Making a Mouse a Human: Human‑Like Tuberculosis Pathology in Mice Without the ROS/RNS Killing Myth
Author(s): Professor. William R. Jacobs Jr.
Murine models of tuberculosis have been criticized as poor surrogates for human disease because standard inbred strains rarely develop the necrotic, hypoxic granulomas that dominate advanced human pulmonary tuberculosis. Guiewi Makafe et al. show that this limitation reflects model selection rather than an intrinsic failure of the mouse. In Nos2‑deficient mice, they establish aerosol-route infection and a vaccine‑primed challenge system (immunization with mc²6230, H37Rv ΔRD1 ΔpanCD, followed by virulent Mtb challenge) that yields reproducible hypoxic necrotic lesions whose microenvironment contributes to poor chemotherapy response. This work strengthens the case for pathology‑relevant murine platforms while providing a timely opportunity to correct a persistent misconception: reactive nitrogen and oxygen species (RNS/ROS) are essential regulators of inflammation and lesion evolution in tuberculosis, but they should not be treated as the principal sterilizing effector mechanisms in vivo. Pairing lesion‑realistic models with genetic systems that directly report immune sterilization may be the most efficient route to uncovering the macrophage execution pathways that actually kill Mtb.
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