Neutrophil accumulation is associated with lung pathology during active tuberculosis (ATB). However, the molecular mechanism or mechanisms by which neutrophils accumulate in the lung and contribute to TB immunopathology are not fully delineated. Using the well-established mouse model of TB, our new data provide evidence that the alarmin S100A8/A9 mediates neutrophil accumulation during progression to chronic TB. Depletion of neutrophils or S100A8/A9 deficiency resulted in improved Mycobacterium tuberculosis (Mtb) control during chronic but not acute TB. Mechanistically, we demonstrate that, following Mtb infection, S100A8/A9 expression is required for upregulation of the integrin molecule CD11b specifically on neutrophils, mediating their accumulation during chronic TB disease. These findings are further substantiated by increased expression of S100A8 and S100A9 mRNA in whole blood in human TB progressors when compared with nonprogressors and rapidly decreased S100A8/A9 protein levels in the serum upon TB treatment. Furthermore, we demonstrate that S100A8/A9 serum levels along with chemokines are useful in distinguishing between ATB and asymptomatic Mtb-infected latent individuals. Thus, our results support targeting S100A8/A9 pathways as host-directed therapy for TB.

The mechanisms underlying the immunopathology of tuberculous meningitis (TBM), the most severe clinical form of extrapulmonary tuberculosis (TB), are not understood. It is currently believed that the spread of Mycobacterium tuberculosis (Mtb) from the lung is an early event that occurs before the establishment of adaptive immunity. Hence, several innate immune mechanisms may participate in the containment of Mtb infection and prevent extrapulmonary disease manifestations. Natural killer (NK) cells participate in defensive processes that distinguish latent TB infection (LTBI) from active pulmonary TB (PTB). However, their role in TBM is unknown. Here, we performed a cross-sectional analysis of circulating NK cellCID="C008" value="s" phenotype in a prospective cohort of TBM patients ( ) using flow cytometry. Also, we addressed the responses of memory-like NK cell subpopulations to the contact with Mtb antigens in vitro. Finally, we determined plasma levels of soluble NKG2D receptor ligands in our cohort of TBM patients by enzyme-linked immunosorbent assay (ELISA). Our comparative groups consisted of individuals with LTBI ( ) and PTB ( ) patients. We found that NK cells from TBM patients showed lower absolute frequencies, higher CD69 expression, and poor expansion of the CD45RO⁺ memory-like subpopulation upon Mtb exposure in vitro compared to LTBI individuals. In addition, a reduction in the frequency of CD56^brightCD16^- NK cells characterized TBM patients but not LTBI or PTB subjects. Our study expands on earlier reports about the role of NK cells in TBM showing a reduced frequency of cytokine-producing cells compared to LTBI and PTB.

The novel virus SARS-CoV-2 has infected more than 14 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Limited information on the underlying immune mechanisms that drive disease or protection during COVID-19 severely hamper development of therapeutics and vaccines. Thus, the establishment of relevant animal models that mimic the pathobiology of the disease is urgent. Rhesus macaques infected with SARS-CoV-2 exhibit disease pathobiology similar to human COVID-19, thus serving as a relevant animal model. In the current study, we have characterized the transcriptional signatures induced in the lungs of juvenile and old rhesus macaques following SARS-CoV-2 infection. We show that genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. We demonstrate that Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. In contrast, pathways involving VEGF are downregulated in lungs of old infected macaques. Using samples from humans with SARS-CoV-2 infection and COVID-19, we validate a subset of our findings. Finally, neutrophil degranulation, innate immune system and IFN gamma signaling pathways are upregulated in both tuberculosis and COVID-19, two pulmonary diseases where neutrophils are associated with increased severity. Together, our transcriptomic studies have delineated disease pathways to improve our understanding of the immunopathogenesis of COVID-19 to facilitate the design of new therapeutics for COVID-19.

CXCL17 is a novel mucosal chemokine that mediates myeloid cell recruitment and bactericidal activity and highly expressed in the respiratory tract. However, its role in tuberculosis (TB) immunopathogenesis or protection remains unknown. In this study, we evaluated the function of CXCL17 in a mouse model of aerosol infection with the clinical W-Beijing lineage Mycobacterium tuberculosis hypervirulent HN878 strain. Our results show that CXCL17 production increases in the lung of M. tuberculosis–infected mice during acute and chronic stages of infection. Moreover, in vitro M. tuberculosis infection of epithelial cells and myeloid cells induces production of CXCL17. In humans, lower serum CXCL17 levels are observed among active pulmonary TB patients when compared with subjects with latent TB infection and healthy controls, suggesting a protective role. However, mice treated with rCXCL17 show similar lung bacterial burden and inflammation compared with control animals, despite an increased lung myeloid cell accumulation. Finally, CXCL17−/− mice are not more susceptible to TB than wild-type animals. These findings suggest that CXCL17 is induced in both murine epithelial and myeloid cells upon M. tuberculosis infection and increased expression during human latent TB infection. However, CXCL17 may have a dispensable role during pulmonary TB.

Extracellular histones are released in two major forms: free histones and nucleosomes (DNA‐bound histones). However, little distinction has been made between these two forms of circulating extracellular histones. Our study detected increased circulating nucleosomes in acute lung injury patients. Further, our group identified nucleosomes as the leading form of extracellular histones compared to free histones in the plasma of COVID‐19 patients, underscoring the necessity to reassess the forms of circulating histones and nucleosome contributions to immunopathology. Functionally, nucleosomes activated macrophages and induced inflammation in different organs. Mechanistically, we observed nucleosomes activating the NF‐κB signaling, while inhibition of NF‐κB by sulfasalazine attenuated nucleosome‐induced macrophage activation. Taken together, our study indicates that extracellular histones are predominantly released as nucleosomes, playing a critical role in the inflammation of the lungs and other organs.