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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Stevenson, Taylor C; Cywes-Bentley, Colette; Moeller, Tyler D et al. (2018) Immunization with outer membrane vesicles displaying conserved surface polysaccharide antigen elicits broadly antimicrobial antibodies. Proc Natl Acad Sci U S A 115:E3106-E3115
Kinkead, Lauren C; Whitmore, Laura C; McCracken, Jenna M et al. (2018) Bacterial lipoproteins and other factors released by Francisella tularensis modulate human neutrophil lifespan: Effects of a TLR1 SNP on apoptosis inhibition. Cell Microbiol 20:
Kinkead, Lauren C; Fayram, Drew C; Allen, Lee-Ann H (2017) Francisella novicida inhibits spontaneous apoptosis and extends human neutrophil lifespan. J Leukoc Biol 102:815-828
Zhao, Guoyan; Wu, Guang; Lim, Efrem S et al. (2017) VirusSeeker, a computational pipeline for virus discovery and virome composition analysis. Virology 503:21-30
Das, Anshuman; Hirai-Yuki, Asuka; González-López, Olga et al. (2017) TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions. MBio 8:
Grinnage-Pulley, Tara; Mu, Yang; Dai, Lei et al. (2016) Dual Repression of the Multidrug E?ux Pump CmeABC by CosR and CmeR in Campylobacter jejuni. Front Microbiol 7:1097
Ulland, Tyler K; Jain, Nidhi; Hornick, Emma E et al. (2016) Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nat Commun 7:13180
Markosyan, Ruben M; Miao, Chunhui; Zheng, Yi-Min et al. (2016) Induction of Cell-Cell Fusion by Ebola Virus Glycoprotein: Low pH Is Not a Trigger. PLoS Pathog 12:e1005373
Teijaro, John R; Studer, Sean; Leaf, Nora et al. (2016) S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-? autoamplification. Proc Natl Acad Sci U S A 113:1351-6
Lubman, Olga Y; Fremont, Daved H (2016) Parallel Evolution of Chemokine Binding by Structurally Related Herpesvirus Decoy Receptors. Structure 24:57-69

Showing the most recent 10 out of 338 publications