During the year of 2018-2019, we focused on studying the molecular mechanisms of malaria pathogenesis and signaling pathways using Plasmodium yoelii/mouse model. We have made good progresses in several projects: 1. We have completed a multi-year project dissecting the mechanism of Plasmodium yoelii erythrocyte binding-like protein (PyEBL) in regulating host innate response to malaria infection. We found that PyEBL can regulate host immune response and parasite growth by stimulating a strong type I interferon response and T cell differentiation. A C741Y substitution in the protein trafficking domain changes Band 3 tyrosine phosphorylation and surface phosphoserine (PS) exposure on infected red blood cell (RBC), but not the rate of RBC invasion, leading to increased phagocytosis of infected RBCs. This study provides a paradigm shift in our understanding of parasite-host interaction during malarial parasite infection. A manuscript from this work has been submitted. 2. We have finished a project studying a gene called March1. We found that March1 can regulate host response to infections of multiple parasite strains. A manuscript was submitted to Nature Communications, and we have been working on experiments in response to reviewer's comments in the past few months. At the same time, we are generating cell lines to screen small compound inhibitors for therapy. 3. We are finishing up a project characterizing a gene called receptor transporter protein 4 (RTP4) known to promote cell surface expression of G protein-coupled receptors (GPCRs). Our study discovers a new function for the gene; it can regulate host type I interferon (IFN-I) response during malaria infection. We generated rtp4 knockout mice and characterized its roles during malaria infection. A manuscript is under preparation. 4. In collaboration with Dr. Rongfu Wang of Houston Methodist Research Institute, we showed inflammasome activation during malaria infection can negatively regulate MyD88-IRF7 type I IFN signaling and anti-malaria immunity. This work was published in Nature Communications. 5. In collaboration with Dr. Jian Li and colleagues at Xiamen University, we completed a project of developing a microhomology-mediated end joining (MMEJ) based CRISPR/Cas9 method and used the method to generate size mutations in the central repeat region of Plasmodium yoelii circumsporozoite protein (PyCSP). This work was recently published in Int. J. Parasitol. 6. We continued to work on other projects such as characterizing the function of MMP3 in malaria infection and the mechanism of malaria induced anemia and hematopoiesis.
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