Malaria Parasite Genomics, Development, Drug Resistance, Pathogenesis, and host-parasite interaction

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

During the year of 2020-2021, we focused on studying the molecular mechanisms of malaria pathogenesis and signaling pathways using Plasmodium yoelii and Plasmodium berghei parasites. We also have a project studying mechanisms of drug resistance in Plasmodium falciparum. We have made good progresses in several projects: 1, We have shown that MARCH1 is a key molecule that can negatively regulate MAVS-mediated IFN-I responses. Now we are interested in identifying small molecules (drugs) that can inhibit or stimulate MARCH1 activity. We have constructed a cell line that expresses MARCH1, MAVS, and dual luciferases. We have screened several small molecule libraries and identified many candidate compounds that can inhibit MARCH1 activities. We are currently evaluating the candidate compounds, hoping to use the compounds for immunotherapies. 2. We are working on another host gene (mmp3) that has been shown to be highly expressed in malaria parasite infections. We have generated mmp3 knockout mice and are studying the functions of MMP3 in host immune response to malaria parasite infections. We have shown that MMP3 can regulate host IFN-I responses and are studying the mechanism how MMP3 regulates IFN-I responses. 3. We are also studying the molecular mechanism of malaria induced anemia. We have shown that infection with P. yoelii 17XNL inhibits red blood cell (RBC) maturation. We are investing the roles of erythroblastic island (EBI) macrophages in malaria anemia. 4. We have identified 40 olfactory (Olfr) genes that may play a role in host responses to P. yoelii infections. Now we are focusing on some selected Olfr genes and are studying their roles in host IFN-I responses. We have showed that over expression of the Olfr genes can stimulate IFN-I responses and increase phosphorylation levels of IRF3 and TBK1. Additionally, we have identified a putative legend that can activate several Olfr proteins. 5, We sequenced and assembled the genome of Plasmodium yoelii N67, an important parasite for studying host IFN-I responses. We recently published the results in BMC Genomics 2021 (https://doi.org/10.1186/s12864-021-07555-9). 6. We are still working on two P. falciparum E3 ubiquitin ligases. We have shown that knocking-down of the E3 ubiquitin ligase genes affected parasite responses to several anti-malarial drugs. A manuscript is being prepared for publication. 7, We also published two invited reviews. One entitled: Host-Malaria Parasite Interactions and Impacts on Mutual Evolution in Fron. Cell Infect Microbiol 2020, 10:587933.doi: 10.3389/fcimb.2020.587933. A second one is: Type I Interferons And Malaria: A Double-Edge Sword Against A Complex Parasitic Disease. Front Cell Infect Microbiol 2020 https://doi.org/10.3389/fcimb.2020.594621. doi: 10.3389/fcimb.2020.594621.