Biology and Biomedical Sciences: Immunology
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Wayne M Yokoyama
The orthopoxviridae are large, complex DNA viruses with important historical and clinical significance. Members of this genus encode numerous proteins known to subvert the immune response to infection, providing a useful system to probe required host responses for resistance and survival. Natural killer: NK) cells provide an essential innate response to infection through direct lysis of infected cells and cytokine production. The innate anti-viral response following infection is associated with NK cell population expansion in draining LNs, where they are normally a rare population. We have identified mechanisms underlying NK cell expansion following orthopoxviral infection and have examined viral inhibition of the NK cell-mediated host response.
Since close contact with cowpox virus: CPXV), a natural pathogen of rodents, causes zoonotic infections in humans, we employed a footpad model of infection in mice to determine the requirement of NK cells for resistance to orthopoxviral infection. Systemic depletion of NK cells prior to CPXV infection resulted in increased viral replication and systemic dissemination. Recruitment of NK cells to the draining LN was pertussis toxin sensitive indicating chemokine receptor dependence. Candidate chemokine receptors were identified by comprehensive analysis of chemokine mRNA expression in the draining LN in conjunction with chemokine receptor expression on NK cells. We determined that CXCR3 was intrinsically required for NK cell recruitment to the draining LN in an interferon-γ: IFN-γ) dependent manner. Additionally, a non-overlapping requirement for subcapsular sinus macrophages was required for NK cell recruitment.
CPXV inhibited full maturation of NK cells leading to incomplete activation following infection. We found that NK cells recruited to the draining LN did not produce IFN-γ or up-regulate surface activation markers. The inhibition of NK cell production of IFN-γ was CPXV specific, multifactorial and complex. Despite this phenotype, cytotoxic function of NK cells was preserved through uninhibited production of granzyme B. We have demonstrated that the innate response to CPXV infection induces chemokine-mediated recruitment of NK cells to the draining LN where they limit replication and dissemination despite specific inhibition by CPXV.
Pak-Wittel, Melissa Anne, "Natural Killer Cell Recruitment and Activation Following Orthopoxviral Infection" (2012). All Theses and Dissertations (ETDs). 1016.