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

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During the year 2021-2022, 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 progress in several projects: 1, Continued from our report last year, now we have identified several small molecules (drugs) that can inhibit or stimulate MARCH1 activity in vitro. We are currently evaluating the candidate compounds in vivo. Some of these compounds are immune modulators that have been used in trials of different human diseases. We hope to use some of the compounds to treat cerebral malaria caused by Plasmodium berghei ANNK and severe malaria by Plasmodium yoelii N67C. Traditional antimalarial drugs kill the parasites directly, but the drug pressures may lead to mutations conferring drug resistance. Host immune modulators can be explored for treating malaria with a reduced chance of drug resistance. 2. We have finished a study on the molecular mechanism of malaria-induced anemia. We have shown that infection with P. yoelii 17XNL inhibits red blood cell (RBC) maturation. We invested the roles of erythroblast island (EBI) macrophages in malaria anemia and showed that EBI macrophages from 17XNL infected mice were defective in supporting erythrocyte maturation in vitro and in vivo. A manuscript from this study was submitted recently. 3. We have shown that over-expression of some Olfr genes could stimulate type I interferon (INF-I) responses and increase phosphorylation levels of IRF3 and TBK1. We have made good progress in the mechanism of how the olfactory receptors (Olfr) regulate INF-I response and identified a putative molecular signaling pathway. Additionally, we have identified a potential ligand that can activate several Olfr proteins. We are writing a manuscript for publication now. 4. We have finished a project on a P. falciparum E3 ubiquitin ligase and its role in protein ubiquitination. We showed that knocking down the E3 ubiquitin ligase gene affected parasite responses to several antimalarial drugs and changed the protein levels of some drug transporters. A manuscript is under revision now. We are working on another E3 ubiquitin ligase and hope to have a second manuscript ready soon. 5. We are still 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 of how MMP3 regulates IFN-I responses. 6, We sequenced and assembled the genome of another P. yoelii strain (N67C), an isogenic parasite of N67. We are comparing its genome with that of N67 to identify polymorphic sites that may contribute to the differences in virulence and stimulation of host responses. 7, We also published two invited reviews in 2022. One entitled: Genetic mapping of determinants in drug resistance, virulence, disease susceptibility, and interaction of host-rodent malaria parasites in Parasitol. International. 91 (2022) 102637. A second one is: The origin, isolation, and biological characterization of rodent malaria parasites. Parasitol. International. 91 (2022) 102636. 8, In collaboration with Drs. Rongfu Wand and Xiao Yu, we continued to work on the mechanism of host INF-I responses to malaria parasite infections. We showed that activation of cGAS-STING pathway by P. yoelii N67C infection influences host immunity and mortality by induction of CD11b+Ly6+ proinflammatory monocytes, identifying a previously unrecognized role of cGAS-STING-MyD88-p38 signaling pathway (Adv. Sci. 2022, 9, 2103701).