Fatal Sindbis virus infection of neonatal mice in the absence of encephalitis
- PMID: 8862401
- DOI: 10.1006/viro.1996.0508
Fatal Sindbis virus infection of neonatal mice in the absence of encephalitis
Abstract
A comparative pathogenesis study was performed in neonatal mice using a molecularly cloned laboratory variant of Sindbis strain AR339, designated TRSB, and a single-site attenuated mutant of TRSB derived by site-directed mutagenesis of the E2 glycoprotein from Ser to Arg at residue 114 (TRSBr114). TRSB caused 100% mortality with an average survival time of 3.0 +/- 0.7 days, whereas mice inoculated with TRSBr114 exhibited an attenuated disease course with 46% mortality and an extended average survival time of 7.5 +/- 3.4 days for those animals that died. Reduced virulence of TRSBr114 was characterized by delayed appearance of detectable virus, relative to TRSB, and by lower peak virus titers in both sera and brains of infected mice. TRSB infection induced very high peak serum titers of interferon alpha/beta (215,000 units/ml compared to 2100 units/ml for TRSBr114). In situ hybridization analysis demonstrated replication of TRSB in brain, but only minimal histopathological changes and no evidence of encephalitis were observed. However, extensive extraneural lesions and viral replication were found in skin, connective tissue, and muscle. Moreover, dramatic involution of the thymus and loss of hematopoietic tissues were observed in the absence of virus replication at these sites, suggesting the involvement of a systemic physiological stress response in TRSB infection. TRSBr114 infection did not cause thymic lesions. Otherwise, the attenuated mutant demonstrated a similar pattern of tissue and organ involvement, but lesions and positive in situ hybridization signal were much more limited in scope and intensity compared to TRSB. TRSBr114-infected mice developed myositis and encephalomyelitis approximately 6 days postinfection. Therefore, TRSB-infected animals may succumb to an early syndrome associated with the stress response, preventing their survival for a time sufficient for the development of encephalitis. Alternatively, a systemic stress response, as evidenced by thymic involution, may result in immunosuppression, thus contributing to the absence of encephalitis. In any event, the attenuating mutation in the E2 glycoprotein significantly altered the course of Sindbis-induced disease by limiting virus replication and associated damage early in infection. Mutant-infected animals survived beyond Day 4 and progressed to a classical encephalomyelitis from which about half recovered.
Similar articles
-
TNFalpha, interferon, and stress response induction as a function of age-related susceptibility to fatal Sindbis virus infection of mice.Virology. 1999 Oct 25;263(2):339-48. doi: 10.1006/viro.1999.9913. Virology. 1999. PMID: 10544107
-
Sindbis virus infection of neonatal mice results in a severe stress response.Virology. 1997 Jan 6;227(1):234-8. doi: 10.1006/viro.1996.8289. Virology. 1997. PMID: 9007079
-
Infection of neonatal mice with sindbis virus results in a systemic inflammatory response syndrome.J Virol. 1999 Dec;73(12):10387-98. doi: 10.1128/JVI.73.12.10387-10398.1999. J Virol. 1999. PMID: 10559357 Free PMC article.
-
Pathogenesis of Semliki Forest virus encephalitis.J Neurovirol. 2002 Dec;8 Suppl 2:66-74. doi: 10.1080/135502802901068000. J Neurovirol. 2002. PMID: 12491154 Review.
-
The role of antibody in recovery from alphavirus encephalitis.Immunol Rev. 1997 Oct;159:155-61. doi: 10.1111/j.1600-065x.1997.tb01013.x. Immunol Rev. 1997. PMID: 9416509 Review.
Cited by
-
Macromolecular Synthesis Shutoff Resistance by Myeloid Cells Is Critical to IRF7-Dependent Systemic Interferon Alpha/Beta Induction after Alphavirus Infection.J Virol. 2019 Nov 26;93(24):e00872-19. doi: 10.1128/JVI.00872-19. Print 2019 Dec 15. J Virol. 2019. PMID: 31578290 Free PMC article.
-
Characterization of chikungunya virus induced host response in a mouse model of viral myositis.PLoS One. 2014 Mar 25;9(3):e92813. doi: 10.1371/journal.pone.0092813. eCollection 2014. PLoS One. 2014. PMID: 24667237 Free PMC article.
-
Rational design of a live-attenuated eastern equine encephalitis virus vaccine through informed mutation of virulence determinants.PLoS Pathog. 2019 Feb 11;15(2):e1007584. doi: 10.1371/journal.ppat.1007584. eCollection 2019 Feb. PLoS Pathog. 2019. PMID: 30742691 Free PMC article.
-
Increased immunogenicity of a DNA-launched Venezuelan equine encephalitis virus-based replicon DNA vaccine.J Virol. 2007 Dec;81(24):13412-23. doi: 10.1128/JVI.01799-07. Epub 2007 Oct 3. J Virol. 2007. PMID: 17913817 Free PMC article.
-
Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion.J Exp Med. 2016 Dec 12;213(13):2931-2947. doi: 10.1084/jem.20160303. Epub 2016 Nov 29. J Exp Med. 2016. PMID: 27899441 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources