Molecular profiling of immunity to infectious disease using human challenge models

The development of effective anti-parasite vaccines is hindered by the current lack of understanding of the mechanisms underlying immunity to parasitic infections. Martha Cooper's PhD thesis demonstrates that experimental human challenge models of parasite infection are a valuable tool to decipher molecular mechanisms of immunity to these globally significant pathogens. Extended abstract: In humans, malaria and hookworm are caused by Plasmodium and Necator or Ancylostoma species parasites, respectively, and result in severe health and socioeconomic consequences in endemic regions, predominantly in tropical areas of the world. Eradication goals for these parasites are hindered by the lack of effective and licensed vaccines. To facilitate the rational development of vaccines against malaria and hookworm, improved understanding of immune responses associated with protection against these parasites in humans is required. Controlled Human Infection (CHI), defined as the purposeful infection of volunteers with a pathogen of interest, is a valuable tool for studying the immune response to pathogen infection under controlled conditions. To define molecular immune responses to human parasitic infection, the studies presented in this thesis employed CHI models of malaria and hookworm infection in combination with a systems immunology approach that included targeted and whole transcriptome quantitation of coding and non-coding RNA molecules, immune cell quantitation, and multiplexed cytokine detection. Firstly, an algorithm was developed to ensure the accurate normalisation and analysis of targeted transcriptomic data generated using NanoString nCounter. This tool was made freely available in an open-source R package called NanoStringClustR which may be obtained at gitub.com/MarthaCooper/NanoStringClustR. Secondly, a blood-stage controlled human malaria infection (CHMI) model was used to define and compare coding and non-coding transcriptomic responses to P. vivax and P. falciparum infection in previously naïve healthy human volunteers. This study indicated that the transcriptomic response associated with cellular immunity to Plasmodium spp. parasites were largely species-specific, and identified a panel of defined miRNA and target mRNA pairs that associated with the immune response to P. vivax infection. Finally, a CHI model involving experimental infection of humans with N. americanus was used to comprehensively profile the immune response to hookworm in peripheral blood and at the site of infection in the duodenum. To the best of our knowledge, this study represents the first in-depth characterization of systemic and mucosal immune responses to human hookworm infection, and defined both similarities and differences in responses between biological compartments and to common mouse models. Overall, the studies in this thesis advance our understanding of human immune responses to Plasmodium and Necator species parasites at the molecular level. This information would be expected to contribute to the rational development of vaccines effective against these major pathogens