Global Metabolomic Profiling of Host Red Blood Cells Infected with Babesia divergens Reveals Novel Antiparasitic Target Pathways

Abstract

Human babesiosis is caused by apicomplexan parasites of the Babesia genus and is associated with transfusion-transmitted illness and relapsing disease in immunosuppressed populations. Through its continuous cycles of invasion, proliferation, and egress, B. divergens radically changes the metabolic environment of the host red blood cell, allowing us opportunities to study potential chemical vulnerabilities that can be targeted by drugs.

Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review

“…Further research is needed to improve the efficacy of Babesia treatments, including clinical studies using fosinopril, an angiotensin-converting enzyme inhibitor (ACE), which has recently been identified as a potent anti-parasitic drug with efficacy in vitro against Babesia duncani [195]. Another approach that deserves further study, is based on the metabolomic profiling of B. duncani, which identified parasite-mediated modulation of RBC metabolite levels of all classes, including lipids, where the interruption of cholesterol scavenging from the host cell led to premature parasite egress, and chemical targeting of the hydrolysis of acyl glycerides led to the buildup of malformed parasites [196]. The use of orlistat, a potent inhibitor of the lipase that degrades acylglycerides, has been shown to disrupt B. divergens merozoite membrane formation in culture, inhibiting merozoite maturation before egress [196].…”

“…Another approach that deserves further study, is based on the metabolomic profiling of B. duncani, which identified parasite-mediated modulation of RBC metabolite levels of all classes, including lipids, where the interruption of cholesterol scavenging from the host cell led to premature parasite egress, and chemical targeting of the hydrolysis of acyl glycerides led to the buildup of malformed parasites [196]. The use of orlistat, a potent inhibitor of the lipase that degrades acylglycerides, has been shown to disrupt B. divergens merozoite membrane formation in culture, inhibiting merozoite maturation before egress [196]. No clinical studies have been performed to date using orlistat for the treatment of B. divergens, which is an FDA-approved drug for the treatment of obesity [197].…”

Serum metabolomic profiles in BALB/c mice induced by Babesia microti infection

“…There are only a few existing studies of the metabolome of Babesia. Previous investigations assessed differences in the metabolism of free merozoites and infected RBCs (iRBCs) during B. divergens infection and in the urine metabolic profiles of dogs with B. canis infection using metabolomics approaches (Fernańdez-Garcia et al, 2021;Kulešet al, 2021;Beri et al, 2023). Recent research on metabolic profiling was based on erythrocytes separated from B. microti-infected mice and found sabotage of metabolic pathways in iRBCs, including amino acid, lipid, and nucleotide metabolism and the tricarboxylic acid cycle (Gong et al, 2023).…”