VEGFR1 blockade reduces Mycobacterium tuberculosis-induced pathology in immunocompromised mice

Abstract

Mycobacterium tuberculosis (Mtb) is a major public health concern that caused 1.6 million deaths in 2021. New treatments are needed, especially in immunocompromised individuals, such as patients with HIV coinfection, who are severely impacted by the disease. We have recently reported that blocking VEGFR1, a receptor that is present on monocytes and contributes to their recruitment to the sites of infection, limits Mtb-induced pathology in immunocompetent mice of both Mtb-resistant (C57BL/6J) and Mtb-supersusceptible (C3HeB/FeJ) strains (Harding et al., 2019). These results offer a way to reduce lung pathology without impeding host defense. Here, we extend this finding by showing that VEGFR1 blockade has similar effects in immunocompromised (RAG1KO) mice as well, measured by a reduction in the area of inflammation and without a change in bacterial burden. Following treatment with the VEGFR1 blocker SU5416, we have found an elevated ratio and an increase in the absolute number of neutrophil granulocytes in the Mtb-infected lungs in both immunosufficient and immunocompromised mice. Surprisingly however, this did not result in exacerbated pathology as the majority of the recruited neutrophils remained in the lung vasculature. Our results indicate that further evaluation of VEGFR1 blockers as an adjunctive treatment to antitubercular drug therapy for immunocompromised populations could be worthwhile. Supported by grants from NIH (R01 HL128778 and R01 NS123449)