Last data update: Sep 16, 2024. (Total: 47680 publications since 2009)
Records 1-4 (of 4 Records) |
Query Trace: Szretter KJ [original query] |
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Simvastatin and oseltamivir combination therapy does not improve the effectiveness of oseltamivir alone following highly pathogenic avian H5N1 influenza virus infection in mice
Belser JA , Szretter KJ , Katz JM , Tumpey TM . Virology 2013 439 (1) 42-6 Nonspecific anti-inflammatory drugs have been purported to reduce the burden of severe influenza disease. We demonstrate that, unlike oseltamivir administration, simvastatin administration did not reduce morbidity, mortality, or viral load of mice infected with H1N1 or H5N1 viruses. No added benefit to the efficacy of oseltamivir therapy was observed when mice were treated in combination with simvastatin. Modest reductions in lung cytokine production in H5N1 but not H1N1 virus-infected simvastatin-treated mice indicate a potential benefit for statin use in mitigating disease following severe virus infection. |
Mice lacking both TNF and IL-1 receptors exhibit reduced lung inflammation and delay in onset of death following infection with a highly virulent H5N1 virus
Perrone LA , Szretter KJ , Katz JM , Mizgerd JP , Tumpey TM . J Infect Dis 2010 202 (8) 1161-70 BACKGROUND: Highly pathogenic avian influenza viruses of the H5N1 subtype continue to cross the species barrier to infect humans and cause severe disease. It has been suggested that an exaggerated immune response contributes to the pathogenesis of H5N1 virus infection in mammals. In particular, H5N1 virus infections are associated with a high expression of the proinflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). METHODS: We investigated the compounding affects of both cytokines on the outcome of H5N1 virus disease by using triple mutant mice deficient in 3 signaling receptors, TNF-R1, TNF-R2, and IL-1-RI. RESULTS: Triple mutant mice exhibited reduced morbidity and a significant delay in mortality following lethal challenge with a lethal H5N1 virus, whereas no such differences were observed with the less virulent A/PR/8/34 (H1N1) virus. H5N1-infected triple mutant mice displayed diminished cytokine production in lung tissue and a quantifiable decrease of macrophages and neutrophils in the lungs postinfection. Moreover, morphometric analysis of airway sections revealed less extensive inflammation in H5N1-infected triple mutant mice, compared with infected wild-type mice. CONCLUSIONS: The combined signaling from the TNF or IL-1 receptors promotes maximal lung inflammation that may contribute to the severity of disease caused by H5N1 virus infection. |
Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection
Cilloniz C , Pantin-Jackwood MJ , Ni C , Goodman AG , Peng X , Proll SC , Carter VS , Rosenzweig ER , Szretter KJ , Katz JM , Korth MJ , Swayne DE , Tumpey TM , Katze MG . J Virol 2010 84 (15) 7613-24 Periodic outbreaks of highly pathogenic avian H5N1 influenza viruses, and the current H1N1 pandemic, highlight the need for a more detailed understanding of influenza virus pathogenesis. To investigate the host transcriptional response induced by pathogenic influenza viruses, we used a functional genomics approach to compare gene expression profiles in lungs from 129S6/SvEv mice infected with either the fully reconstructed H1N1 1918 pandemic virus (1918) or the highly pathogenic avian H5N1 virus Vietnam/1203/04 (VN/1203). Although both viruses reached similar titers in the lung and caused a lethal infection, the mean time of death was 6 days for VN/1203-infected animals and 9 days for mice infected with the 1918 virus. VN/1203-infected animals also exhibited an earlier and more potent inflammatory response. This response included induction of genes encoding components of the inflammasome. VN/1203 was also able to disseminate to multiple organs, including the brain, which correlated with changes in the expression of genes associated with hematological functions and lipoxin biogenesis and signaling. Both viruses elicited expression of type I interferon (IFN)-regulated genes in wild-type mice and to a lesser extent in mice lacking the type I IFN receptor, suggesting alternative or redundant pathways for IFN signaling. Our findings suggest that VN/1203 is more pathogenic in mice as a consequence of several factors, including the early and sustained induction of the inflammatory response, the additive or synergistic effects of up-regulated components of the immune response, and inhibition of lipoxin-mediated anti-inflammatory responses, which correlated with the ability of VN/1203 to disseminate to extrapulmonary organs. |
Use of animal models to understand the pandemic potential of highly pathogenic avian influenza viruses
Belser JA , Szretter KJ , Katz JM , Tumpey TM . Adv Virus Res 2009 73 55-97 It has been 40 years since the last influenza pandemic and it is generally considered that another could occur at any time. Recent introductions of influenza A viruses from avian sources into the human population have raised concerns that these viruses may be a source of a future pandemic strain. Therefore, there is a need to better understand the pathogenicity of avian influenza viruses for mammalian species so that we may be better able to predict the pandemic potential of such viruses and develop improved methods for their prevention and control. In this review, we describe the virulence of H5 and H7 avian influenza viruses in the mouse and ferret models. The use of these models is providing exciting new insights into the contribution of virus and host responses toward avian influenza viruses, virus tropism, and virus transmissibility. Identifying the role of individual viral gene products and mapping the molecular determinants that influence the severity of disease observed following avian influenza virus infection is dependent on the use of reliable animal models. As avian influenza viruses continue to cause human disease and death, animal pathogenesis studies identify avenues of investigation for novel preventative and therapeutic agents that could be effective in the event of a future pandemic. |
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