Protective and Pathologic Roles of the Immune Response to Mouse Hepatitis Virus Type 1: Implications for Severe Acute Respiratory Syndrome

Khanolkar, Aaruni; Hartwig, Stacey M.; Haag, Brayton A.; Meyerholz, David K.; Epping, Lecia L.; Haring, Jodie S.; Varga, Steven M.; Harty, John T.

doi:10.1128/jvi.00355-09

Cited by 46 publications

(93 citation statements)

References 89 publications

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“…Interestingly, infection by MHV 2 days prior to PR8 also reduced the severity of PR8 infection. Unlike RV, MHV causes morbidity and mortality in mice, though virulence depends on the mouse strain (30,31,59). We have observed dose-dependent severity of MHV in BALB/c mice.…”

Section: Discussionmentioning

confidence: 69%

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

González

Ijezie

Balemba

et al. 2018

J Virol

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Influenza viruses and rhinoviruses are responsible for a large number of acute respiratory viral infections in human populations and are detected as copathogens within hosts. Clinical and epidemiological studies suggest that coinfection by rhinovirus and influenza virus may reduce disease severity and that they may also interfere with each other's spread within a host population. To determine how coinfection by these two unrelated respiratory viruses affects pathogenesis, we established a mouse model using a minor serogroup rhinovirus (rhinovirus strain 1B [RV1B]) and mouse-adapted influenza A virus (A/Puerto Rico/8/1934 [PR8]). Infection of mice with RV1B 2 days before PR8 reduced the severity of infection by a low or medium, but not high, dose of PR8. Disease attenuation was associated with an early inflammatory response in the lungs and enhanced clearance of PR8. However, coinfection by RV1B did not reduce PR8 viral loads early in infection or inhibit replication of PR8 within respiratory epithelia or Inflammation in coinfected mice remained focal compared to diffuse inflammation and damage in the lungs of mice infected by PR8. The timing of RV1B coinfection was a critical determinant of protection, suggesting that sufficient time is needed to induce this response. Finally, disease attenuation was not unique to RV1B: dose-dependent coinfection by a murine coronavirus (mouse hepatitis virus strain 1 [MHV-1]) also reduced the severity of PR8 infection. Unlike RV1B, coinfection with MHV-1 reduced early PR8 replication, which was associated with upregulation of beta interferon (IFN-β) expression. This model is critical for understanding the mechanisms responsible for influenza disease attenuation during coinfection by unrelated respiratory viruses. Viral infections in the respiratory tract can cause severe disease and are responsible for a majority of pediatric hospitalizations. Molecular diagnostics have revealed that approximately 20% of these patients are infected by more than one unrelated viral pathogen. To understand how viral coinfection affects disease severity, we inoculated mice with a mild viral pathogen (rhinovirus or murine coronavirus), followed 2 days later by a virulent viral pathogen (influenza A virus). This model demonstrated that rhinovirus can reduce the severity of influenza A virus, which corresponded with an early but controlled inflammatory response in the lungs and early clearance of influenza A virus. We further determined the dose and timing parameters that were important for effective disease attenuation and showed that influenza disease is also reduced by coinfection with a murine coronavirus. These findings demonstrate that coinfecting viruses can alter immune responses and pathogenesis in the respiratory tract.

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Section: Discussionmentioning

confidence: 69%

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

González

Ijezie

Balemba

et al. 2018

J Virol

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“…In the preliminary experiments, a subjective mouse wellness score (25) was worse in the first 2 days for the LPS groups, but was essentially the same for all groups from day 4 to day 7 (data not shown). Additionally, although the mice lost weight over the first 48 -72 h, by the end of the observation period Measurements performed at time of harvest (48 h) demonstrate that creatinine was significantly higher in both AKI groups vs. respective controls (PBS and LPS).…”

Section: Expression Of Mcp-1 Increases In Aki and Alimentioning

confidence: 83%

Antecedent acute kidney injury worsens subsequent endotoxin-induced lung inflammation in a two-hit mouse model

Basu

Donaworth²,

Wheeler³

et al. 2011

American Journal of Physiology-Renal Physiology

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Acute kidney injury (AKI) contributes greatly to morbidity and mortality in critically ill adults and children. Patients with AKI who subsequently develop lung injury are known to suffer worse outcomes compared with patients with lung injury alone. Isolated experimental kidney ischemia alters distal lung water balance and capillary permeability, but the effects of such an aberration on subsequent lung injury are unknown. We present a clinically relevant two-hit murine model wherein a proximal AKI through bilateral renal ischemia (30 min) is followed by a subsequent acute lung injury (ALI) via intratracheal LPS endotoxin (50 g at 24 h after surgery). Mice demonstrated AKI by elevation of serum creatinine and renal histopathological damage. Mice with ALI and preexisting AKI had increased lung neutrophilia in bronchoalveolar lavage fluid and by myeloperoxidase activity over Sham-ALI mice. Additionally, lung histopathological damage was greater in ALI mice with preexisting AKI than Sham-ALI mice. There was uniform elevation of monocyte chemoattractant protein-1 in kidney, serum, and lung tissue in animals with both AKI and ALI over those with either injury alone. The additive lung inflammation after ALI with antecedent AKI was abrogated in MCP-1-deficient mice. Taken together, our two-hit model demonstrates that kidney injury may prime the lung for a heightened inflammatory response to subsequent injury and MCP-1 may be involved in this model of kidney-lung cross talk. The model holds clinical relevance for patients at risk of lung injury after ischemic injury to the kidney.

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“…Subsequent publications have confirmed that variable sensitivity to MHV-1 infection is a consequence of the innate and adaptive immune responses (Khanolkar et al, 2009a) and that MHV infection inhibits IFN production (Zhou and Perlman, 2007). Notably, MHV-1-specific T and B cell responses exert protective effects that minimize morbidity in C57Bl/6 mice (Khanolkar et al, 2009a). Given the contribution of innate and adaptive immune responses to morbidity in MHV-1 infection of C57Bl/6 mice and the accumulating data that WAP proteins influence susceptibility to infection, employing ps20 +/+ and ps20 À/À C57Bl/6 mice we examined the effects of ps20 on the immune response to MHV-1 infection.…”

Section: Introductionmentioning

confidence: 92%

“…A/J mice are more susceptible to MHV-1 infection compared to C57Bl/6 mice (Albuquerque et al, 2006;Khanolkar et al, 2009a). To assess the role of ps20 in MHV-1 infection of A/J mice, mice were pre-treated with the anti-ps20 FAb fragmented antibody IG7 at either 2 or 6 h prior to MHV-1 infection.…”

Section: Ps20 Confers Protection From Mhv-1 Infection In Vivomentioning

confidence: 99%

“…In an earlier report we described a mouse model of respiratory MHV-1 infection, wherein A/J mice are more susceptible to intranasal respiratory MHV-1 infection than C57Bl/6 mice, associated with differences in the host innate immune response, specifically the interferon (IFN) response (Albuquerque et al, 2006;Baig and Fish, 2008). Subsequent publications have confirmed that variable sensitivity to MHV-1 infection is a consequence of the innate and adaptive immune responses (Khanolkar et al, 2009a) and that MHV infection inhibits IFN production (Zhou and Perlman, 2007). Notably, MHV-1-specific T and B cell responses exert protective effects that minimize morbidity in C57Bl/6 mice (Khanolkar et al, 2009a).…”

Section: Introductionmentioning

confidence: 98%

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WFDC1/ps20: A host factor that influences the neutrophil response to murine hepatitis virus (MHV) 1 infection

et al. 2012

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The whey acidic protein family member, WFDC1/ps20 is a permissivity factor in HIV infection. Herein we describe a contrasting role for ps20 in limiting MHV-1 infection. Intranasal MHV-1 infection produces a respiratory infection in mice. Using ps20 knockout mice we provide evidence that intranasal MHV-1 infection results in increased lung viral titers in ps20(-/-) compared to ps20(+/+) mice. Accompanying MHV-1 infection we observe an increase in the number of neutrophils infiltrating the BAL and an increase in the percentage of neutrophils in the lung draining lymph nodes of ps20(-/-) compared with ps20(+/+) mice. Gene expression levels for the neutrophil chemoattractants CXCL1 and CXCL2 are elevated in the lungs of ps20(-/-) mice post-MHV-1 infection. Characterization of the immune cell profile in naïve ps20(-/-) mice revealed an increase in circulating neutrophils compared to ps20(+/+) mice. No notable differences in other immune cell profiles were observed between the ps20(+/+) and ps20(-/-) mice. Accordingly, we examined MHV-1 infection of neutrophils and provide evidence that neutrophils isolated from ps20(-/-) mice are more susceptible to MHV-1 infection than neutrophils isolated from ps20(+/+) mice. These data suggest roles for ps20 in regulating expression of neutrophil-specific chemotactic factors, thereby potentially modulating neutrophil migration, and in modulating neutrophil susceptibility to MHV-1 infection.

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Protective and Pathologic Roles of the Immune Response to Mouse Hepatitis Virus Type 1: Implications for Severe Acute Respiratory Syndrome

Cited by 46 publications

References 89 publications

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

Attenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse Model

Antecedent acute kidney injury worsens subsequent endotoxin-induced lung inflammation in a two-hit mouse model

WFDC1/ps20: A host factor that influences the neutrophil response to murine hepatitis virus (MHV) 1 infection

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