SummaryAll living cells are subject to agents that promote DNA damage. A particularly lethal lesion are interstrand cross-links (ICL), a property exploited by several anticancer chemotherapies. In yeast and humans, an enzyme that plays a key role in repairing such damage are the PSO2/SNM1 nucleases. Here, we report that Trypanosoma brucei, the causative agent of African trypanosomiasis, possesses a bona fide member of this family (called TbSNM1) with expression of the parasite enzyme able to suppress the sensitivity yeast pso2Δ mutants display towards mechlorethamine, an ICL-inducing compound. By disrupting the Tbsnm1 gene, we demonstrate that TbSNM1 activity is nonessential to the medically relevant T. brucei life cycle stage. However, trypanosomes lacking this enzyme are more susceptible to bi-and tri-functional DNA alkylating agents with this phenotype readily complemented by ectopic expression of Tbsnm1. Genetically modified variants of the null mutant line were subsequently used to establish the anti-parasitic mechanism of action of nitrobenzylphosphoramide mustard and aziridinyl nitrobenzamide prodrugs, compounds previously shown to possess potent trypanocidal properties while exhibiting limited toxicity to mammalian cells. This established that these agents, following activation by a parasite specific type I nitroreductase, produce metabolites that promote formation of ICLs leading to inhibition of trypanosomal growth.
A 65 year-old gentleman had been brought to our Respiratory Emergency Department for patients with respiratory symptoms and a possible COVID-19 infection with a 3-day history of shortness of breath (SOB), fever, a productive cough of yellow sputum, and right-sided chest pain. The patient had received both vaccinations at the time and initially reported no travel history, although later it was revealed that he had recently stayed at a hotel. He tested positive for COVID-19 and had hyponatremia and a raised procalcitonin, indicating a bacterial infection as well. He had been initiated on our local treatment guidelines for COVID with antibiotics, guided by local hospital guidelines. An atypical pneumonia screen returned a positive result for Legionella urine antigen, and his antibiotic regime was changed accordingly. Our patient deteriorated significantly, and despite being escalated to our intensive care unit (ICU), he unfortunately passed away. Our case highlights the importance of early ICU involvement and escalation of antibiotics in cases of suspected concurrent Legionella and COVID-19 infections.
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