Abstract
Abstract Malaria, caused by Plasmodiumparasites is a severe disease affecting millions of people around the world. Plasmodiumundergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening clinical disease of blood-stage malaria. Although the innate immune responses that control Plasmodiuminfection and development in the liver are known to limit clinical malaria and transmission, the mechanism of such responses remain relatively unknown. Here we demonstrate that the DNA of Plasmodiumis sensed by AIM2 (absent in melanoma 2) receptors in the infected hepatocytes, resulting in Caspase-1 activation. However, we observed that Caspase-1 undergoes an unconventional and incomplete proteolytic processing in such hepatocytes, resulting in the activation of the membrane pore-forming protein, Gasdermin D (GSDMD), without the concurrent activation of the inflammasome-associated pro-inflammatory cytokines such as interleukin (IL)-1 and IL-18. Nevertheless, the AIM2-mediated Caspase-1 activation pathway induced the elimination of Plasmodium-infected hepatocytes and a resultant control of malaria in the liver. Supported by grants from NIH (R01 AI168307)
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