Dual role of type I IFN during plasmodium infection (P3056)

Abstract

Abstract The molecular mechanisms regulating the inflammatory response during malaria are still poorly defined. Inflammatory cytokines and type I IFNs induced when innate immune sensors recognize components of the malaria parasite can contribute to clearance of the parasite and in some circumstances these same effectors lead to experimental cerebral malaria (ECM). Infection of C57BL/6 mice with Plasmodium berghei ANKA (PbA) leads to ECM where animals succumb to infection and die. Upon infection with PbA infected red blood cells (iRBCs), C57/Bl6 mice succumb to death 6-12 days post-infection. Recently, we have found that mice lacking the type I IFN receptor, IFNAR-/-, are protected from ECM-mediated death, implicating an important role of type I IFNs in exacerbating the ECM phenotype. Alternatively, when mice are infected with liver-tropic PbA sporozoites, a type I IFN response is induced while the parasites develop inside hepatocytes. This host response is responsible for upregulating interferon stimulated genes (ISGs) and limit the parasite load in the liver. The expression of ISGs are abrogated in IFNAR-/- mice. This protective phenotype is dependent on IRF3/7 and the adaptor MAVS suggesting that parasite RNA is recognized by host cells. Collectively, these findings reveal a dual role of type I IFNs that contribute to ECM-mediated death during PbA blood stage infections, but are also responsible for reducing parasite load during a liver stage infection.