Neutrophils transiently harbor Mycobacterium tuberculosis and represent a metabolically permissive niche for bacterial growth

Abstract

Abstract Neutrophils are rapidly recruited to sites of mycobacterial infection, where they phagocytose bacilli. At the early stage of infection, Mycobacterium tuberculosis is predominantly present in neutrophils, which are also frequently infected in human TB. However, neutrophils are less well studied than other components of the host response to Mtb and much of the available data are conflicting. To better understand the role of neutrophils in tuberculosis, we focused on the fate of Mtb in neutrophils. We demonstrated that Mtb-infected neutrophils are short-lived and actively engulfed by two ontologically distinct lung macrophages, alveolar and interstitial macrophages in vivo. RNA-seq data also confirms the expression of efferocytosis-related genes in both types of macrophages. Importantly, Mtb remains viable in lung macrophages after being transported from neutrophils, implying a critical step for Mtb spreading between host phagocytes. Furthermore, neutrophils upregulate CD64 and reveal a more activated phenotype. Exploitation of reporter Mtb strains, we observed comparable replication status of Mtb in both CD64+ and CD64− neutrophils, indicating that Mtb replication is independent of the neutrophil activation state. Mechanistically, although CD64+ neutrophils are more glycolytically active than CD64− neutrophils, CD64+ neutrophils highly express CD36, and internalize greater amounts of fatty acid, LDL and oxLDL, the preferred nutrients for Mtb growth. In conclusion, our data support the hypothesis that neutrophils function as a transient carrier that delivers Mtb to macrophages. The metabolic state in neutrophils is distinct from macrophages yet still represents a hospitable environment supporting bacterial growth.