Immune correlates of protection from Rift Valley fever virus



 DESCRIPTION (provided by applicant): Candidate: I hold an MD/PhD and am a pediatric infectious disease physician and basic scientist. Every step in my career journey has been focused towards the goal of becoming a physician scientist. I am at the beginning of my first faculty appointment, and find that this time is a unique one in which I have the opportunity to broaden my skills in the area of immunology. My main goal during the time of the K08 award is to develop expertise in state of the art experimental immunology. I will achieve this via didactic instruction, accompanied by mentorship from several virologists and immunologists in the context of the proposed research project examining the role of CD4 T cells in preventing Rift Valley fever virus encephalitis. My primary mentor, Paul Spearman, MD, is a viral immunologist as well as a physician scientist and my division director. As a career and science mentor, he will guide my research progress over the time of the award, facilitate advisory committee meetings, and provide career development assistance including R01 proposal development and review. In the next 5 years I plan to capitalize on these newly gained skills to establish myself as an expert in studies of the interaction between host immune responses and emerging viruses. Environment: My appointment is in the Division of Pediatric Infectious Disease, Department of Pediatrics in the Emory University School of Medicine. The Department of Pediatrics at Emory is ranked ninth in the 2014 NIH rankings for Departments of Pediatrics for NIH based funding. This Department has an established track record of supporting junior physician scientists. There are numerous resources available to me at Emory for both research and career development. The experiments will be performed in the BSL-3E space at the US Centers for Disease Control and Prevention, where I hold a guest researcher appointment in the Viral Special Pathogens Branch and will have the expert mentorship and support from Christina Spiropoulou, PhD, team lead. Research: Rift Valley fever virus (RVFV) is a mosquito borne virus that causes disease in people and animals in Africa and the Middle East. In the past few years several new live attenuated vaccines have become available for use in livestock. The basis of attenuation for all of these vaccines is the deletion/modification of the viral virulence factor, NSs. These Del NSs viruses generate a protective immune response in animals, in that vaccinated animals are protected from challenge with wild-type virus. However, until recently, little was known about which specific components of the immune response were important for this protection. We reported that mice that were depleted of their CD4 T cells developed encephalitis following infection with the Del NSs virus, suggesting that some function of the CD4 T cell was important for providing protection from this virus. In this proposal, we will first determine the mechanism (viral vs. immune mediated) of Del NSs encephalitis in the CD4 depleted mice. Then, since there are at least 5 different types of CD4 T cells with various roles, we will characterize the CD4 T cell subsets that are activated and functional during Del NSs infection and begin to examine each subset individually to determine how they contribute to protection from encephalitis. Finally the role of B cells and antibodies in protection from encephalitis will be defined. These experiments will establish correlates of immunity against RVFV in the mouse model. These data will be used to design future studies targeted at examining immune correlates of protection in humans.