ORCID

https://orcid.org/0000-0002-7983-4985

Date of Award

Spring 5-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Viruses with large DNA genomes, such as cowpox virus, encode many open-reading frames involved in the modulation of the host immune system, facilitating escape from immune detection or downregulation of specific aspects of the host immune response. Investigation of virally-encoded immunoevasins has been instrumental in understanding host-pathogen interactions. Here, we focus on the cowpox virus immunoevasin Orthopoxvirus MHC Class I-like Protein (OMCP) and demonstrate for the first time that OMCP facilitates cowpox virus virulence in vivo. We have previously documented that OMCP binds the activating receptor NKG2D on NK cells as well as the orphan receptor FCRL5 on innate B cells. By using NKG2D-deficient, FCRL5-deficient, and wild type mice, as well as recombinant cowpox viruses lacking OMCP or expressing a mutated form of OMCP that does not bind NKG2D, we were able to delineate the impact of OMCP targeting of each receptor. We found that OMCPs virulence in vivo could largely be attributed to blocking NKG2D-mediated NK cell responses with no apparent effect due to binding to FCRL5 bearing innate B cells. Interestingly, the delay in weight recovery observed in mice surviving WT cowpox compared to OMCP-deficient cowpox infection was not observed in NKG2D-deficient mice and was abrogated in WT mice by the depletion of NK cells on day 8 post-infection. Additionally, we show that monomeric OMCP has a low affinity for FCRL5, although OMCP tetramers bind FCRL5 bearing cells well. We further demonstrate that the OMCP binding interfaces for NKG2D and FCRL5 are distinct, raising the possibility that the low affinity binding to FCRL5 may be overcome by multivalent presentation of OMCP through clustering of OMCP complexes on cells expressing NKG2D. This work delineates the impact of OMCP targeting of NKG2D and FCRL5 on cowpox virus virulence in vivo and highlights the importance of NKG2D-mediated control of orthopoxviruses.

Language

English (en)

Chair and Committee

Anthony Wayne . French Yokoyama

Committee Members

Michael Diamond, Mary Dinauer, Brian Edelson, Daved Fremont,

Comments

Permanent URL: https://doi.org/10.7936/K7F18X18

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