Hypervirulent Mycobacterium tuberculosis strain triggers necrotic lung pathology associated with enhanced recruitment of neutrophils in resistant C57BL/6 mice

Abstract

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) that in most cases induces irreversible necrosis of lung tissue as a result of excessive inflammatory reactions. The murine model of TB in resistant C57BL/6 mice infected with reference Mtb strains is widely used in TB studies; however, these mice do not show a necrotic pathology, which restricts their use in studies of irreversible tissue damage. Recently, we demonstrated that necrotic lung lesions could be induced in the C57BL/6 mice by highly virulent Mtb strains belonging to the modern Beijing sublineage. However, the pathogenic mechanisms leading to necrosis in this model were not elucidated. In this study, we investigated the dynamics of lung lesions in mice infected with highly virulent Beijing Mtb strain M299, compared with those infected with laboratory Mtb strain H37Rv. The data demonstrate that necrotic lung lesions in mice infected by the strain M299 were associated with enhanced recruitment of myeloid cells, especially neutrophils, and increased levels of proinflammatory cytokines, consistent with exacerbated inflammation. High levels of IFN-γ production contributed to the control of bacterial growth. Further progression to chronic disease was associated with a reduction in the levels of inflammatory mediators in the lungs, the accumulation of foamy macrophages and partial healing of the necrotic tissue by fibrosis. At a late stage of disease, degradation of foamy cells resulted in the liberation of accumulated lipids and persisting bacilli and further activation of inflammation, which promoted lung consolidation. Overall, our studies show that C57BL/6 mice infected with highly virulent Mtb strain may serve as a TB model reproducing an exacerbated inflammatory response in a resistant host to hypervirulent mycobacteria, leading to irreversible necrotic lung lesions.

Increased Neutrophil Count and Decreased Neutrophil CD15 Expression Correlate With TB Disease Severity and Treatment Response Irrespective of HIV Co-infection

“…Furthermore, our data are consistent with clinical studies and experimental infections showing that acute pulmonary tuberculosis is accompanied by an influx of neutrophils ( 26 , 41 ). In mice, for example, neutrophil influx is associated with mycobacterial burden and lung pathology, and their depletion in chronic infection leads to decreased CFU and improved survival ( 26 , 42 – 44 ). It is important to note, however, that the influx of neutrophils is not unique to TB disease and has been well-described in other inflammatory conditions such as asthma, influenza and bacterial or viral pneumonia ( 45 – 47 ).…”

Toll-like Receptor 2 Prevents Neutrophil-Driven Immunopathology during Infection with Mycobacterium tuberculosis by Curtailing CXCL5 Production

“…Increased pathology and enhanced susceptibility to M. tuberculosis infection are consistently associated with dysregulated neutrophil recruitment to the lungs (24)(25)(26)(27)(28). Human TB is also associated with a neutrophil-driven type 1 interferon signature (29), and neutrophils are the predominant infected cells in the airways of patients with active TB (30).…”

BCG-induced T cells shape Mycobacterium tuberculosis infection before reducing the bacterial burden

“…The recent finding that AM infection is non-inflammatory and poorly induces chemokines may help explain the covert nature of early infection (Rothchild, A.C. et al 2019. bioRxiv: 520791). Furthermore, the replication and spread within the AM population, a process associated with cell death of infected macrophages and phagocytosis by other macrophages, likely involves apoptosis, as necrotic cell death is associated with chemokine release and recruitment of MDM/PMN (19). Perhaps vaccine-induced T cells that express receptors for apoptotic “find-me” signals could co-localize with infected AM and exhibit earlier Mtb control compared to BCG-induced T cells, which may not express such receptors (20).…”