Viral determinants of age-dependent virulence of Sindbis virus for mice

Tucker, Pamela C.; Strauss, Ellen G.; Kühn, Richard; Strauss, James H.; Griffin, Diane E.

doi:10.1128/jvi.67.8.4605-4610.1993

Cited by 95 publications

(64 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SINV causes rash and arthritis in humans and encephalomyelitis in mice [3]. After intracerebral or intranasal inoculation of mice, SINV quickly spreads throughout the central nervous system (CNS) with virus replication mostly in neurons of the olfactory tract and hippocampus, and motor neurons of the brainstem and spinal cord [4,5]. Amounts of infectious virus in brain and spinal cord peak 2-3 days after infection.…”

Section: Models Of Rna Virus Cns Infectionmentioning

confidence: 99%

Clearance of virus infection from the CNS

Griffin

Metcalf

2011

Current Opinion in Virology

View full text Add to dashboard Cite

Viruses that cause encephalomyelitis infect neurons and recovery from infection requires noncytolytic clearance of virus from the nervous system to avoid damaging these irreplaceable cells. Several murine model systems of virus infection have been used to identify clearance mechanisms. Quantitative analysis of Sindbis virus clearance over 6 months shows three phases: day 5-7, clearance of infectious virus, but continued presence of viral RNA; day 8-60, decreasing levels of viral RNA; day 60-180, maintenance of viral RNA at low levels. Antiviral antibody and interferon-γ have major roles in clearance with a likely role for IgM as well as IgG antibody. Long-term residence of virus-specific immune cells in the nervous system is necessary to prevent virus reactivation.

show abstract

Section: Models Of Rna Virus Cns Infectionmentioning

confidence: 99%

Clearance of virus infection from the CNS

Griffin

Metcalf

2011

Current Opinion in Virology

View full text Add to dashboard Cite

show abstract

“…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%

“…Effects of nsP3 MD mutations on severity of SINV encephalomyelitis in mice. The TE WT strain of SINV causes fatal encephalomyelitis in 2-week-old mice (52). To determine the role of the nsP3 MD in the pathogenesis of encephalomyelitis, we infected 2-week-old CD1 mice intracranially with 1,000 PFU of WT SINV and nsP3 MD mutants N24A, G32A, G32E, G32S, Y114A, and TM ( Fig.…”

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

View full text Add to dashboard Cite

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...

show abstract

“…Sindbis virus (SINV), the prototypical alphavirus, is the most widespread alphavirus and causes rash and arthritis in humans (6). In mice, SINV causes encephalomyelitis, the severity of which depends on virus and host factors, including host age and genetic background and virus strain (7)(8)(9)(10). SINV strains with various degrees of pathogenicity for mice have been developed by passage in vitro and in vivo and by construction of recombinant viruses.…”

mentioning

confidence: 99%

“…TE12 is a recombinant SINV strain with the E1 and E2 envelope glycoproteins from NSV inserted into the Toto1101 background and has intermediate virulence, with approximately 50% mortality in adult B6 mice (10). Strains with variable virulence allow for identification of factors associated with immunopathogenesis and death as well as recovery and virus clearance (7).…”

mentioning

confidence: 99%

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

Martin

Griffin

2018

J Virol

View full text Add to dashboard Cite

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.

show abstract

Viral determinants of age-dependent virulence of Sindbis virus for mice

Cited by 95 publications

References 34 publications

Clearance of virus infection from the CNS

Clearance of virus infection from the CNS

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

Contact Info

Product

Resources

About