Mousepox in inbred mice innately resistant or susceptible to lethal infection with ectromelia virus V. Genetics of resistance to the Moscow strain

Brownstein, David G.; Bhatt, P. N.; Jacoby, Robert O.

doi:10.1007/bf01313876

Cited by 26 publications

(24 citation statements)

References 10 publications

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“…There was no difference found between males and females for virus spread or titers of virus in the organs harvested (data not shown), and the levels of virus in the male and female gonads were comparable. This observation is different from that observed with ectromelia virus-infected animals, which do exhibit a sex-dependent susceptibility (7,8). The error estimations for the viral titers at early times were large, which is reflective of significant variation in the onset of disease.…”

Section: Patterns Of Disease In Micecontrasting

confidence: 54%

Roles of Vaccinia Virus Genes E3L and K3L and Host Genes PKR and RNase L during Intratracheal Infection of C57BL/6 Mice

Rice

Turner

Embury

et al. 2011

J Virol

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The importance of the 2-5 oligoadenylate synthetase (OAS)/RNase L and double-stranded RNA (dsRNA)-dependent protein kinase (PKR) pathways in host interferon induction resulting from virus infection in response to dsRNA has been well documented. In poxvirus infections, the interactions between the vaccinia virus (VV) genes E3L and K3L, which target RNase L and PKR, respectively, serve to prevent the induction of the dsRNA-dependent induced interferon response in cell culture. To determine the importance of these host genes in controlling VV infections, mouse single-gene knockouts of RNase L and PKR and double-knockout mice were studied following intratracheal infection with VV, VV⌬K3L, or VV⌬E3L. VV caused lethal disease in all mouse strains. The single-knockout animals were more susceptible than wild-type animals, while the RNase L ؊/؊ PKR ؊/؊ mice were the most susceptible. VV⌬E3L infections of wild-type mice were asymptomatic, demonstrating that E3L plays a critical role in controlling the host immune response. RNase L ؊/؊ mice showed no disease, whereas 20% of the PKR ؊/؊ mice succumbed at a dose of 10 8 PFU. Lethal disease was routinely observed in RNase L ؊/؊ PKR ؊/؊ mice inoculated with 10 8 PFU of VV⌬E3L, with a distinct pathology. VV⌬K3L infections exhibited no differences in virulence among any of the mouse constructs, suggesting that PKR is not the exclusive target of K3L. Surprisingly, VV⌬K3L did not disseminate to other tissues from the lung. Hence, the cause of death in this model is respiratory disease. These results also suggest that an unanticipated role of the K3L gene is to facilitate virus dissemination.Small-animal (mouse) models to study poxvirus pathogenesis have been employed for decades and have provided invaluable insight into host-virus interactions and mechanistic insight as to how individual viral genes influence the host response. Infection of mice by various routes continues to be productive for study of a number of orthopoxviruses, including vaccinia virus (VV), ectromelia virus, cowpox virus, and rabbitpox virus (23, 24, 44, 45, 48-50, 67, 75, 77). The general purpose of these infected mouse studies is to provide surrogate models for human smallpox virus infection and host response to evaluate antiviral drug efficacy and the effectiveness of various smallpox vaccines. Advantages of mouse models include their relatively low cost, small size of the animals, and the fact that there are many mouse mutant strains available for genes that control responses to infection.A number of routes for the initiation of poxvirus infections in mice have been studied, including intranasal (i.n.), intratracheal (i.t.), and intradermal (i.d.) (ear pinnae, footpad) routes and scarification. Other routes, such as the intracranial (i.c.) or intraperitoneal (i.p.) route, are rarely used today because they do not effectively reproduce "natural" infection conditions. Arguably, the most relevant routes of infection in terms of human disease are the i.n. and i.t. routes, because smallpox is transmitted via th...

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Section: Patterns Of Disease In Micecontrasting

confidence: 54%

Roles of Vaccinia Virus Genes E3L and K3L and Host Genes PKR and RNase L during Intratracheal Infection of C57BL/6 Mice

Rice

Turner

Embury

et al. 2011

J Virol

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“…This dose of virus consistently killed 100 percent of D 2 mice and less than 5% of B 6 mice as reported previously [5].…”

Section: Mouse Inoculationssupporting

confidence: 74%

Ectromelia virus replication in major target organs of innately resistant and susceptible mice after intravenous infection

Brownstein

Bhatt

Gras

1993

Archives of Virology

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Summary. The kinetics of ectromelia virus replication in the spleen and liver and of a/13 interferon production in the spleen were determined during the first 3 days after intravenous infection with the virulent Moscow strain in resistant C57 BL/6 and susceptible DBA/2 mice. Virus replication in the spleen as measured by assays for virus DNA and infectious centers was suppressed in C57 BL/ 6 mice relative to DBA/2 mice within the first 1 or 2 days of infection. Infectious centers increased in DBA/2 mice but not in C57 BL/6 mice. Differences in virus replication between strains were less discrete when spleens were assayed for infectious virus than when they were assayed for infectious centers because infectious centers of most C57 BL/6 mice had more infectious virus than infectious centers of DBA/2 mice. Virus replication in the liver, the major target organ, as measured by virus DNA and infectious virus assays, was suppressed in C57 BL/6 mice relative to DBA/2 mice 3 days after infection but not before that interval. The results indicate that genetic control of ectromelia virus replication begins within the first 1 or 2 days of infection in the spleen but is delayed in the liver and that genetic control is directed at the prevention of virus spread more than at virus replication.

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“…The mousepox model has been used successfully to investigate the pathogenesis of generalized viral infections, experimental epidemiology, cell-mediated immunity to viral infections, and mechanisms of genetic resistance to infection and disease expression (1)(2)(3)(4). Importantly, these investigations have shown that various strains of mice are resistant or susceptible to mousepox infection (4)(5)(6). For instance, breeds of mice most sensitive to infection are Swiss and inbred strains such as A and A͞J (both H-2 a ), BALB͞c and DBA (both H-2 d ), and C3H (H-2 k ) (6,7).…”

mentioning

confidence: 99%

Enhanced resistance in STAT6-deficient mice to infection with ectromelia virus

Mahalingam

Karupiah

Takeda

et al. 2001

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

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We inoculated BALB͞c mice deficient in STAT6 (STAT6 ؊/؊ ) and their wild-type (wt) littermates (STAT6 ؉/؉ ) with the natural mouse pathogen, ectromelia virus (EV). STAT6 ؊/؊ mice exhibited increased resistance to generalized infection with EV when compared with STAT6 ؉/؉ mice. In the spleens and lymph nodes of STAT6 ؊/؊ mice, T helper 1 (Th1) cytokines were induced at earlier time points and at higher levels postinfection when compared with those in STAT6 ؉/؉ mice. Elevated levels of NO were evident in plasma and splenocyte cultures of EV-infected STAT6 ؊/؊ mice in comparison with STAT6 ؉/؉ mice. The induction of high levels of Th1 cytokines in the mutant mice correlated with a strong natural killer cell response. We demonstrate in genetically susceptible BALB͞c mice that the STAT6 locus is critical for progression of EV infection. Furthermore, in the absence of this transcription factor, the immune system defaults toward a protective Th1-like response, conferring pronounced resistance to EV infection and disease progression.

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Mousepox in inbred mice innately resistant or susceptible to lethal infection with ectromelia virus V. Genetics of resistance to the Moscow strain

Cited by 26 publications

References 10 publications

Roles of Vaccinia Virus Genes E3L and K3L and Host Genes PKR and RNase L during Intratracheal Infection of C57BL/6 Mice

Roles of Vaccinia Virus Genes E3L and K3L and Host Genes PKR and RNase L during Intratracheal Infection of C57BL/6 Mice

Ectromelia virus replication in major target organs of innately resistant and susceptible mice after intravenous infection

Enhanced resistance in STAT6-deficient mice to infection with ectromelia virus

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