Immunity Switches and Macrophage Manipulations: Trauma, Ovulation, and Depression as Latent Tuberculosis Reactivation...

Inflammation is the immune system's natural response to initial tuberculosis infection. Tuberculosis bacteria have gained adaptations to manipulate the inflammatory process, sometimes settling into latency and containment in granulomas, ensuring their survival. Grounded in an evolutionary framework, this hypothesis-driven narrative synthesis centers upon immune-related switches, macrophage manipulations, and the critical roles of vascular endothelial growth factor A (VEGFA) in the body, exploring how this pro-inflammatory mitogen expressed by M1 macrophages frames risks for latent tuberculosis reactivation. The review focuses on trauma, ovulation, and depression, three case studies of pro-inflammatory switches creating risks for reactivation because of M1 macrophage polarization, the up-regulation of VEGFA expression, and angiogenesis (the sprouting of new blood vessels). A biological rationale is extended for why skeletal tuberculosis is so often connected with onsets in childhood, why adolescent and reproductive age females may experience heightened risks for latent tuberculosis reactivation relative to males, and why there is a potential for latent tuberculosis reactivation following onsets of depression. The immunity switches and reactivation risks of trauma, ovulation, and depression are problematic, particularly in contexts of endemic tuberculosis if large numbers of people are routinely latently infected, and among individuals with natural "high producer" VEGFA phenotypes, or those with strong type 1/M1/T_H1 or type 3/M1/T_H17 pro-inflammatory switch tendencies, and in infections with tuberculosis bacteria possessing macrophage- and granuloma-manipulating adaptations (virulence factors). Arguably, any disease or physiological state engaging pro-inflammatory switches (common and sometimes chronic in the modern population) and M1 macrophage polarizations, and any drug treatments or therapeutics intending to alter VEGFA expression should be considered for latent tuberculosis reactivation risk.