Date of Award
Doctor of Philosophy (PhD)
Chikungunya virus (CHIKV) is a re-emerging pathogen that causes a high fever, painful arthritis and a macular rash. The current outbreak began in Kenya in 2004 and spread throughout the Indian Ocean area and Southeast Asia, infecting millions. During this outbreak, more severe disease manifestations, including lethality, were reported for the first time. To understand one possible reason for this change in severity, we explored the impact of genetic changes in the virus on disease pathogenesis. In addition, we dissected the role of type I interferon (IFN) subtypes in CHIKV infection. From these studies, we have gained important insight into the viral and host factors that contribute to CHIKV pathogenesis.
To test if one factor contributing to the increased disease severity is genetic changes in the viral genome we compared the pathogenesis of two strains: the first from Senegal in 1983 (37997) and the second from La Reunion in 2006 (LR2006 OPY1). Neonatal mice infected with LR2006 OPY1 developed prolonged viremia, elevated viral loads in the muscle, hind limb weakness and massive myonecrosis compared to 37997-infected mice. A detailed analysis revealed that the LR2006 OPY1 strain displayed a unique ability to infect myofibers following intradermal infection. This difference in tropism appeared to be due to its ability to access the myofiber niche since both infected myofibers and established similar viral loads when given intramuscularly. Thus, LR2006 OPY1 has an enhanced ability to infect myofibers during a natural infection which contributes to severe muscle damage. Studies to identify the genetic differences responsible for the myofiber phenotype are ongoing.
Central to the control of acute CHIKV infection is the type I interferon response which induces a potent anti-viral state and modulates the immune response. To further evaluate the role of IFNs during CHIKV infection, we characterized mice lacking specific IFN subtypes. Mice lacking IFN-kappa displayed a modest increase in lethality compared to wild-type mice, and increases in viral loads late in infection, particularly in the brain. Surprisingly, IFN-kappa-/- were resistant to CHIKV-induced lethality, and had similar viral loads and proinflammatory cytokine induction as wild-type mice, suggesting the mechanism for IFN-kappa; is distinct from other IFN subtypes. Recombinant tools are being developed to further analyze the function of IFN-kappa.
Together these data provide important insight into the host factors that control pathogenesis and offer evidence that genetic differences in viral strains that alter tropism can contribute to changes in disease severity. Understanding these factors will aid in the development of future therapeutics that target CHIKV infection.
Chair and Committee
Deborah J Lenschow
Jacco Boon, Marco Colonna, Michael S Diamond, Anthony R French, Wayne M Yokoyama
Rohatgi, Anjali, "Viral and Innate Immune Factors Controlling Disease Susceptibility During Chikungunya Virus Infection" (2015). Arts & Sciences Electronic Theses and Dissertations. 490.