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Dissertation
Genetic determinants of susceptibility to herpes simplex virus encephalitis in the murine host
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2011
DOI:
https://doi.org/10.17918/00009362
Abstract
Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen. This double-stranded DNA virus commonly infects people, but only rarely causes a severe life-threatening encephalitis. The host innate immune system initiates the early response to infection and is crucial for protection from herpes simplex encephalitis (HSE) in both the murine and human host. Toll-like receptors (TLRs) are pattern recognition receptors that are activated in response to conserved pathogen motifs. A role for HSV-1 ligation of TLRs 2, 3, and 9 has been observed with stimulation of these pathways providing protection and inhibition leading to susceptibility to infection. Like TLRs 2 and 3, TLR7 senses nucleic acids in the endosome; however, a role for this receptor has not been established in HSV-1 infection. Here we show that murine susceptibility to HSE is dependent on TLR7 dose. We infected B6. Yaa mice bearing two genomic copies of TLR7, wild-type B6 mice with one copy of TLR7, and B6. TLR7 -/Y mice with no copies of TLR7 both peripherally in the footpad and intracranially. B6. Yaa mice were resistant, B6 mice exhibited an intermediate phenotype, and B6. TLR7-/Y mice were susceptible to these infections. Surprisingly, the Yaa-mediated protection that we observed was not associated with decreased viral load, but was associated with a decreased early inflammatory response. This is the first example of natural TLR7 overexpression providing protection from an infectious agent. Upon activation of pattern recognition receptors, interferons are produced and exert antiviral effects. Tyrosine kinase 2 (Tyk2) is an adaptor molecule that transduces signals from the type I interferon receptor into the cell. We utilized mice with different alleles of Tyk2 to assess the effect of diminished signaling through this pathway on HSE susceptibility. Mice bearing the mutant Tyk2 allele were susceptible to HSE at doses ranging from 1 x 10 6 PFU to 1 x 107 PFU, while mice bearing the wild-type allele were more resistant at these same doses. Thus, a single nucleotide change is sufficient to increase HSV induced mortality. These data demonstrate the importance of the innate immune system and control of inflammation on susceptibility to HSE.
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Details
- Title
- Genetic determinants of susceptibility to herpes simplex virus encephalitis in the murine host
- Creators
- Angela Richardson
- Contributors
- Elizabeth P. Blankenhorn (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiii, 164 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021889085304721