Min Zhang

Min Zhang, PhD

Assistant Research Professor of Pharmacology & Toxicology

Bio

For the past 10 years most of my efforts have been dedicated to studying the translational control in Plasmodium parasites and structure-based malaria vaccine development.

Research Interests

1. Translational control in the latent parasites related to drug resistance and transmission.

Rresearch accomplishments

Plasmodium sporozoites in mosquitoes, and gametocytes in patient blood, are adapted for long-term survival while maintaining their infectivity. I have identified two proteins that control the latency of malaria sporozoites that reside in the salivary glands of mosquitoes: Plasmodium eukaryotic initiation factor 2α (eIF2α) kinase eIK2, and phosphatase UIS2 (J. Exp. Med. 207, 1465-1474; PLoS Pathog. 12, e1005370). I also found another eIF2α kinase, PK4, which leads to the arrest of global protein synthesis in blood-stage schizonts (Proc. Natl. Acad. Sci. USA 109, 3956-3961). In summary, I have uncovered the mechanism of malaria latency in the normal malaria life cycle, and summarized my research accomplishments in a review paper (Eukaryot. Cell 12:161-167).

Current work

Artemisinin and its derivatives are the most potent anti-malaria drugs. Nevertheless, artemisinin therapy is associated with accumulation of latent parasites and with recrudescence of Plasmodium infection, which is a clinical treatment failure. Artemisinin resistance is a major threat to global public health. The focus of my interest is the translational control in the drug resistant and artemisinin-induced latent parasites. 

Plasmodium eIF2α is phosphorylated during the parasite transmission from mammalian host to mosquito. I'm investigating the role of eIF2α phosphorylation during the transmission.

2. Structure-based immunogen design in malaria vaccine discovery.

Rresearch accomplishments

RTS,S/AS01 , trade name Mosquirix , is a only licensed human malaria vaccine. Phase III trial data demonstrated that the standard three-dose vaccination (RTS,S-SD) reduced clinical malaria cases by <50%. A fixed dose of RTS,S vaccine regimen improved immunogenicity and protection against infection. RTS,S vaccine is based on Plasmdoium falciparum circumsporozoite protein (PfCSP).The human malaria parasite P. falciparum does not infect mouse. It is imperative to generate a tool to evaluate the protection efficacy of human malaria vaccines based on PfCSP and systematically assess formulation, molecular composition and regimen using a high-throughput animal experimental model. A highly infectious rodent malaria P. yoelii parasite bearing a full length of PfCSP was generated. The P. yoelii CSP (PyCSP) is replaced by PfCSP in the recombinant parasite, PfCSP/Py. The PfCSP/Py parasite is as highly infectious as the parental wild type parasite, and only 5 mosquito bites or intravenous injection of 50 sporozoites could successfully transmit the parasite to a mouse. The PfCSP/Py parasite represents a unique tool to evaluate PfCSP-based immunity and protection in a mouse model.

Current work

I'm working on structure-based immunogen design and layer-by-layer multiple antigen nano-delivery of malaria vaccine.

https://www.ncbi.nlm.nih.gov/myncbi/browse/collection/51868077/?sort=date&direction=ascending

Key Publications

Translational control through phosphorylation of eIF2α is critical to malaria latency.

a). Zhang M, Mishra S, Sakthivel R, Fontoura BM, Nussenzweig V.UIS2: A Unique Phosphatase Required for the Development of Plasmodium Liver Stages. PLoS Pathog. 2016; 12(1):e1005370.

b). Zhang M, Joyce BR, Sullivan WJ Jr, Nussenzweig V.Translational control in Plasmodium and toxoplasma parasites. Eukaryot Cell. 2013; 12(2):161-7.
c). Zhang M, Mishra S, Sakthivel R, Rojas M, Ranjan R, Sullivan WJ Jr, Fontoura BM, Ménard R, Dever TE, Nussenzweig V. PK4, a eukaryotic initiation factor 2α(eIF2α) kinase, is essential for the development of the erythrocytic cycle of Plasmodium. Proc Natl Acad Sci U S A. 2012; 109(10):3956-61.
d). Zhang M, Fennell C, Ranford-Cartwright L, Sakthivel R, Gueirard P, Meister S, Caspi A, Doerig C, Nussenzweig RS, Tuteja R, Sullivan WJ Jr, Roos DS, Fontoura BM, Ménard R, Winzeler EA, Nussenzweig V.The Plasmodium eukaryotic initiation factor-2alpha kinase IK2 controls the latency of sporozoites in the mosquito salivary glands. J Exp Med. 2010; 207(7):1465-74.

Malaria Vaccine based on Plasmdoium falciparum circumsporozoite protein (PfCSP).

a). Zhang M, Kaneko I, Tsao T, Mitchell R, Nardin EH, Iwanaga S, Yuda M, Tsuji M. A highly infectious Plasmodium yoelii parasite, bearing Plasmodium falciparum circumsporozoite protein. Malar J. 2016; 15(1):201.
b). Zhang M, Mandraju R, Rai U, Shiratsuchi T, Tsuji M. Monoclonal Antibodies against Plasmodium falciparum Circumsporozoite Protein. Antibodies 2017; 6(3), 11.
c). Huang J, Li X, Coelho-dos-Reis JG, Zhang M, Mitchell R, Nogueira RT, Tsao T, Noe AR, Ayala R, Sahi V, Gutierrez GM, Nussenzweig V, Wilson JM, Nardin EH, Nussenzweig RS, Tsuji M. Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria. J Immunol Methods. 2015 ; 427:42-50.
d). Li X, Huang J, Zhang M, Funakoshi R, Sheetij D, Spaccapelo R, Crisanti A, Nussenzweig V, Nussenzweig RS, Tsuji M. Human CD8+ T cells mediate protective immunity induced by a human malaria vaccine in human immune system mice. Vaccine. 2016; 34:4501-6.
e). Huang J, Tsao T, Zhang M, Tsuji M. Circumsporozoite protein-specific K(d)-restricted CD8+ T cells mediate protective antimalaria immunity in sporozoite-immunized MHC-I-K(d) transgenic mice. Mediators Inflamm. 2014;728939.
f). Huang J, Tsao T, Zhang M, Rai U, Tsuji M, Li X. A sufficient role of MHC class I molecules on hepatocytes in anti-plasmodial activity of CD8 (+) T cells in vivo. Front Microbiol. 2015; 6:69.
g). Xiangming Li, Akira Kawamura, Chasity D. Andrews, Jessica Miller, Douglass Wu, Min Zhang, Tiffany Tsao, Ryota Funakoshi, Jing Huang, Deena A Oren, Neal N. Padte, Steven A Porcelli, Chi-Huey Wong, Stefan H.I. Kappe, David D Ho, Moriya Tsuji. Colocalization of a CD1d-Binding Glycolipid with a Radiation-Attenuated Sporozoite Vaccine in Lymph Node-Resident Dendritic Cells for a Robust Adjuvant Effect. J Immunol. 2015;195(6):2710-21.

https://www.ncbi.nlm.nih.gov/myncbi/browse/collection/51868077/?sort=date&direction=ascending

Connect


zhanmin@iu.edu 


PHARMACOLOGY & TOXICOLOGY
MS A401 PHTX
Indianapolis, IN