Person:

Goodman, Russell

Wide-spread protozoan parasites carry endosymbiotic dsRNA viruses with uncharted implications to the human host. Among them, Trichomonas vaginalis, a parasite adapted to the human genitourinary tract, infects globally ∼250 million each year rendering them more susceptible to devastating pregnancy complications (especially preterm birth), HIV infection and HPV-related cancer. While first-line antibiotic treatment (metronidazole) commonly kills the protozoan pathogen, it fails to improve reproductive outcome. We show that endosymbiotic Trichomonasvirus, highly prevalent in T. vaginalis clinical isolates, is sensed by the human epithelial cells via Toll-like receptor 3, triggering Interferon Regulating Factor -3, interferon type I and proinflammatory cascades previously implicated in preterm birth and HIV-1 susceptibility. Metronidazole treatment amplified these proinflammatory responses. Thus, a new paradigm targeting the protozoan viruses along with the protozoan host may prevent trichomoniasis-attributable inflammatory sequelae.

Rapid advances in genetics have led to an increased understanding of the genetic determinants of human disease, including many gastrointestinal (GI) disorders. Coupled with a proliferation of genetic testing services, this has resulted in a clinical landscape where commercially available genetic tests for GI disorders are now widely available. In this review, we discuss the current status of clinical genetic testing for GI illnesses, review the available testing options, and briefly discuss indications for and practical aspects of such testing. Our goal is to familiarize the practicing gastroenterologist with this rapidly changing and important aspect of clinical care.

An elevated intracellular NADH/NAD+ ratio, or “reductive stress,” has been associated with multiple diseases, including disorders of the mitochondrial electron transport chain (ETC). As the intracellular NADH/NAD+ ratio can be in near-equilibrium with the circulating lactate/pyruvate ratio, we hypothesized that reductive stress could be alleviated by oxidizing extracellular lactate into pyruvate. We engineered LOXCAT, a fusion of bacterial lactate oxidase (LOX) and catalase (CAT), which irreversibly converts lactate and oxygen to pyruvate and water. Addition of recombinant LOXCAT to the media of cultured human cells with a defective ETC was able to decrease the extracellular lactate/pyruvate ratio, normalize the intracellular NADH/NAD+ ratio, upregulate glycolytic ATP production, and restore cellular proliferation. In mice, tail-vein injected LOXCAT reduced circulating lactate/pyruvate ratio, blunted a metformin-induced rise in blood lactate/pyruvate, and improved NADH/NAD+ balance in heart and brain. Our study lays the groundwork for a class of injectable therapeutic enzymes that alleviate intracellular redox imbalances by directly targeting circulating redox-coupled metabolites.