AUTHOR=Peterson Mariko S. , Joyner Chester J. , Lapp Stacey A. , Brady Jessica A. , Wood Jennifer S. , Cabrera-Mora Monica , Saney Celia L. , Fonseca Luis L. , Cheng Wayne T. , Jiang Jianlin , Soderberg Stephanie R. , Nural Mustafa V. , Hankus Allison , Machiah Deepa , Karpuzoglu Ebru , DeBarry Jeremy D. , MaHPIC-Consortium , Tirouvanziam Rabindra , Kissinger Jessica C. , Moreno Alberto , Gumber Sanjeev , Voit Eberhard O. , Gutierrez Juan B. , Cordy Regina Joice , Galinski Mary R. , Anderson Dave C. , Ay Ferhat , Brito Cristiana F. A. , Barnwell John W. , DeBarry Megan , Bosinger Steven E. , Chien Jung-Ting , Choi Jinho , Gupta Anuj , Humphrey Jay C. , Ibegbu Chris , Jiang Xuntian , Jones Dean P. , Lackman Nicolas , Lamb Tracey J. , Lee Frances E.-H. , Roche Karine Gaelle Le , Li Shuzhao , Meyer Esmeralda V.S. , Moncada-Giraldo Diego M. , Pohl Dan Ory, Jan , Safaei Saeid , Sanz Ignacio , Smith Maren , Tharp Gregory , Tran ViLinh , Trippe Elizabeth D. , Uppal Karan , Warrenfeltz Susanne , Williams Tyrone , Woods Zerotti L. TITLE=Plasmodium knowlesi Cytoadhesion Involves SICA Variant Proteins JOURNAL=Frontiers in Cellular and Infection Microbiology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.888496 DOI=10.3389/fcimb.2022.888496 ISSN=2235-2988 ABSTRACT=

Plasmodium knowlesi poses a health threat throughout Southeast Asian communities and currently causes most cases of malaria in Malaysia. This zoonotic parasite species has been studied in Macaca mulatta (rhesus monkeys) as a model for severe malarial infections, chronicity, and antigenic variation. The phenomenon of Plasmodium antigenic variation was first recognized during rhesus monkey infections. Plasmodium-encoded variant proteins were first discovered in this species and found to be expressed at the surface of infected erythrocytes, and then named the Schizont-Infected Cell Agglutination (SICA) antigens. SICA expression was shown to be spleen dependent, as SICA expression is lost after P. knowlesi is passaged in splenectomized rhesus. Here we present data from longitudinal P. knowlesi infections in rhesus with the most comprehensive analysis to date of clinical parameters and infected red blood cell sequestration in the vasculature of tissues from 22 organs. Based on the histopathological analysis of 22 tissue types from 11 rhesus monkeys, we show a comparative distribution of parasitized erythrocytes and the degree of margination of the infected erythrocytes with the endothelium. Interestingly, there was a significantly higher burden of parasites in the gastrointestinal tissues, and extensive margination of the parasites along the endothelium, which may help explain gastrointestinal symptoms frequently reported by patients with P. knowlesi malarial infections. Moreover, this margination was not observed in splenectomized rhesus that were infected with parasites not expressing the SICA proteins. This work provides data that directly supports the view that a subpopulation of P. knowlesi parasites cytoadheres and sequesters, likely via SICA variant antigens acting as ligands. This process is akin to the cytoadhesive function of the related variant antigen proteins, namely Erythrocyte Membrane Protein-1, expressed by Plasmodium falciparum.