Abstract

Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains a major cause of morbidity and mortality worldwide. Increasing lines of evidence indicate that certain individuals, which are termed resisters, are naturally resistant to TB infection. The resister phenotype has been linked to host efficient innate immune responses, but the underlying mechanisms and the key immune factors remain unclear. Here, we find that upon Mtb infection, monocyte-derived macrophages (MDMs) from TB resisters exhibited distinctly higher production of TNF-α, IL-1β and IL-6, higher ratio of bacteria in acidic vacuoles, and lower intracellular bacterial loads, as compared to that from the healthy controls, individuals with latent TB infection, and TB patients. Such enhanced anti-Mtb immune capacity of macrophages from resisters largely depends on histone deacetylase 6 (HDAC6), whose expression is specifically maintained in MDMs from TB resisters during Mtb infection. Furthermore, we demonstrate that HDAC6 is required for acidification of Mtb-containing phagosomes in macrophages, thus controlling the intracellular survival of Mtb. Taken together, these findings unravel an indispensable role of HDAC6 in human innate resistance against Mtb infection, suggesting that HDAC6 may serve as a marker for individual TB risk as well as a novel host-directed anti-TB therapeutic target.