Epidemiology and Immunopathogenesis of Ebola and Flaviviruses

Abstract

The spillover of emerging viruses into human populations continuously threatens public health. From 2013-2016, Ebola virus (EBOV) caused an explosive outbreak in West Africa with more than 28,000 cases, 11,000 of which were fatal. Simultaneously, from 2015-2016, Asian Zika virus (ZIKV) caused an unprecedented epidemic wave with an estimated 1.5 million infections and associated neuropathology throughout dengue virus (DENV) endemic regions of the Americas and the Caribbean. In response to these outbreaks, we employed seroepidemiological techniques and utilized a modified anthrax toxin delivery system to study the antibody and T cell responses in individuals infected or exposed to EBOV, African and Asian ZIKV, and DENV. Prior to the 2015-2016 outbreak, the incidence of ZIKV in Africa had not been evaluated and the prevalence estimates for DENV were scarce. We showed continued human transmission of ZIKV and DENV and phylogenetic analysis revealed evidence for distinct African ZIKV strains circulating in West Africa for decades. T cell analysis demonstrated that individuals mount sustained specific and cross-reactive responses to nonstructural protein 3 (NS3) during the acute and late convalescent phases. Development of a T cell diagnostic based on responses to NS3 distinguishes human infections by African ZIKV and DENV. We confirmed this finding in human immunodeficiency virus (HIV)-infected and uninfected individuals from Salvador, Brazil. We also showed that HIV-infection is associated with T cell responses that are lower in magnitude to ZIKV and DENV proteins. These findings fill a critical knowledge gap in the epidemiological research on ZIKV/DENV in Africa and have important implications for vaccine and diagnostic development. Serological surveys conducted after the 2013-2016 EBOV outbreak revealed that a significant portion of transmission events went undetected because some individuals contracted infection with few if any symptoms. While several hypotheses could explain this phenomenon, including properties of the infecting virus, low inoculum, route of transmission, or various host factors, a robust immune response is also a potential explanation. We identified EBOV antibody-positive individuals from Lagos, Nigeria and the Democratic Republic of Congo who had not experienced Ebola virus disease (EVD)-like illness. We showed that the seropositive asymptomatic individuals from Lagos had virus-specific T cell responses to the nucleoprotein, matrix protein, and glycoprotein that were greater in magnitude when compared to survivors of severe EVD. These findings suggest that T cell immunity may protect against severe EVD, which has important implications for understanding the immunopathogenesis of EVD and EBOV vaccine development.