| Summary: | Malaria and tuberculosis together account for more than 2 million deaths worldwide each year. The present body of work examines interactions between these leading pathogens and cross-cutting themes in innate immunity to both diseases. Not only are malaria and tuberculosis important threats to public health in their own right, but malaria-tuberculosis co-infection appears to generate more severe pathology than either disease on its own, and malaria may exacerbate primary or re-activation tuberculosis (Chapter 2). Moreover, both diseases appear to share common host defense pathways, including CD36, a macrophage cell surface receptor important for innate immunity (Chapter 3). Biomarkers of host defense pathways common to both malaria and tuberculosis distinguish between clinical disease phenotypes and predict mortality in severe malaria (Chapters 4-7). Biomarker discovery led to the identification of angiopoitetin-2 (Ang-2) as a surrogate marker of disease severity in malaria and a potential therapeutic target. Nitric oxide, in addition to its antimycobacterial properties, is known to inhibit Ang-2 release from the endothelium, and is therefore hypothesized to improve outcomes in African children with severe malaria (Chapters 8 and 9). A broad range of methods are applied to address these diseases and their interactions, ranging from mammalian cell culture experiments in vitro, animal models of disease, analysis of human samples, and clinical epidemiology (randomized controlled trial). Translational aspects of this research are emphasized, outlining how advances in understanding of infectious disease pathogenesis can be applied to improved diagnosis, prognosis, and novel adjunctive therapies for two of the leading global infectious threats.
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