Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis

Baxter, Victoria K.; Glowinski, Rebecca M; Braxton, Alicia M.; Potter, Michelle C.; Slusher, Barbara S.; Griffin, Diane E.

doi:10.1016/j.virol.2017.05.013

Cited by 20 publications

(25 citation statements)

References 87 publications

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“…In IRF7-deficient mice, the levels of IFNa, but not IFNb, were decreased in brain and spinal cord, and, as previously observed after CNS infection with LCMV [84], the induction of ISGs was the same or higher compared to that for WT mice, and initial control of virus replication was similar. Furthermore, previous studies have shown that the inhibition of SINV clearance alone does not lead to neuronal death or fatal outcome [45,[85][86][87], indicating a role for IRF7 in regulating neuronal cell death by autonomous or non-cell autonomous processes. Although neurons do not produce IFN in response to alphavirus infection in vitro, the expression of functionally mature IRF7 increases with neuronal maturation [88].…”

Section: Irf3à/à Mice Develop Fatal Disease After Infection With Wnvmentioning

confidence: 96%

“…Inflammatory cells were primarily noted around vessels as perivascular cuffs and within the tissue parenchyma of infected mice and were minimal in mock-infected controls. Inflammation was quantified on coded slides using previously established scoring systems [45,46]. In the brain, the scores for mock-infected mice were typically less than 1, while the brains of infected mice had scores greater than 2, with IRF3À/À brains having the highest scores at both 5 and 7 days (Fig.…”

Section: Cns Inflammation and Cell Death In The Cns Of Sinv-infected mentioning

confidence: 99%

“…An additional point was given for excessive parenchymal cellularity, allowing for a maximum score of 4. Spinal cord sections were scored using a modified 0-2/3 scale as previously described [45]: 0, no detectable inflammation; 1, one to two small inflammatory foci; 2, greater than two inflammatory foci per spinal cord or moderate to marked inflammatory foci. An additional point was given for excessive parenchymal cellularity, allowing for a maximum score of 3.…”

Section: Histologymentioning

confidence: 99%

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Interferon regulatory factors 3 and 7 have distinct roles in the pathogenesis of alphavirus encephalomyelitis

Schultz

Troisi

Baxter

et al. 2019

Journal of General Virology

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Interferon (IFN) regulatory factors (IRFs) are important determinants of the innate response to infection. We evaluated the role(s) of combined and individual IRF deficiencies in the outcome of infection of C57BL/6 mice with Sindbis virus, an alphavirus that infects neurons and causes encephalomyelitis. The brain and spinal cord levels of Irf7, but not Irf3 mRNAs, were increased after infection. IRF3/5/7À/À and IRF3/7À/À mice died within 3-4 days with uncontrolled virus replication, similar to IFNa receptordeficient mice, while all wild-type (WT) mice recovered. IRF3À/À and IRF7À/À mice had brain levels of IFNa that were lower, but brain and spinal cord levels of IFNb and IFN-stimulated gene mRNAs that were similar to or higher than WT mice without detectable serum IFN or increases in Ifna or Ifnb mRNAs in the lymph nodes, indicating that the differences in outcome were not due to deficiencies in the central nervous system (CNS) type I IFN response. IRF3À/À mice developed persistent neurological deficits and had more spinal cord inflammation and higher CNS levels of Il1b and Ifng mRNAs than WT mice, but all mice survived. IRF7À/À mice died 5-8 days after infection with rapidly progressive paralysis and differed from both WT and IRF3À/À mice in the induction of higher CNS levels of IFNb, tumour necrosis factor (TNF) a and Cxcl13 mRNA, delayed virus clearance and more extensive cell death. Therefore, fatal disease in IRF7À/À mice is likely due to immune-mediated neurotoxicity associated with failure to regulate the production of inflammatory cytokines such as TNFa in the CNS.

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Section: Irf3à/à Mice Develop Fatal Disease After Infection With Wnvmentioning

confidence: 96%

Section: Cns Inflammation and Cell Death In The Cns Of Sinv-infected mentioning

confidence: 99%

Section: Histologymentioning

confidence: 99%

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Interferon regulatory factors 3 and 7 have distinct roles in the pathogenesis of alphavirus encephalomyelitis

Schultz

Troisi

Baxter

et al. 2019

Journal of General Virology

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“…To analyze the importance of nsP3 MD function for neurovirulence and the induction of innate and adaptive antiviral immune responses in the CNS, we have introduced similar mutations into the nsP3 MD of the TE strain of SINV, a well-characterized mouse model of alphavirus encephalomyelitis that causes fatal disease in 2-week-old mice (5,(52)(53)(54). Previous studies have shown that mutation D10A in the ADPr-binding site is not tolerated, while mutation N24A results in viable virus with impaired shutoff of host protein synthesis and decreased virulence (55,56).…”

mentioning

confidence: 99%

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

Abraham

McPherson

Dasovich

et al. 2020

mBio

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Macrodomain (MD), a highly conserved protein fold present in a subset of plus-strand RNA viruses, binds to and hydrolyzes ADP-ribose (ADPr) from ADPribosylated proteins. ADPr-binding by the alphavirus nonstructural protein 3 (nsP3) MD is necessary for the initiation of virus replication in neural cells, whereas hydrolase activity facilitates replication complex amplification. To determine the importance of these activities for pathogenesis of alphavirus encephalomyelitis, mutations were introduced into the nsP3 MD of Sindbis virus (SINV), and the effects on ADPr binding and hydrolase activities, virus replication, immune responses, and disease were assessed. Elimination of ADPr-binding and hydrolase activities (G32E) severely impaired in vitro replication of SINV in neural cells and in vivo replication in the central nervous systems of 2-week-old mice with reversion to wild type (WT) (G) or selection of a less compromising change (S) during replication. SINVs with decreased binding and hydrolase activities (G32S and G32A) or with hydrolase deficiency combined with better ADPr-binding (Y114A) were less virulent than WT virus. Compared to the WT, the G32S virus replicated less well in both the brain and spinal cord, induced similar innate responses, and caused less severe disease with full recovery of survivors, whereas the Y114A virus replicated well, induced higher expression of interferon-stimulated and NF-B-induced genes, and was cleared more slowly from the spinal cord with persistent paralysis in survivors. Therefore, MD function was important for neural cell replication both in vitro and in vivo and determined the outcome from alphavirus encephalomyelitis in mice. IMPORTANCE Viral encephalomyelitis is an important cause of long-term disability, as well as acute fatal disease. Identifying viral determinants of outcome helps in assessing disease severity and developing new treatments. Mosquito-borne alphaviruses infect neurons and cause fatal disease in mice. The highly conserved macrodomain of nonstructural protein 3 binds and can remove ADP-ribose (ADPr) from ADPribosylated proteins. To determine the importance of these functions for virulence, recombinant mutant viruses were produced. If macrodomain mutations eliminated ADPr-binding or hydrolase activity, viruses did not grow. If the binding and hydrolase activities were impaired, the viruses grew less well than the wild-type virus, induced similar innate responses, and caused less severe disease, and most of the infected mice recovered. If binding was improved, but hydrolase activity was decreased, the virus replicated well and induced greater innate responses than did the WT, but clearance from the nervous system was impaired, and mice remained paralyzed. Therefore, macrodomain function determined the outcome of alphavirus encephalomyelitis. Citation Abraham R, McPherson RL, Dasovich M, Badiee M, Leung AKL, Griffin DE. 2020. Both ADP-ribosyl-binding and hydrolase activities of the alphavirus nsP3 macrodomain affect neurovirulence in mice. mBio 11:e03253-1...

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“…Many cells can produce IL-10, but regulatory T cells play a major role during viral infections of multiple organs, including the CNS (21,(32)(33)(34)(35), and are important determinants of NSV infection outcome in susceptible and resistant strains of mice (20). SINV-induced neurologic disease is a manifestation of the inflammatory response to infection rather than virus replication per se (36)(37)(38). In both NSV-and TE12-induced encephalomyelitis, IL-10 deficiency and more severe disease were associated with fewer Tregs in the CNS than in the CNS of WT mice (19).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis

Martin

Griffin

2018

J Virol

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Alphaviruses are an important cause of mosquito-borne outbreaks of arthritis, rash, and encephalomyelitis. Previous studies in mice with a virulent strain (neuroadapted SINV [NSV]) of the alphavirus Sindbis virus (SINV) identified a role for Th17 cells and regulation by interleukin-10 (IL-10) in the pathogenesis of fatal encephalomyelitis (K. A. Kulcsar, V. K. Baxter, I. P. Greene, and D. E. Griffin, Proc Natl Acad Sci U S A 111:16053-16058, 2014, https://doi.org/10.1073/pnas.1418966111). To determine the role of virus virulence in generation of immune responses, we analyzed the modulatory effects of IL-10 on disease severity, virus clearance, and the CD4 T cell response to infection with a recombinant strain of SINV of intermediate virulence (TE12). The absence of IL-10 during TE12 infection led to longer morbidity, more weight loss, higher mortality, and slower viral clearance than in wild-type mice. More severe disease and impaired virus clearance in IL-10 mice were associated with more Th1 cells, fewer Th2 cells, innate lymphoid type 2 cells, regulatory cells, and B cells, and delayed production of antiviral antibody in the central nervous system (CNS) without an effect on Th17 cells. Therefore, IL-10 deficiency led to more severe disease in TE12-infected mice by increasing Th1 cells and by hampering development of the local B cell responses necessary for rapid production of antiviral antibody and virus clearance from the CNS. In addition, the shift from Th17 to Th1 responses with decreased virus virulence indicates that the effects of IL-10 deficiency on immunopathologic responses in the CNS during alphavirus infection are influenced by virus strain. Alphaviruses cause mosquito-borne outbreaks of encephalomyelitis, but determinants of outcome are incompletely understood. We analyzed the effects of the anti-inflammatory cytokine IL-10 on disease severity and virus clearance after infection with an alphavirus strain of intermediate virulence. The absence of IL-10 led to longer illness, more weight loss, more death, and slower viral clearance than in mice that produced IL-10. IL-10 influenced development of disease-causing T cells and entry into the brain of B cells producing antiviral antibody. The Th1 pathogenic cell subtype that developed in IL-10-deficient mice infected with a less virulent virus was distinct from the Th17 subtype that developed in response to a more virulent virus, indicating a role for virus strain in determining the immune response. Slow production of antibody in the nervous system led to delayed virus clearance. Therefore, both the virus strain and the host response to infection are important determinants of outcome.

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Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis

Cited by 20 publications

References 87 publications

Interferon regulatory factors 3 and 7 have distinct roles in the pathogenesis of alphavirus encephalomyelitis

Interferon regulatory factors 3 and 7 have distinct roles in the pathogenesis of alphavirus encephalomyelitis

Both ADP-Ribosyl-Binding and Hydrolase Activities of the Alphavirus nsP3 Macrodomain Affect Neurovirulence in Mice

Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis

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