Integrating Lung Physiology, Immunology, and Tuberculosis

Torrelles, Jordi B.; Schlesinger, Larry S.

doi:10.1016/j.tim.2017.03.007

Cited by 109 publications

(106 citation statements)

References 97 publications

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“…The fact that the Nrf2 transcriptional response has not been reported previously, despite numerous published studies of Mtb-infected macrophages, highlights the importance of using in vivo systems to dissect lung-specific immunological events ( 43 ). Our results suggest that established in vitro models do not adequately replicate the initial host response to Mtb.…”

Section: Discussionmentioning

confidence: 99%

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

Nemeth

et al. 2019

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Nemeth

et al. 2019

Preprint

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“…The foundations of what is known were laid through natural history and autopsy studies in the pre-chemotherapy era. The necessary steps to develop TBM include the pathogen surviving its initial encounter with the innate immune system at the respiratory epithelium and establishment of primary infection in the lung parenchyma with characteristic granulomatous inflammation [5][6][7] . Spread beyond the lungs likely occurs through the blood and may be preceded by local invasion to the lymphatic system.…”

Section: Tbm Pathogenesismentioning

confidence: 99%

Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

Cresswell¹,

Davis²,

Sharma³

et al. 2019

Wellcome Open Res

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The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.

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“…Mtb infection begins when airborne bacilli are inhaled and phagocytosed by alveolar macrophages (Torrelles and Schlesinger, 2017). This activates pattern-recognition receptors that bind bacterial constituents, leading to expression of proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-α) that are important for Mtb control .…”

Section: Introductionmentioning

confidence: 99%

An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

Penn

Netter

Johnson

et al. 2017

Preprint

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Although macrophages are armed with potent anti-bacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophageintrinsic bacterial control, and the Mtb strategies to overcome them are poorly understood. To further study these processes, we used a systematic affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two new factors involved in Mtb pathogenesis -the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl -/macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between anti-bacterial and anti-viral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map as a resource for developing a deeper understanding of the intricate interactions between Mtb and its host.

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Integrating Lung Physiology, Immunology, and Tuberculosis

Cited by 109 publications

References 97 publications

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

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

Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics

An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

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