recruitment in the CNS of rA59/S JHM -infected mice as compared with A59-infected animals (Rempel et al 2004b;Scott et al, 2008). Additionally, JHM.SD induces more macrophage chemoattractants, such as macrophage inflammatory protein-1a and -1b (MIP-1a and MIP-1b) and MIP-2, consistent with the greater number of macrophages recruited into the CNS during JHM.SD infection (Iacono et al, 2006;Rempel et al, 2004b).…”

Section: Innate Immune Responsementioning

confidence: 98%

“…Quantification of virus specific T cells after JHM 2.2-V-1 infection showed that priming and the initiation of T-cell expansion occurs in the cervical lymph nodes (CLNs). The induction of a robust T-cell response does not map to spike, as rA59/S JHM induces a strong T-cell response and infectious viral titers similar to A59 are detected in CLNs (Cowley et al, 2010;Iacono et al, 2006;Macnamara et al, 2008;Rempel et al, 2004b). After initial expansion in the CLNs, T cells expand further in the spleen before trafficking to the brain .…”

Section: Adaptive Immune Responsementioning

confidence: 99%

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Murine coronavirus neuropathogenesis: determinants of virulence

Cowley

Weiss

2010

Journal of NeuroVirology

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Murine coronavirus, mouse hepatitis virus (MHV), causes various diseases depending on the strain and route of inoculation. Both the JHM and A59 strains, when inoculated intracranially or intranasally, are neurovirulent. Comparison of the highly virulent JHM isolate, JHM.SD, with less virulent JHM isolates and with A59 has been used to determine the mechanisms and genes responsible for high neuropathogenicity of MHV. The focus of this review is on the contributions of viral spread, replication and innate and adaptive immunity to MHV neuropathogenesis. JHM.SD spreads more quickly among neurons than less neurovirulent MHVs, and is able to spread in the absence of the canonical MHV receptor, CEACAM1a. The observation that JHM.SD infects more cells and expresses more antigen, but produces less infectious virus per cell than A59 implies that efficient replication is not always a correlate of high neurovirulence. This is likely due to the unstable nature of the JHM.SD spike protein (S). JHM.SD induces a generally protective innate immune response; however, the strong neutrophil response may be more pathogenic than protective. In addition JHM.SD induces only a minimal T cell response, while the strong T cell response and the concomitant IFNγ induced by the less neurovirulent A59 is protective. Differences in the S and nucleocapsid (N) proteins between A59 and JHM.SD contribute to JHM.SD neuropathogenicity. The hemmagglutinin-esterase (HE) protein may enhance neuropathogenicity of some MHV isolates, but is unlikely a major contributor to the high neuroviruence of JHM.SD. Further data suggests that neither the internal (I) protein, nor nonstructural proteins ns4, and ns2 are significant contributors to neurovirulence.

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“…of the two viruses (data not shown), although the T-cell response was reported to significantly contribute to the neurovirulence of the MHV-JHM. JHM induces a weak T-cell response, while the less virulent MHV-A59 induces strong responses (Iacono et al, 2006;Rempel et al, 2004). Conclusively, microglia infiltration was predominant in the brains of suckling mice infected with MK and MK-p10 strains.…”

mentioning

confidence: 82%

Neuropathogenesis of a mouse-adapted porcine epidemic diarrhea virus infection in suckling mice

Kotani

Shirato

Nagata

et al. 2013

Journal of General Virology

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A mouse-adapted porcine epidemic diarrhea virus, MK-p10, showed higher neurovirulence in suckling mice than a non-adapted MK strain. There was no difference in virus growth, whereas clear differences between these two virus infections existed in the type of target cells infected, the spread of virus and the cytokine levels produced in the brain. In the early phase of infection, neurons, astrocytes and neural progenitor cells were infected by MK-p10, whereas neural progenitor cells were the only target cells infected by MK. On days 4-5 post-inoculation, MK-p10 antigens were distributed in a number of neurons in a wide area of the brain; however, antigens were restricted in MK infection. In moribund mice in both infection groups, viral antigens were found in a wide area of the brain. The wide spectrum of initial target cells following MK-p10 infection, as well as its faster spread in the brain, may be evidence of enhanced virulence in suckling mice.Porcine epidemic diarrhea virus (PEDV) is an enveloped alphacoronavirus with a single-stranded, positive-sense RNA genome of about 30 kb and is a causative agent for diarrhoea in pigs. It induces mild intestinal disease in adult pigs, whereas it causes lethal diarrhoea in piglets (Pensaert & de Bouck, 1978). However, the pathogenesis of diseases caused by PEDV is not well understood, since there are no animal models available for the study of infection.We have recently obtained a PEDV strain adapted to suckling mice (Shirato et al., 2010). Although the neurovirulence of PEDV has not been described thus far in pigs, we reported the establishment of a highly neurovirulent strain of PEDV via adaptation of a celladapted MK strain (Kusanagi et al., 1992) to the mouse brain (Shirato et al., 2010). MK showed weak neurovirulence when injected into a suckling mouse brain, whereas MK-p10 showed increased neurovirulence. When inoculated with MK-p10 via the oral route, mice showed slight weight loss with no other clinical symptoms, but no viral antigen or histological changes were observed in the intestine. In this study, we investigated the enhanced neuropathological features of the MK-p10 strain compared with those of the MK strain in suckling mice by histopathological and immunochemical analysis. Our study suggests that the alteration of the cell tropism in the suckling mouse brain, as well as the faster spread of the virus to a variety of cells, mainly neurons, leads to higher neurovirulence in the adapted MK-p10 strain.MK and MK-p10 were prepared as previously reported (Shirato et al., 2010). Pregnant BALB/c mice were obtained from Japan SLC and Sankyo Labo Service Corporation, and newborn mice were inoculated intracerebrally with 10 ml containing ca 10 4 p.f.u. virus solution. Those mice were clinically observed and their brains were histologically or immunohistochemically examined. Kaplan-Meier analysis was used for statistics, and P,0.05 was considered to be statistically significant. Animal experiments were approved by the Committees on Experimental Animals, National Inst...

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Mouse hepatitis virus neurovirulence: evidence of a linkage between S glycoprotein expression and immunopathology

Cited by 30 publications

References 34 publications

CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis

CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis

Murine coronavirus neuropathogenesis: determinants of virulence

Neuropathogenesis of a mouse-adapted porcine epidemic diarrhea virus infection in suckling mice

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