Alveolar macrophages up-regulate a non-classical innate response toMycobacterium tuberculosisinfectionin vivo

Abstract

Alveolar macrophages (AMs) are the first cells to be infected during Mycobacterium tuberculosis (Mtb) infection. Thus the AM response to infection is the first of many steps leading to initiation of the adaptive immune response, which is required for efficient control of infection. A hallmark of Mtb infection is the delay of the adaptive response, yet the mechanisms responsible for this delay are largely unknown. We developed a system to identify, sort and analyze Mtb-infected AMs from the lung within the first 10 days of infection. In contrast to what has been previously described using in vitro systems, we find that Mtb-infected AMs up-regulate a cell-protective antioxidant transcriptional signature that is dependent on the lung environment and not dependent on bacterial virulence. Computational approaches including pathway analysis and transcription factor binding motif enrichment analysis identify Nrf2 as a master regulator of the response of AMs to Mtb infection. Using knock-out mouse models, we demonstrate that Nrf2 drives the expression of the cell protective transcriptional program and impairs the ability of the host to control bacterial growth over the first 10 days of infection. Mtb-infected AMs exhibit a highly delayed pro-inflammatory response, and comparisons with uninfected AMs from the same infected animals demonstrate that inflammatory signals in the lung environment are blocked in the Mtb-infected cells. Thus, we have identified a novel lung-specific transcriptional response to Mtb infection that impedes AMs from responding rapidly to intracellular infection and thereby hinders the overall immune response.One Sentence SummaryIn response to Mtb infection in vivo, alveolar macrophages fail to up-regulate the canonical pro-inflammatory innate response and instead induce an Nrf2-dependent cell protective transcriptional program, which in turn impairs the host’s control of bacterial growth.

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

“…LTBI had no impact on the proportions of cell-types infected ( Figure S8). In other studies (currently submitted), we have shown that MTB-infected AMs display a highly delayed pro-inflammatory reponse over the first 10 days of infection 26 The bacterial burden in LTBI mice at 10 days following high-dose (~3000 CFU) aerosol infection, was approximately 3-fold lower than in control mice ( Figure S9). The majority of bacteria were in AMs ( Figure 4G) and significantly fewer AMs were infected in LTBI mice ( Figure 4G).…”

Desferrioxamine Supports Metabolic Function in Primary Human Macrophages Infected With Mycobacterium tuberculosis

“…hAMs are the first cells to be infected during Mtb infection in vivo (50,51). To validate the clinical utility of DFX in supporting inflammatory and immunometabolic profiles during early Mtb infection, the effect of DFX on transcript levels of IL1β, PFKFB3, GAPDH, and PKM2 was examined.…”

Roles for phthiocerol dimycocerosate lipids in Mycobacterium tuberculosis pathogenesis

“…Nonetheless, a recent study used microscopy to localize a fluorescent Mtb in alveolar macrophages as early as 48 h post-infection, confirming these cells to be the first immune cells to encounter the bacteria in mice lungs [36]. Alveolar macrophages are more permissive to Mtb intracellular growth, being the main bacterial reservoir during early infection [36, 65, 66]. Perhaps, the immunomodulatory role of PDIM, reported by Cambier and colleagues, is effective only during this first encounter with the host, protecting the bacteria from host innate immune response, and delaying the recruitment of immune cells and adaptative response.…”