New insights into interferon-mediated immune responses elicited by Plasmodium liver stage infection. Unravelling the role of Viperin induction

Abstract

Malaria is a mosquito-borne infectious disease caused by Plasmodium parasites. Despite the efforts being put into the malaria control, the development of efficient therapies has been hindered by the lack of knowledge on the parasite-elicited immune responses. Recent work showed that Plasmodium triggers an innate type I IFN response in the liver, resulting in the induction of interferonstimulated genes (ISGs). Viperin, an antiviral molecule, is one of the most induced ISGs in the host's antiplasmodial response. This thesis aims at characterizing the interferon-mediated immune responses triggered by Plasmodium liver stage infection, providing an integrated view of the potential cellular effectors of intrahepatic parasite control. A time course analysis throughout P. berghei infection revealed that type I and type II interferons-regulated expression of ISGs present two waves of induction coincident with different stages of the parasite's life cycle. A first peak occurs at 42 hours post-infection (hpi) and is followed by a higher peak of induction at 84 hpi, which was identified as potentially being mediated by innate lymphoid cells, whose functionality is yet to be explored. Furthermore, we proposed to unravel the role of Viperin induction during Plasmodium liver infection. In vivo bioluminescence measurements revealed that mice lacking Viperin exhibited a higher liver stage burden compared with wild type mice at 42 hpi. The investigation of the cellular mediators of Viperin's expression in the liver was also performed through qRT-PCR and flow cytometry, identifying the hepatocytes and monocytes as the major sources of Viperin at 42 and 84 hpi, respectively. This thesis reveals a cell population exhibiting the type I interferon signature that may act as effectors on controlling either a primary or secondary infection. Moreover, knowledge on the role of Viperin can significantly contribute to the design of new antiplasmodial strategies by increasing the knowledge on the host-parasite interactions.