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"The F-box protein Fbp1 shapes the immunogenic potential of Cryptococcus neoformans"

by
Jorge A. Masso-Silva
Infection, Immunity and Inflammation Program
M.S, 2010, Centro de Investigaciones Biologicas del Noroeste, Mexico
B.S. 2007, Universidad Autonoma de Baja California Sur, Mexico


Thesis Advisor: Amariliz Rivera, PhD
Assistant Professor
Department of Pediatrics
Center for Immunity and Inflammation

Friday, December 1, 2017
1:00 P.M., Cancer Center, G-1196


Abstract

Cryptococcus neoformans is the main etiological agent of Cryptococcal meningitis and causes over 250,000 infections per year. The vast majority of cryptococcal infections occur in patients with compromised immune function. Although it is well appreciated that adaptive immunity and CD4+ T cells are crucial for defense against cryptococcosis, our understanding of factors that control the development of effective immunity to this fungus is incomplete. In previous studies the F-box protein Fbp1 was identified as a novel determinant of C. neoformans virulence. Deletion of Fbp1 (fbp1ƒ´) in the highly virulent H99 serotype A strain resulted in an hypovirulent phenotype in vivo such that 100% of mice infected with fbp1ƒ´ survived the infection. In this study we uncovered that the hypovirulence of fbp1ƒ´ yeast is linked to the development of a robust host immune response. Infection with fbp1ƒ´ promoted the increased differentiation of Th1 and Th17 cells and lower Th2 responses as compared to the parental strain H99. Infection with fbp1ƒ´ also induced the rapid influx of CCR2+ monocytes and their differentiation into monocyte-derived dendritic cells (mo-DCs). Depletion of CCR2+ monocytes and their derivative mo-DCs resulted in impaired activation of a protective inflammatory response and the rapid mortality of mice infected with fbp1ƒ´. Mice lacking B and T cells also developed fungal meningitis and succumbed to infection with fbp1ƒ´ thus demonstrating that adaptive immune responses against fbp1ƒ´ help to maintain the long-term survival of the host. Moreover, we find that the enhanced immunogenicity of fbp1ƒ´ yeast cells can be harnessed to confer protection against a subsequent infection with the virulent H99 parental strain. Vaccine-induced protection was dependent on lymphocytes and IFN£^. Altogether, our findings suggest that Fbp1 functions as a novel virulence factor that shapes the immunogenicity of C. neoformans.


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