Genetics of Malaria Inflammatory Responses: A Pathogenesis Perspective

Despite significant progress in combating malaria in recent years the burden of severe disease and death due to Plasmodium infections remains a global public health concern. Only a fraction of infected people develops severe clinical syndromes motivating a longstanding search for genetic determinants of malaria severity. Strong genetic effects have been repeatedly ascribed to mutations and allelic variants of proteins expressed in red blood cells but the role of inflammatory response genes in disease pathogenesis has been difficult to discern. We revisited genetic evidence provided by inflammatory response genes that have been repeatedly associated to malaria, namely TNF, NOS2, IFNAR1, HMOX1, TLRs, CD36, and CD40LG. This highlighted specific genetic variants having opposing roles in the development of distinct malaria clinical outcomes and unveiled diverse levels of genetic heterogeneity that shaped the complex association landscape of inflammatory response genes with malaria. However, scrutinizing genetic effects of individual variants corroborates a pathogenesis model where pro-inflammatory genetic variants acting in early infection stages contribute to resolve infection but at later stages confer increased vulnerability to severe organ dysfunction driven by tissue inflammation. Human genetics studies are an invaluable tool to find genes and molecular pathways involved in the inflammatory response to malaria but their precise roles in disease pathogenesis are still unexploited. Genome editing in malaria experimental models and novel genotyping-by-sequencing techniques are promising approaches to delineate the relevance of inflammatory response gene variants in the natural history of infection thereby will offer new rational angles on adjuvant therapeutics for prevention and clinical management of severe malaria.