Do Babesia microti Hosts Share a Blood Group System Gene Ortholog, Which Could Generate an Erythrocyte Antigen That Is Essential for Parasite Invasion?

The United States of America (US) has the highest annual number of human babesiosis cases caused by <i>Babesia microti</i> (<i>Bm</i>). <i>Babesia</i>, like malaria-causing <i>Plasmodium,</i> are protozoan parasites that live within red blood cells (RBCs). Both infectious diseases can be associated with hemolysis and organ damage, which can be fatal. Since babesiosis was made a nationally notifiable condition by the Centers for Disease Control and Prevention (CDC) in January 2011, human cases have increased, and drug-resistant strains have been identified. Both the <i>Bm</i> ligand(s) and RBC receptor(s) needed for invasion are unknown, partly because of the difficulty of developing a continuous in vitro culture system. Invasion pathways are relevant for therapies (e.g., RBC exchange) and vaccines. We hypothesize that there is at least one RBC surface antigen that is essential for <i>Bm</i> invasion and that all <i>Bm</i> hosts express this. Because most RBC surface antigens that impact <i>Plasmodium</i> invasion are in human blood group (hBG) systems, which are generated by 51 genes, they were the focus of this study. More than 600 animals with at least one hBG system gene ortholog were identified using the National Center for Biotechnology Information (NCBI) command-line tools. Google Scholar searches were performed to determine which of these animals are susceptible to <i>Bm</i> infection. The literature review revealed 28 <i>Bm</i> non-human hosts (NHH). For 5/51 (9.8%) hBG system genes (e.g., <i>RhD</i>), no NHH had orthologs. This means that RhD is unlikely to be an essential receptor for invasion. For 24/51 (47.1%) hBG system genes, NHH had 4-27 orthologs. For the <i>ABO</i> gene, 15/28 NHH had an ortholog, meaning that this gene is also unlikely to generate an RBC antigen, which is essential for <i>Bm</i> invasion. Our prior research showed that persons with blood type A, B, AB, O, RhD+, and RhD- can all be infected with <i>Bm</i>, supporting our current study's predictions. For 22/51 (43.1%) hBG system genes, orthologs were found in all 28 NHH. Nineteen (37.3%) of these genes encode RBC surface proteins, meaning they are good candidates for generating a receptor needed for <i>Bm</i> invasion. In vitro cultures of <i>Bm</i>, experimental <i>Bm</i> infection of transgenic mice (e.g., a CD44 KO strain), and analyses of <i>Bm</i> patients can reveal further clues as to which RBC antigens may be essential for invasion.