This application addresses Broad Challenge area (04) Clinical research and SpecificChallenge topic, (AI-102) the human immune response to infection andimmunization-profiling via modern immunological and systems biology.Malaria remains a major source of morbidity and mortality in many countries. Fundamentalquestions such as the mechanisms of immunity, the role of the immune system in cerebraldisease and the mechanism of loss of malaria immunity in HIV infected adults remainpoorly understood. The clinical relevance of these issues is extremely high. Patients thatdevelop cerebral malaria have a 15% mortality rate despite potent antimalarials. HIV hasresulted in hundreds of thousands of additional symptomatic infections in adults whopreviously were immune. Understanding mechanisms of cerebral malaria and protectionmediated by the immune system will guide interventions to improve survival rates andlessen HIV related malaria. The lack of understanding of the immune systems role in theseclinical scenarios is in part due to a lack of comprehensive analysis of the immuneresponse in natural cohorts. We propose to carry out immune profiling through newmethods of whole genome transcription in malaria infected patients to provide anunbiased view of immune response in malaria infection. This analysis will be carriedout in two phenotypically highly characterized cohorts 1) children with cerebral malaria 2)adults with HIV/malaria co-infection. There is prior evidence to suggest that a deregulated,pro-inflammatory immune response is the mechanism that gives rise to cerebral malaria.
Specific Aim I will address this hypothesis through whole genome transcriptional profiling ina cerebral malaria disease cohort. Through an ongoing study of cerebral malaria,peripheral blood aliquots are available to analyze host transcriptional responses.Comparison of whole genome transcriptional responses to other datasets including mildmalaria and systemic inflammatory syndrome will be carried out. We will develop aprediction model for survivors vs. non survivors of cerebral malaria with the goal ofdeveloping biomarkers that can be used in patient care. Our second specific aim is basedon the clinical observation that HIV infected adults lose their natural immunity to malariadisease. Typically immune adults are frequently infected but have no physical symptomsor laboratory abnormalities. HIV infected patients have an increase in the risk ofasymptomatic parasitemia, symptomatic malaria and more severe disease; this increaseis inversely proportional to CD4+ T cell count. The basis of this loss of immunity isunknown. Through the analysis of a second cohort, we will characterize the immuneresponse to malaria in HIV negative and HIV positive adults. Using biostatistical andcomputational analysis we will identify the genes and biological pathways that havealtered expression based on CD4+T cell counts. These studies may provide insight intocomponents of protective immunity in malaria. Conversely we will further understandhow HIV impacts patients' immune response to malaria which may inform studies of HIVand other pathogens. All datasets will be compared to previously published relevanttranscriptional host response profiling using systems biology and computational biologyapproaches to develop broader models of immune response to pathogens.This study brings together two components that are critical for high impact, high qualityclinical research. The first is the clinical expertise in the disease and the experience andcohorts to carry out high quality field research in malaria and HIV. The second is theexperience and creativity of the analysis team which include epidemiologists,biostatisticians and computational biologists. This proposal has brought together anoutstanding team with these skills to provide high impact results to inform pathogenesismodels and vaccine/drug development in malaria.
Malaria remains a major source of morbidity and mortality worldwide. The mechanisms of severe malaria which is associated with a 15% mortality rate and the mechanisms of natural immunity remain poorly defined. The immune response is central to these important clinical questions. We propose to carry out comprehensive immune response analysis in very specialized patient groups to understand the details of host response in malaria that causes coma and to explore why HIV infected adults lose their natural immunity to malaria. These analyses will inform vaccine strategies and drug development to reduce the burden of malaria.
|Feintuch, Catherine Manix; Saidi, Alex; Seydel, Karl et al. (2016) Activated Neutrophils Are Associated with Pediatric Cerebral Malaria Vasculopathy in Malawian Children. MBio 7:e01300-15|
|Subramaniam, Krishanthi S; Skinner, Jeff; Ivan, Emil et al. (2015) HIV Malaria Co-Infection Is Associated with Atypical Memory B Cell Expansion and a Reduced Antibody Response to a Broad Array of Plasmodium falciparum Antigens in Rwandan Adults. PLoS One 10:e0124412|
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|Krupka, Malkie; Seydel, Karl; Feintuch, Catherine M et al. (2012) Mild Plasmodium falciparum malaria following an episode of severe malaria is associated with induction of the interferon pathway in Malawian children. Infect Immun 80:1150-5|