VEGFR Blockade Reduces Mycobacterium tuberculosis-Induced Lung Pathology in Immunocompromised Mice

Mycobacterium tuberculosis (Mtb) remains a significant public health threat, responsible for 1.6 million deaths in 2021. The development of new treatments is particularly urgent for immunocompromised individuals, including those with Mtb/HIV coinfection, who experience severe disease outcomes. Previous studies demonstrated that blockade of VEGFR1, a receptor expressed on monocytes that mediates their recruitment to infection sites, limits Mtb-induced pathology in immunocompetent mice of both Mtb-resistant (C57BL/6J) and Mtb-susceptible (B6.C3H-sst1) strains. The present study extends these findings by evaluating the VEGFR1/2 blockade strategy in immunocompromised hosts. Treatment with the VEGFR1/2 blocker SU5416 (semaxanib) reduced monocyte infiltration into the lungs of Mtb-infected immunocompromised RAG1KO mice without affecting bacterial protection. Reduced monocyte recruitment improved lung pathology. VEGFR1/2 blockade also decreased the number of NK cells in the lungs of RAG1KO mice. Notably, an elevated ratio and increased absolute number of neutrophil granulocytes were observed in the Mtb-infected lungs of both immunocompetent and immunocompromised mice following SU5416 administration. However, this increase in neutrophils did not exacerbate lung pathology, as most recruited granulocytes remained within the lung vasculature. The beneficial effect of VEGFR1/2 blockade in RAG1KO animals suggests that further investigation of VEGFR blockers, such as SU5416, as adjunctive therapy to anti-tuberculosis drug regimens for immunocompromised populations with tuberculosis is warranted.