The global burden of severe falciparum malaria: An immunological and genetic perspective on pathogenesis

Plasmodium falciparum malaria is a leading global cause of morbidity and mortality of infectious disease origin. Here, we focus largely on P. falciparum malaria in sub-Saharan Africa since this geographic region bears the greatest disease burden, resulting in exceedingly high rates of morbidity and mortality. The life cycle, etiology, and epidemiology of P. falciparum are also presented. In addition, we provide a detailed discussion of the pathophysiology of severe, life-threatening complications of falciparum malaria such as cerebral malaria (CM), severe malarial anemia (SMA), hyperparasitemia, hypoglycemia, hyperlactatemia, electrolyte and fluid imbalances, renal dysfunction, metabolic acidosis, and respiratory distress (RD) (Marsh et al. 1995; WHO 2000). A comprehensive overview on the role of cytokines, chemokines, growth factors, effector molecules, and antibodies is also presented in the context of innate and acquired immunity. Since susceptibility to falciparum malaria and the clinical outcomes that result following an infection are conditioned by genetic variation, a detailed description of different genetic studies is presented, including the candidate gene approach, linkage disequilibrium (LD), and genomewide association (GWA) studies. Lastly, we provide a detailed description of the statistical modeling we have employed to examine the association between malaria disease outcomes and host genetic and immunological factors.