Using rabbit lungs and primary rabbit and human macrophages, as well as human monocytic THP‐1‐derived macrophages for infection with Mtb strains (H37Rv, HN878, or CDC1551) that differ in virulence, we show that NLRP3 inflammasome activation by HIF‐1α and GBP1 leads to elevated mitochondrial stress, apoptosis, and necrosis during progressive infection by HN878. The gene discussed is HIF1A; the disease is infection.