<i>Mycobacterium tuberculosis</i> replicates within necrotic human macrophages

Lerner, Thomas R.; Borel, Sophie; Dj, Greenwood; Repnik, Urška; Russell, Mark; Herbst, Susanne; Jones, Martin L.; Collinson, Lucy M.; Griffiths, Gareth; Gutierrez, Maximiliano G.

doi:10.1083/jcb.201603040

Cited by 110 publications

(117 citation statements)

References 36 publications

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“…2c ). This pro-survival signature was unexpected based on our data on human primary macrophages (Lerner et al, 2017), although consistent with previous live-cell observations that active M. tuberculosis replication in primary hLECs was not associated with significant host cell death (Lerner et al, 2016). We confirmed by RT-qPCR that the expression of the pro-inflammatory cytokine IL-6 as well as the type I IFN responsive cytokines CXCL10 (IP10) and IFN-β were significantly upregulated after infection in hLECs ( Fig.…”

Section: Resultssupporting

confidence: 92%

Mycobacterium tuberculosis cording in the cytosol of live lymphatic endothelial cells

et al. 2019

Preprint

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18The ability of Mycobacterium tuberculosis to form serpentine cords is intrinsically related to 19 its virulence, but specifically how M. tuberculosis cording contributes to pathogenesis 20 remains obscure. We show that several M. tuberculosis clinical isolates form intracellular 21 cords in primary human lymphatic endothelial cells (hLEC) in vitro and also in the lymph 22 nodes of patients with tuberculosis. We identified via RNA-seq a transcriptional programme 23 in hLEC that activates cellular pro-survival and cytosolic surveillance of intracellular 24 pathogens pathways. Consistent with this, cytosolic access of hLEC is required for 25 intracellular M. tuberculosis cording; and cord formation is dependent on the M. 26 tuberculosis ESX-1 type VII secretion system and the mycobacterial lipid PDIM. Finally, we 27show that M. tuberculosis cording is a novel size-dependent mechanism used by the 28 pathogen to evade xenophagy in the cytosol of endothelial cells. These results provide a 29 mechanism that explains the long-standing association between M. tuberculosis cording and 30 virulence. 31Bacterial xenophagy is the process that regulates the removal of cytosolic bacteria after 64 damage to phagosomal membranes during selective macroautophagy (Galluzzi et al., 2017). 65This pathway constitutes one of the first cell autonomous defence pathways against 66 intracellular pathogens (Deretic and Levine, 2009; Gutierrez et al., 2004). A fraction of the 67 M. tuberculosis population damage phagosomes to access the cytosol and are subsequently 68 recognised by autophagic adaptors and the xenophagy machinery. This process targets M. 69 tuberculosis into autophagosomes and thus the lysosomal degradation pathway (Watson et 70 al., 2012). Whereas there is a large body of literature demonstrating autophagy as an anti-71 mycobacterial pathway (Deretic et al., 2009), recent evidence shows that M. tuberculosis 72 can eventually block the fusion of autophagosomes with lysosomes (Lerner et al., 2016; 73 Romagnoli et al., 2012) and in mice, M. tuberculosis can evade autophagic responses in vivo 74 (Kimmey et al., 2015). 75 76 M. tuberculosis mostly infects macrophages although there is compelling evidence that a 77 minor proportion of M. tuberculosis is found infecting various non-myeloid cells in the lungs 78and lymph nodes in vivo (Ganbat et al., 2016; Lerner et al., 2015; Nair et al., 2016; Randall et 79 al., 2015). The role that these M. tuberculosis subpopulations play in TB pathogenesis in 80 different cell types (e.g. immune vs non-immune) is unclear. We previously showed in 81 extrapulmonary tuberculosis that a subpopulation of M. tuberculosis is found in human 82 lymphatic endothelial cells (hLEC) in lymph node biopsies and these cells could represent a 83 reservoir for M. tuberculosis in infected patients (Lerner et al., 2016). 84 85 Here we discovered that M. tuberculosis forms large intracellular cords consisting of up to 86 thousands of individual bacteria arranged end-to-end in hLEC in vitro and in biopsies of 87 ...

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Section: Resultssupporting

confidence: 92%

Mycobacterium tuberculosis cording in the cytosol of live lymphatic endothelial cells

et al. 2019

Preprint

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“…Of note, activation of Toll‐like receptor (TLR) signalling through recognition of pathogen‐associated molecular patterns leads to the transcriptional activation of genes encoding for pro‐inflammatory cytokines, chemokines and anti‐bacterial and antiviral molecules. For instance, TLR2/6; TLR4 and TLR9 serve as recognition receptors for Mycobacteria tuberculous to activate the innate immunity response of host . LPS together with IFNγ have been widely used for the induction of M1 polarization model to study regulatory molecular mechanism for polarization.…”

Section: Discussionmentioning

confidence: 99%

HMGN2 regulates non‐tuberculous mycobacteria survival via modulation of M1 macrophage polarization

Wang

Chen

Ren

et al. 2019

J Cellular Molecular Medi

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Non‐tuberculous mycobacteria (NTM), also known as an environmental and atypical mycobacteria, can cause the chronic pulmonary infectious diseases. Macrophages have been suggested as the main host cell to initiate the innate immune responses to NTM infection. However, the molecular mechanism to regulate the antimicrobial immune responses to NTM is still largely unknown. Current study showed that the NTM clinical groups, Mycobacterium abscessus and Mycobacterium smegmatis, significantly induced the M1 macrophage polarization with the characteristic production of nitric oxide (NO) and marker gene expression of iNOS, IFNγ, TNF‐α, IL1‐β and IL‐6. Interestingly, a non‐histone nuclear protein, HMGN2 (high‐mobility group N2), was found to be spontaneously induced during NTM‐activated M1 macrophage polarization. Functional studies revealed that HMGN2 deficiency in NTM‐infected macrophage promotes the expression of M1 markers and the production of NO via the enhanced activation of NF‐κB and MAPK signalling. Further studies exhibited that HMGN2 knock‐down also enhanced IFNγ‐induced M1 macrophage polarization. Finally, we observed that silencing HMGN2 affected the survival of NTM in macrophage, which might largely relevant to enhanced macrophage polarization into M1 phenotype under the NTM infection. Collectively, current studies thus suggested a novel function of HMGN2 in regulating the anti‐non‐tuberculous mycobacteria innate immunity of macrophage.

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“…In the later stages and chronic disease, the infection is associated with responses mediated by M2 macrophages, whose weak microbicidal activity and ability to eliminate bacteria are linked to the occurrence of the lesions observed during disease evolution. [265][266][267][268][269] In leprosy, macrophages are the primary cells that exert microbicidal activity. Thus, the role of macrophages in the response to M. leprae has been widely described and is correlated with the expression of certain cytokines that are classical representatives of the cellular immune response, such as TNF-α and IFN-γ.…”

Section: Autophagymentioning

confidence: 99%

<p>Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases</p>

Sousa¹,

Vasconcelos²,

Quaresma³

2019

IDR

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Macrophages are a functionally heterogeneous group of cells with specialized functions depending not only on their subgroup but also on the function of the organ or tissue in which the cells are located. The concept of macrophage phenotypic heterogeneity has been investigated since the 1980s, and more recent studies have identified a diverse spectrum of phenotypic subpopulations. Several types of macrophages play a central role in the response to infectious agents and, along with other components of the immune system, determine the clinical outcome of major infectious diseases. Here, we review the functions of various macrophage phenotypic subpopulations, the concept of macrophage polarization, and the influence of these cells on the evolution of infections. In addition, we emphasize their role in the immune response in vivo and in situ, as well as the molecular effectors and signaling mechanisms used by these cells. Furthermore, we highlight the mechanisms of immune evasion triggered by infectious agents to counter the actions of macrophages and their consequences. Our aim here is to provide an overview of the role of macrophages in the pathogenesis of critical transmissible diseases and discuss how elucidation of this relationship could enhance our understanding of the host–pathogen association in organ-specific immune responses.

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Mycobacterium tuberculosis replicates within necrotic human macrophages

Abstract: Mycobacterium tuberculosis triggers macrophage cell death by necrosis, but it is unclear how this affects bacterial replication. Lerner et al. show that this pathogen replicates within necrotic human macrophages before disseminating to other cells upon loss of plasma membrane integrity.

Cited by 110 publications

References 36 publications

Mycobacterium tuberculosis cording in the cytosol of live lymphatic endothelial cells

Mycobacterium tuberculosis cording in the cytosol of live lymphatic endothelial cells

HMGN2 regulates non‐tuberculous mycobacteria survival via modulation of M1 macrophage polarization

<p>Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases</p>

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