Early alveolar macrophage response and IL-1R-dependent T cell priming determine transmissibility of Mycobacterium tuberculosis strains

Abstract

Mechanisms underlying variability in transmission of Mycobacterium tuberculosis strains remain undefined. By characterizing high and low transmission strains of M.tuberculosis in mice, we show here that high transmission M.tuberculosis strain induce rapid IL-1R-dependent alveolar macrophage migration from the alveolar space into the interstitium and that this action is key to subsequent temporal events of early dissemination of bacteria to the lymph nodes, Th1 priming, granulomatous response and bacterial control. In contrast, IL-1R-dependent alveolar macrophage migration and early dissemination of bacteria to lymph nodes is significantly impeded in infection with low transmission M.tuberculosis strain; these events promote the development of Th17 immunity, fostering neutrophilic inflammation and increased bacterial replication. Our results suggest that by inducing granulomas with the potential to develop into cavitary lesions that aids bacterial escape into the airways, high transmission M.tuberculosis strain is poised for greater transmissibility. These findings implicate bacterial heterogeneity as an important modifier of TB disease manifestations and transmission.

Transcriptome and chromatin accessibility mapping reveals a type I Interferon response triggered by Mycobacterium tuberculosis infection

“…DEG unique to ΔPPM1A cells include IL1A , which is important for Mtb clearance, T cell priming, and granuloma formation (Di Paolo et al . 2015; Lovey et al . 2022).…”

“…Notable DEG unique to WT cells included upregulated C1QA, which is a strong marker of active TB (Dijkman et al 2020), and downregulated NOXA, which is involved with nitric oxide mechanisms. DEG unique to △PPM1A cells include IL1A, which is important for Mtb clearance, T cell priming, and granuloma formation (Di Paolo et al 2015;Lovey et al 2022). In PPM1A + cells, several interesting genes are upregulated, including IL24 and IL32, which are known as correlates of protection against TB (Ma et al 2011;Montoya et al 2014;Koeken et al 2020).…”

Increased Heme Oxygenase 1 Expression upon a Primary Exposure to the Respiratory Syncytial Virus and a Secondary Mycobacterium bovis Infection

“…The mycobacteria acquire a dormant state that increases the expression of HO-1 to produce carbon monoxide and promote an anti-inflammatory state in the host cells [ 23 , 56 ]. Accordingly, the increased detection of HO-1 and the possibility of macrophages containing bacilli in a dormant state ( Figure 3 ) can be related to the presence of mycobacteria in the epithelium [ 57 , 58 ]. In this context, tissue oxygenation is impeded, favoring the conditions in which the Mycobacterium is put into a dormant state through triglyceride metabolism [ 59 , 60 , 61 ].…”

Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management

“…In mice, high transmission strains induce alveolar macrophages, in an interleukin-1 receptor-dependent manner, to migrate into the lung interstitium. This ultimately leads to granuloma formation with potential cavitary lesions, which enable the M. tuberculosis bacilli to enter the airways (Lovey et al, 2022). Aggregates of M. tuberculosis, when compared to single bacteria, face less acidification in macrophage phagosomes, are associated with an increase in bacterial replication and initiate the death of the macrophage that can lead to a macrophage-death cascade (Mahamed et al, 2017;Rodel et al, 2021).…”