Exploring the Role of Low-Density Neutrophils During Mycobacterium tuberculosis Infection

Abstract

Tuberculosis (TB) is caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), which primarily infects the lungs but can also cause extrapulmonary disease. Both the disease outcome and the pathology of TB are driven by the immune response mounted by the host. Infection with Mtb elicits inflammatory host responses that are necessary to control infection, but can also cause extensive tissue damage when in excess, and thus must be precisely balanced. In particular, excessive recruitment of neutrophils to the site of infection has been associated with poor control of Mtb infection, prompting investigations into the roles of neutrophils in TB disease outcomes. Recent studies have revealed that neutrophils can be divided into subpopulations that are differentially abundant in TB disease states, highlighting the potential complexities in determining the roles of neutrophils in Mtb infection. Specifically, neutrophils can be separated into normal (NDN) and low-density neutrophils (LDNs) based on their separation during density gradient centrifugation and surface marker expression. LDNs are present in higher numbers during active TB disease and increase in frequency with disease progression, although their direct contribution to TB is still unknown. In addition, the abundance of LDNs has also been associated with the severity of other lung infections, including COVID-19. In this review, we discuss recent findings regarding the roles of LDNs during lung inflammation, emphasizing their association with TB disease outcomes. This review highlights the importance of future investigations into the relationship between neutrophil diversity and TB disease severity.

The interaction of macrophages and CD8 T cells in bronchoalveolar lavage fluid is associated with latent tuberculosis infection

“…We collected the BALF from patients with LTBI and TB and assessed cell composition and architecture using scRNA-seq. Data from three healthy control donors (HC) were downloaded from our public database [ 4 ] . The BALF from seven patients with TB was collected from the diseased regions of the lung and the lesion-offside normal lung tissues from three patients with TB (TBN).…”

“…However, it is extremely difficult to obtain lung tissue samples from Mtb-infected populations, particularly those with LTBI. Several previous studies have used animal models, including monkeys and mice, to simulate human immune responses against Mtb infection [ 3 , 4 ]. However, owing to the differences in the immune responses of certain species, the latent infection state in animal models remains controversial.…”

Evaluation of the innate immune response of caprine neutrophils against Mycobacterium avium subspecies paratuberculosis in vitro

“…The existence of distinct neutrophil subsets or temporary functional states has been demonstrated in several species [ 62 ], including naïve cattle [ 63 ]. Some subsets have demonstrated an increased phagocytic activity [ 64 ] and, in active tuberculosis, low density neutrophils are present in high numbers, but its role is still unknown [ 65 ], these recent findings show that the available information about neutrophils and their role in mycobacterial diseases is scarce. Regarding neutrophil degranulation in response to Map , it was clearly directional, with MPO + granules observed mostly over bacterial clumps.…”

Rapid lethality of mice lacking the phagocyte oxidase and Caspase1/11 followingMycobacterium tuberculosisinfection

“…A recent report characterizing the susceptibility of mice deficient in Nos2 found that GR1 int granulocytes were long-lived, unable to control bacterial growth, and were not suppressive even with increased IL10 production (33). In humans, low density granulocyte populations are associated with severe susceptibility to TB and may be analogous to these permissive GR1 int cells seen in susceptible mice (37). It is possible that these granulocytes are not directly driving the susceptibility but rather are associated with uncontrolled TB disease caused by other defects in the host response.…”