Tick-borne infections have been increasing in the United States and worldwide, including the Babesia parasite which can cause human babesiosis. Symptoms of this serious pathogen include malarial-like sickness, coagulation disruption, pulmonary symptoms, and kidney failure. A new, multi-institutional study assesses the nuclear genome sequence of B. duncani, a pathogen transmitted by the hard tick Dermacentor albipictus. This is the first study to characterize the genomic, epigenomic, structural, and transcriptional properties of the pathogen.
Genomic Sequencing
A team of researchers, including Pallavi Singh, postdoctoral associate (infectious diseases) and Choukri Ben Mamoun, PhD, professor of medicine (infectious diseases) and of microbial pathogenesis at Yale School of Medicine, used a recently developed method to continuously culture B. duncani in human red blood cells in vitro in order to examine its biology, pathogenesis, and virulence and to determine its major vulnerabilities, which could be exploited for the development of novel therapies. Using a multi-omics approach, they determined that the genome consists of five chromosomes encoding more than 4000 proteins including new families of proteins predicted to play a role in parasite virulence.
The authors identified 842 core proteins, which are shared between B. duncani and other members of the Apicomplexa phylum. They further demonstrated that B. duncani is a defining member of a distinct clade among Babesia species that infect humans and animals. Their reconstitution of the metabolic functions and secretory mechanisms of the parasite helped identify distinctive cellular functions, which could be suitable targets for the development of new diagnostic tests and therapies.
Sequencing Unveils Previously Unknown Multigene Families
The authors uncovered new multigene families that they classified into two groups: those that are unique to B. duncani and those that have orthologs in other parasites. These genes were shown to undergo transcriptional repression, a pattern reminiscent of that of virulence genes of the human malaria parasite Plasmodium falciparum. The authors suggest that some of these genes might also function during the tick transmission phase, a stage of the parasite life cycle that remains poorly understood.
Uncovering New Drugs for Treatment of Human Babesiosis
Multi-omics approaches such as the one described in this study could help identify new strategies to detect and inhibit pathogens. By mining the proteome of B. duncani, the authors were able to uncover several potential drug targets, including the dihydrofolate reductase-thymidylate synthase enzyme. Their analysis of the sequence of this enzyme suggested that this parasite could be susceptible to a class of antiparasitic drugs known as antifolates. Using an in vitro proliferation assay optimized for this parasite, they demonstrated that indeed two antifolates, pyrimethamine and WR-99210, are potent inhibitors of B. duncani growth within human red blood cells.
In addition to Singh and Ben Mamoun, other Yale authors include Pratap Vydyam, postdoctoral associate (infectious diseases); Tiffany Fang, Yale undergraduate student; Shalev Gihaz, postdoctoral associate (infectious diseases); and former lab members Jose Thekkiniath and Muhammad Munshi. Researchers from other universities in the U.S., France, Spain, and Mexico contributed to this international collaboration.
To learn more, read “Babesia duncani multi-omics identifies virulence factors and drug targets.”
The Department of Internal Medicine’s Section of Infectious Diseases engages in comprehensive and innovative patient care, research, and educational activities for a broad range of infectious diseases. Learn more at Infectious Diseases.