Viruses are adept at immune evasion. For example, they can block specific steps in MHC class I (MHC-I) biosynthesis to thwart cytotoxic T lymphocytes (CTLs). However, host natural killer (NK) cells are better able to kill targets lacking MHC-I, a host fail-safe mechanism described by the missing-self hypothesis which has not been tested during an infection. On the other hand, viruses encode molecules that block NK cell activation by either enhancing the action of MHC-l-specific NK cell inhibitory receptors or blocking the action of NK cell activation receptors, such as NKG2D, which recognizes "stress"-induced ligands. This "arms" race between the pathogen and the host deserves further study because it illuminates how the immune system works in limiting pathogen invasion. In the last funding period, the Yokoyama laboratory collaborated with the Buller laboratory to show that NK cells were important in controlling poxvirus infection. In addition, they initiated studies on cowpox virus (CPXV) that is endemic in rodents. They showed that CPXV uses two open reading frames (ORFs) to down-regulate MHC-I expression. On the other hand, in collaboration with the Carayannopoulos laboratory, they showed that CPXV also encodes a molecule which blocks NKG2Dmediated activation. These findings provide an opportunity to test the missing-self hypothesis in the context of a viral infection. Finally, the poxviruses are distinguished by encoding a large number of other genes that are dispensable for viral growth and replication in vitro;most of these genes probably encode molecules that interact with the host to evade immune reactions. Therefore, the specific aims of this proposal are to: 1) Study viral mechanisms for MHC-I down-regulation. 2) Test the "missing-self" hypothesis by ascertaining the effect of MHC-I down-regulation and/or NKG2D inhibitor on innate and adaptive immune responses during in vivo infections. 3) Explore other viral strategies to evade innate immune responses. Thus, these studies on viral immune evasion will illuminate innate host immune response mechanisms responsible for viral control and will be done in collaboration with Drs. Carayannopoulos and Daved Fremont, among others in the MRCE.
Viruses are adept at evading the host's immune system. By better understanding viral immune evasion, we will gain a greater appreciation for how the immune system works, what are the most important immune components, and how to counteract viral subversion.
|Bandyopadhyay, Sarmistha; Long, Matthew E; Allen, Lee-Ann H (2014) Differential expression of microRNAs in Francisella tularensis-infected human macrophages: miR-155-dependent downregulation of MyD88 inhibits the inflammatory response. PLoS One 9:e109525|
|Virgin, Herbert W (2014) The virome in mammalian physiology and disease. Cell 157:142-50|
|Bialasiewicz, Seweryn; McVernon, Jodie; Nolan, Terry et al. (2014) Detection of a divergent Parainfluenza 4 virus in an adult patient with influenza like illness using next-generation sequencing. BMC Infect Dis 14:275|
|Rasmussen, Jed A; Post, Deborah M B; Gibson, Bradford W et al. (2014) Francisella tularensis Schu S4 lipopolysaccharide core sugar and O-antigen mutants are attenuated in a mouse model of tularemia. Infect Immun 82:1523-39|
|Patel, Dhara A; Patel, Anand C; Nolan, William C et al. (2014) High-throughput screening normalized to biological response: application to antiviral drug discovery. J Biomol Screen 19:119-30|
|Rohatgi, Anjali; Corbo, Joseph C; Monte, Kristen et al. (2014) Infection of myofibers contributes to increased pathogenicity during infection with an epidemic strain of chikungunya virus. J Virol 88:2414-25|
|Ermler, Megan E; Traylor, Zachary; Patel, Krupen et al. (2014) Rift Valley fever virus infection induces activation of the NLRP3 inflammasome. Virology 449:174-80|
|Moorman, Nathaniel J; Murphy, Eain A (2014) Roseomics: a blank slate. Curr Opin Virol 9:188-93|
|Canny, Susan P; Reese, Tiffany A; Johnson, L Steven et al. (2014) Pervasive transcription of a herpesvirus genome generates functionally important RNAs. MBio 5:e01033-13|
|Barker, Jason H; Kaufman, Justin W; Zhang, De-Sheng et al. (2014) Metabolic labeling to characterize the overall composition of Francisella lipid A and LPS grown in broth and in human phagocytes. Innate Immun 20:88-103|
Showing the most recent 10 out of 257 publications