Type I interferon (IFN) provides an initial component of innate immune resistance to viral infection and replication by inducing a large set of antiviral effector proteins capable of inhibiting diverse viruses at multiple points in the infection. Inherent to the effectiveness of this response are cellular signaling pathways that first trigger IFN gene induction in response to infection and subsequently trigger IFN-stimulated gene (ISG) expression in response to secreted IFN. IFN gene induction proceeds through two distinct pathways, a cytosolic signaling system triggered by viral nucleic acid in the cytoplasm that operates in most infected cells and a transmembrane pathway dependent on Toll-like receptor (TLR) proteins that is critical in dendritic cells. The essential nature of the IFN system in antiviral immunity has been demonstrated by genetic and biochemical data, but its ultimate effectiveness is limited by viral evasion through the action of viral virulence factors that impaire IFN action. The underlying hypothesis of our proposed research is that through better understaning the molecular mechanisms of IFN induction and action and their impairment by viral evasion, we will be able to devise novel therapeutics based on augmenting innate immunity and inhibiting viral evasion. This project focuses on three distinct viruses that each impair the IFN pathway, influenza A virus, vaccinia virus, and chikungunya virus;will analyze the interaction between viruses and IFN signaling in a unique set of genetically modified dendritic cells lines;and will develop a platform to screen for small molecule inhibitors of viral virulence. This work will be performed in close collaboration with other members of the innate immunity team, Drs. Easier, Garcia-Sastre, and Wu. This project is well integrated into the mission of the RCE. Innate immunity has emerged as an essential component of the key focus areas of the RCE, impacting on adaptive immunity and being critical for athe adjuvant effects of vaccines;providing an important diagnostic indication of infection;and uncovering a novel approach to therapeutics by targeting the interaction between the innate immune system and virulence factors. Knowledge gained in these studies will also be applicable to microbial innate immunity that relies on similar mechanisms.
Emerging and re-emerging viral diseases are a growing concern in the world. Innate immunity represents an early and essential aspect of antiviral resistance, but its effectiveness is limited by the action of viral virulence components. A better understanding of the mechanisms of innate immunity and its evasion by viruses will allow development of novel approaches to therapy and drug discovery.
|Johnson, Joshua C; Martinez, Osvaldo; Honko, Anna N et al. (2014) Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells. Antiviral Res 107:102-9|
|Gough, Daniel J; Marié, Isabelle J; Lobry, Camille et al. (2014) STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation. Blood 124:2252-61|
|Kazakov, Teymur; Kuznedelov, Konstantin; Semenova, Ekaterina et al. (2014) The RimL transacetylase provides resistance to translation inhibitor microcin C. J Bacteriol 196:3377-85|
|Rajsbaum, Ricardo; Garcia-Sastre, Adolfo; Versteeg, Gijs A (2014) TRIMmunity: the roles of the TRIM E3-ubiquitin ligase family in innate antiviral immunity. J Mol Biol 426:1265-84|
|Lo, Michael K; Bird, Brian H; Chattopadhyay, Anasuya et al. (2014) Single-dose replication-defective VSV-based Nipah virus vaccines provide protection from lethal challenge in Syrian hamsters. Antiviral Res 101:26-9|
|Mackow, Erich R; Dalrymple, Nadine A; Cimica, Velasco et al. (2014) Hantavirus interferon regulation and virulence determinants. Virus Res 187:65-71|
|Varshney, Avanish K; Wang, Xiaobo; Aguilar, Jorge L et al. (2014) Isotype switching increases efficacy of antibody protection against staphylococcal enterotoxin B-induced lethal shock and Staphylococcus aureus sepsis in mice. MBio 5:e01007-14|
|Chung, Lawton K; Philip, Naomi H; Schmidt, Valentina A et al. (2014) IQGAP1 is important for activation of caspase-1 in macrophages and is targeted by Yersinia pestis type III effector YopM. MBio 5:e01402-14|
|DiLillo, David J; Tan, Gene S; Palese, Peter et al. (2014) Broadly neutralizing hemagglutinin stalk-specific antibodies require Fc?R interactions for protection against influenza virus in vivo. Nat Med 20:143-51|
|Szaba, Frank M; Kummer, Lawrence W; Duso, Debra K et al. (2014) TNF? and IFN? but not perforin are critical for CD8 T cell-mediated protection against pulmonary Yersinia pestis infection. PLoS Pathog 10:e1004142|
Showing the most recent 10 out of 549 publications