Editors' ChoiceTuberculosis

Platelets worsen tuberculosis disease progression: Specific mechanism TBD

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Science Translational Medicine  03 Jun 2020:
Vol. 12, Issue 546, eabc8940
DOI: 10.1126/scitranslmed.abc8940

Abstract

Platelets contribute to the progression of tuberculosis by impairing the oxidative burst of alveolar macrophages via an unknown mechanism.

Evidence of tubercular decay in prehistoric skeletal remains and Egyptian mummies demonstrates the scourge that Mycobacterium tuberculosis (Mtb) has been for thousands of years. At present, a quarter of the world’s population is estimated to be infected, and more than 1.5 million people die annually from tuberculosis (TB)—making it the leading cause of death from a single pathogen. The key to Mtb’s lethality is its ability to evade human immune responses. Transmitted via inhalation, invading bacilli encounter alveolar macrophages that serve as the body’s first line of defense. In the never-ending evolutionary game of cat and mouse between immune cells and pathogens, Mtb has multiple defenses that blunt macrophage killing mechanisms. To further elucidate the factors contributing to Mtb’s evasive abilities, Scheuermann et al. investigated the role of platelets in shaping the immune response to TB.

The lung was recently discovered as an important site of thrombopoiesis; platelets have also been found to be key activators of the immune system. After demonstrating that platelets cocultured with monocytes infected with Mtb hampered monocytic bactericidal killing, Scheuermann and colleagues used a mouse model of primary progressive pulmonary TB to investigate the role of platelets in pulmonary TB progression. Mice were depleted of platelets at different stages of infection with Mtb. Mice depleted early after Mtb inoculation experienced a significant survival advantage compared with controls or those undergoing delayed platelet depletion, whereas platelet reconstitution reversed beneficial effects. Canonical activation does not appear to be necessary for platelets to exert detrimental effects on the immune response, as treatment with aspirin, clopidogrel, or eptifibatide had no effect on survival. Although platelets are known to activate immune cells, no changes in the number of lung-residing myeloid cells were observed in platelet-depleted animals, and the frequencies of B and T cell subsets were unaffected. Intriguingly, platelet-depleted mice were found to have significantly increased total cellular reactive oxygen species concentrations—a key component of the macrophage bactericidal arsenal.

The apparent hampering of cell-intrinsic defense mechanisms of lung resident myeloid cells may be the smoking gun for how platelets facilitate TB disease progression. Why platelets have this effect is unclear; one possibility is that it may be a protective mechanism to limit oxidative injury to the lung, which Mtb has evolved to exploit. Although promising, whether leveraging platelet-macrophage interactions proves to be a means to eliminate the scourge of Mtb is to be determined.

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