Genetic Control of Neuroadapted Sindbis Virus Replication in Female Mice Maps to Chromosome 2 and Associates with Paralysis and Mortality

Thach, Dzung C.; Kleeberger, Steven R.; Tucker, Pamela C.; Griffin, Diane E.

doi:10.1128/jvi.75.18.8674-8680.2001

Cited by 21 publications

(16 citation statements)

References 49 publications

(19 reference statements)

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“…Regarding host genetic factors, disease susceptibility differences between BALB/c and BALB/cBy mice have previously been identified in both neuroadapted SV and Theiler's murine encephalomyelitis virus (TMEV) infections (Nicholson et al 1994; Thach et al 2000), but the molecular basis for this difference remains unknown. The closest explanations to date include variability in the host immune response elicited in these two hosts (Nicholson et al 1994), and a still unidentified quantitative trait locus on chromosome 2 (Thach et al 2001). In our hands, the susceptibility difference between these two closely related strains lies broadly in target cell susceptibility during infection (Fig.…”

Section: Discussionmentioning

confidence: 99%

Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development

et al. 2014

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While alphaviruses spread naturally via mosquito vectors, some can also be transmitted as aerosols making them potential bioterrorism agents. One such pathogen, western equine encephalitis virus (WEEV), causes fatal human encephalitis via multiple routes of infection and thus presumably via multiple mechanisms. Although WEEV also produces acute encephalitis in non-human primates, a small animal model that recapitulates features of human disease would be useful for both pathogenesis studies and to evaluate candidate antiviral therapies. We have optimized conditions to infect mice with a low passage isolate of WEEV, thereby allowing detailed investigation of virus tropism, replication, neuroinvasion, and neurovirulence. We find that host factors strongly influence disease outcome, and in particular that age, gender and genetic background all have significant effects on disease susceptibility independent of virus tropism or replication within the central nervous system. Our data show that experimental variables can be adjusted in mice to recapitulate disease features known to occur in both non-human primates and humans, thus aiding further study of WEEV pathogenesis and providing a realistic therapeutic window for antiviral drug delivery.

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Section: Discussionmentioning

confidence: 99%

Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development

et al. 2014

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“…However, the specific genes involved in susceptibility have been identified for only several viruses (6,13,22,24,28,36). There have been few studies on susceptibility to human viruses and none on susceptibility to human adenoviruses.…”

Section: Qtl Analysis For Identification Of Mav-1 Susceptibility Genementioning

confidence: 99%

“…There have been a number of studies on mouse susceptibility to animal viruses (reviewed in reference 3), including retroviruses (1, 2, 17, 34), poxviruses (10), polyomaviruses (23,37), herpesviruses (11), flaviviruses (24,28), alphaviruses (35,36), and rhabdoviruses (19). However, the specific genes involved in susceptibility have been identified for only several viruses (6,13,22,24,28,36).…”

Section: Qtl Analysis For Identification Of Mav-1 Susceptibility Genementioning

confidence: 99%

Identification of Quantitative Trait Loci for Susceptibility to Mouse Adenovirus Type 1

Welton

Chesler

Sturkie

et al. 2005

J Virol

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Adenoviruses cause 5 to 10% of respiratory illnesses in children and are associated with acute pneumonia in children in developing countries, where the viruses are a major cause of illness and death (21). Five to 15% of pediatric bone marrow transplant patients develop adenovirus infections; morbidity ranges from 50 to 80% (8,9,12,16,27,38). However, very little is known about adenovirus pathogenesis, especially contributions of host factors to disease susceptibility. Mouse adenovirus type 1 (MAV-1) provides an excellent model for studying susceptibility to infectious disease because it can be studied in the natural host.Inbred strains of mice with different susceptibilities to MAV-1 infection have been identified previously (14,33). SJL/J mice are highly susceptible to MAV-1 infection, with a 50% lethal dose (LD 50 ) more than 4 log units lower than those for other strains of mice, including C3H/HeJ, BALB/cJ, 129/J, and C57BL/6J (33). In vivo studies with immunodeficient mice have demonstrated the importance of innate and adaptive immunity in response to MAV-1 infections. The presence of T cells contributes to immunopathology during the acute phase of infection and to clearance of virus in long-term infection (25). B cell-deficient mice are highly susceptible to MAV-1 infections and die very early, at 6 to 9 days postinfection (p.i.), of a disseminated infection (26). T cell-independent production of neutralizing antiviral immunoglobulin M is a critical factor for control of MAV-1 infection. Infection of primary cells of susceptible and resistant mice ex vivo gives equivalent yields of virus, and sublethal irradiation renders resistant mice susceptible (33). These results suggest that host immune response factors play a role in susceptibility to MAV-1.We have compared the adaptive immune responses that have been characterized as being important for control of MAV-1 infection (25, 26), as well as NK cell function and induction of cytokines and chemokines by infection, in susceptible and resistant mice (A. Welton and K. Spindler, unpublished data). To date, we have not identified physiological differences between susceptible and resistant strains have been identified by using these approaches. In this report, we show that MAV-1 susceptibility is linked to mouse chromosome 15 (Chr 15) and unlinked to the H-2 major histocompatibility locus. We used a genomewide search strategy, quantitative trait locus (QTL) detection, to identify host factors associated with susceptibility to MAV-1. This method is advantageous because it does not require prior hypotheses of the pathogenic mechanism and can therefore reveal novel pathways. We measured the susceptibility phenotypes of 192 backcross progeny. The analysis identified a major QTL on distal Chr 15 with a highly significant logarithm of odds (LOD) score of 21.2 and a minor QTL on Chr 5 with a suggestive LOD score of 1.2, based on 5,000 permutations of the mapping analysis. A LOD score of 21 means that the odds are 10 21 :1 in favor of linkage. The Chr 15 locus alone accou...

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“…Because CD-1 mice are outbred, we also assessed virulence of these viruses in C57BL/6 mice known to be particularly susceptible to SINV encephalomyelitis (Fig. 4E) (54,55). In 3-week-old C57BL/6 mice, both E2 mutant viruses were more virulent than TE12, with 43% mortality for mice infected with the E2-196 mutant and 77% mortality for mice infected with the E2-318 mutant, in comparison to 14% mortality for mice infected with TE12 (P ϭ 0.0026).…”

Section: Virion Infectivitymentioning

confidence: 99%

Role of N-Linked Glycosylation for Sindbis Virus Infection and Replication in Vertebrate and Invertebrate Systems

Knight

Schultz

Kent

et al. 2009

J Virol

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). In the current study, the effects of altered glycosylation on virion infectivity, growth in cells of vertebrates and invertebrates, heparin binding, virulence in mice, and replication in mosquitoes were assessed. Particle-to-PFU ratios for E1-139 and E2-196 mutant strains were similar to that for TE12, but this ratio for the E1-245 mutant was 100-fold lower than that for TE12. Elimination of either E2 glycosylation site increased virus binding to heparin and increased replication in BHK cells. Elimination of either E1 glycosylation site had no effect on heparin binding but resulted in an approximately 10-fold decrease in virus yield from BHK cells compared to the TE12 amount. No differences in pE2 processing were detected. E2-196 and E2-318 mutants were more virulent in mice after intracerebral inoculation, while E1-139 and E1-245 mutants were less virulent. The E1-245 mutant showed impaired replication in C7/10 mosquito cells and in Culex quinquefasciatus after intrathoracic inoculation. We conclude that the increased replication and virulence of E2-196 and E2-318 mutants are primarily due to increased efficiency of binding to heparan sulfate on mammalian cells. Lack of glycosylation at E1-139 or E1-245 impairs replication in vertebrate cells, while E1-245 also severely affects replication in invertebrate cells.Sindbis virus (SINV), the prototype alphavirus in the family Togaviridae, is an arthropod-borne virus that cycles between mosquitoes and wild birds and causes summertime outbreaks of rashes and arthritis in humans (17, 34). In mice, SINV causes encephalomyelitis and serves as a useful model for the study of alphavirus infections of the central nervous system (CNS). The virion is enveloped and has icosahedral symmetry, with a single linear strand of positive-sense RNA surrounded by a capsid and two transmembrane glycoproteins, E1 and E2, that heterodimerize and then form trimeric spikes on the surface. Each of the viral glycoproteins has two N-linked glycosylation sites at E1 positions 139 and 245 (E1-139 and E1-245) and at E2 positions 196 and 318 (E2-196 and E2-318) that are used (4, 42). Some glycosylation is required for proper folding and transport of the glycoproteins, as total ablation of glycosylation by treatment with tunicamycin results in failure of E1 and E2 to be transported through the Golgi apparatus to the cell surface (31, 32).The type of carbohydrate, high-mannose carbohydrate or complex oligosaccharide, at a glycosylation site varies with the type and growth state of the cell infected (3,18,23,28,29,35,51). In insect cells, all sites have high-mannose sugars (22) due to the absence of N-acetylglucosaminyl-, galactosyl-, and sialyltransferases (5). In vertebrate cells, the distribution of complex and high-mannose carbohydrates is largely determined by the accessibility of the site to processing enzymes in the Golgi apparatus (23).E1 has an extracellular domain that contains the internal fusion peptide. The carbohydrate at E1-139 consists of complex oligosaccharides in vertebrate cell...

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Genetic Control of Neuroadapted Sindbis Virus Replication in Female Mice Maps to Chromosome 2 and Associates with Paralysis and Mortality

Cited by 21 publications

References 49 publications

Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development

Manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development

Identification of Quantitative Trait Loci for Susceptibility to Mouse Adenovirus Type 1

Role of N-Linked Glycosylation for Sindbis Virus Infection and Replication in Vertebrate and Invertebrate Systems

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