The recent unprecedented spread and severe pathogenic features of Zika virus in the Americas have highlighted this emerging pathogen as a major threat to global public health. Substantial efforts have been devoted to examining novel aspects of Zika virus transmission and pathogenesis in the Americas. However, these studies are limited by the lack of Zika virus data from Africa, where the virus was discovered over 70 years ago and is believed to have been silently circulating for decades. Due to the non-specific clinical symptoms of Zika virus infection, temporal challenges of detecting Zika virus RNA, the lack of reliable serological methods to specifically detect Zika virus antibodies, and little concern about this virus until 2014, only 11 human Zika virus infections confirmed by virus isolation or molecular detection of Zika virus RNA have been reported in Africa since its discovery in Uganda in 1947. Further, only five partial-genome sequences and one complete-genome lab-passaged isolate have been documented, all of which derive from human infections in West Africa. A more complete picture of Zika virus population-level exposure and viral genetics from Africa is needed to define the contribution of these factors to the recent emergence and pathogensis of Zika virus, as well as to address the impact of continuous circulation of Zika virus in Africa. This proposal utilizes a unique set of samples collected from two cohorts in Kenya over a 25-year period to address the hypothesis that Zika virus has been continuously circulating in East Africa. In individuals who experience symptoms characteristic of Zika virus infection (fever and/or rash), sera collected at the time of acute febrile illness as well as 2-12 months post-onset of symptoms will allow for studies of both Zika virus seroprevalence and viral genetics in Kenya. The first part of this proposal utilizes an exciting, highly-scalable serological screening approach (PhIP-seq) to identify and distinguish Zika virus-specific IgG antibody responses in non-human primates who have been experimentally infected with Zika virus or Dengue virus, an antigenically-related flavivirus. In the second part of this proposal, Kenyan sera collected 2-12 months post-onset of symptoms, when Zika virus-specific IgG antibodies should be present, will be screened using PhIP-seq to reveal the seroprevalence of Zika virus infections as well as other viral causes of acute febrile illness in these Kenyan cohorts. Lastly, the third part of this proposal will define for the first time the phylogenetic characteristics of circulating strains in Kenya by directly sequencing Zika virus RNA in Kenyan samples collected during acute febrile illness. Understanding the extent of Zika virus transmission in Kenya will link febrile illness to this emerging pathogen and better define its impact on morbidity. Findings from these studies will provide important insights into the roles of population immunity and viral genetics in the emergence and pathogenesis of Zika virus over the past decade, contribute to the development of improved point-of-care flaviviral serological diagnostics, and serve as a foundation for future work examining pathogenic outcomes of Zika virus infections in Africa.
PROJECT NARRIATIVE Recent efforts to elucidate the mechanisms that underlie Zika virus emergence and pathogenesis in the Americas are limited by a lack of data from Africa, where the virus was first discovered over 70 years ago. A more complete picture of Zika virus population-level exposure and viral genetics in Kenya will provide important insights into the contribution of these factors to Zika virus emergence, morbidity, and mortality in order to avoid continued patterns of Zika virus pathogenesis worldwide.