scholarly journals Aggregated Mycobacterium tuberculosis Enhances the Inflammatory Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Hylton E. Rodel ◽  
Isabella A. T. M. Ferreira ◽  
Carly G. K. Ziegler ◽  
Yashica Ganga ◽  
Mallory Bernstein ◽  
...  
Keyword(s):  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Transcriptional Response ◽  
Human Monocyte ◽  
Cell Necrosis ◽  
Macrophage Cell ◽  
Efficient Replication ◽  
Infected Cells ◽  
Nfκb Pathway ◽  
Disease Cell

Mycobacterium tuberculosis (Mtb) bacilli readily aggregate. We previously reported that Mtb aggregates lead to phagocyte death and subsequent efficient replication in the dead infected cells. Here, we examined the transcriptional response of human monocyte derived macrophages to phagocytosis of aggregated Mtb relative to phagocytosis of non-aggregated single or multiple bacilli. Infection with aggregated Mtb led to an early upregulation of pro-inflammatory associated genes and enhanced TNFα signaling via the NFκB pathway. These pathways were significantly more upregulated relative to infection with single or multiple non-aggregated bacilli per cell. Phagocytosis of aggregates led to a decreased phagosome acidification on a per bacillus basis and increased phagocyte cell death, which was not observed when Mtb aggregates were heat killed prior to phagocytosis. Mtb aggregates, observed in a granuloma from a patient, were found surrounding a lesion cavity. These observations suggest that TB aggregation may be a mechanism for pathogenesis. They raise the possibility that aggregated Mtb, if spread from individual to individual, could facilitate increased inflammation, Mtb growth, and macrophage cell death, potentially leading to active disease, cell necrosis, and additional cycles of transmission.

scholarly journals Aggregated Mycobacterium tuberculosis enhances the inflammatory response

2021 ◽  
Author(s):  
Alex Sigal ◽  
Hylton Rodel ◽  
Isabella Markham Ferreira ◽  
Carly Ziegler ◽  
Yasica Ganga ◽  
...  
Keyword(s):  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Inflammatory Response ◽  
Host Cell ◽  
Human Lung ◽  
Transcriptional Response ◽  
Human Macrophage ◽  
Cell Infection ◽  
Host Cell Death ◽  
Nfκb Pathway

Mycobacterium tuberculosis (Mtb) readily aggregates in culture and Mtb aggregates in the lung were observed in experimental Mtb infection. However, the physiological consequences of Mtb aggregation are incompletely understood. Here we examined the human macrophage transcriptional response to aggregated Mtb relative to infection with non-aggregated single or multiple bacilli per host cell. Infection with aggregated Mtb led to an early upregulation of pro-inflammatory associated genes and enhanced TNFα signaling via the NFκB pathway. Both these pathways were significantly upregulated relative to infection with single bacilli, and TNFα signaling was also significantly elevated relative to infection with multiple non-aggregated Mtb. Secretion of TNFα and downstream cytokines were also enhanced. On a longer timescale, aggregate infection led to overall increased acidification per macrophage and a high proportion of death in these cells after aggregate phagocytosis. Host cell death did not occur when Mtb aggregates were heat killed despite such clumps being readily picked up. To validate that Mtb aggregates do occur in the human lung, we document Mtb aggregates surrounding a cavity in a human TB lesion. Aggregates may therefore be present in some lesions and elicit a stronger inflammatory response resulting in recruitment of additional phagocytes and their subsequent death, potentially leading to necrosis and transmission.

scholarly journals Adherent Invasive Escherichia coli Strains from Patients with Crohn's Disease Survive and Replicate within Macrophages without Inducing Host Cell Death

2001 ◽  
Vol 69 (9) ◽  
pp. 5529-5537 ◽  
Author(s):  
Anne-Lise Glasser ◽  
Jerome Boudeau ◽  
Nicolas Barnich ◽  
Marie-Helene Perruchot ◽  
Jean-Frederic Colombel ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Cell Death ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Annexin V ◽  
Human Monocyte ◽  
Peritoneal Macrophages ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Infected Cells

ABSTRACT Escherichia coli strains recovered from Crohn's disease (CD) lesions are able to adhere to and invade cultured intestinal epithelial cells. We analyzed the behavior within macrophages of adherent invasive E. coli (AIEC) strains isolated from patients with CD. All the 15 AIEC strains tested were able to replicate extensively within J774-A1 cells: the numbers of intracellular bacteria increased 2.2- to 74.2-fold at 48 h over that at 1 h postinfection. By use of murine peritoneal macrophages and human monocyte-derived-macrophages, the reference AIEC strain LF82 was confirmed to be able to survive intracellularly. Transmission electron micrographs of AIEC LF82-infected macrophages showed that at 24 h postinfection, infected cells harbored large vacuoles containing numerous bacteria, as a result of the fusion of several vacuoles occurring after 8 h postinfection. No lactate dehydrogenase (LDH) release, no sign of DNA fragmentation or degradation, and no binding to fluorescein isothlocyanate-labeled annexin V were observed with LF82-infected J774-A1 cells, even after 24 h postinfection. LF82-infected J774-A1 cells secreted 2.7-fold more tumor necrosis factor alpha (TNF-α) than cells stimulated with 1 μg of lipopolysaccharide (LPS)/ml. No release of interleukin-1β was observed with LPS-prestimulated J774-A1 cells infected with AIEC LF82. These findings showed that (i) AIEC strains are able to survive and to replicate within macrophages, (ii) AIEC LF82 replication does not induce any cell death of the infected cells, and (iii) LF82-infected J774-A1 cells release high levels of TNF-α. These properties could be related to some features of CD and particularly to granuloma formation, one of the hallmarks of CD lesions.

scholarly journals A Caspase-Independent Pathway Mediates Macrophage Cell Death in Response to Mycobacterium tuberculosis Infection

2007 ◽  
Vol 75 (4) ◽  
pp. 1984-1993 ◽  
Author(s):  
Mary P. O'Sullivan ◽  
Seonadh O'Leary ◽  
Deirdre M. Kelly ◽  
Joseph Keane
Keyword(s):  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Dna Fragmentation ◽  
Treatment Options ◽  
Macrophage Cell ◽  
Mycobacterium Tuberculosis Infection ◽  
Nuclear Condensation ◽  
Independent Manner ◽  
Macrophage Response ◽  
Cell Death Pathway

ABSTRACT Macrophages can undergo apoptosis after infection with Mycobacterium tuberculosis. This macrophage response deprives the bacillus of its niche cell and supports the host response through better antigen presentation. The intracellular pathways of apoptosis that elaborate this macrophage response are not well understood. To address this issue, we investigated the contribution of various apoptosis pathways to M. tuberculosis-induced macrophage cell death. We found that macrophages die in a caspase-independent manner after infection with M. tuberculosis (at multiplicities of infection ranging from 1 to 20). There was evidence for the involvement of both the mitochondria (cleavage of Bid) and the lysosomes (cathepsin-mediated DNA fragmentation) in this cell death pathway. Dying macrophages displayed several features typical of apoptosis, including DNA fragmentation, nuclear condensation, and exposure of phosphatidylserine on the plasma membrane. However, nuclear fragmentation was not observed, which suggests that M. tuberculosis-induced cell death differs in some respects from classical apoptosis. This novel mechanism of cell death was blocked by serine protease inhibitors. A better understanding of this protective macrophage response may direct new vaccine and treatment options.

scholarly journals Reverting the mode of action of the mitochondrial FOF1-ATPase by Legionella pneumophila preserves its replication niche

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Pedro Escoll ◽  
Lucien Platon ◽  
Mariatou Dramé ◽  
Tobias Sahr ◽  
Silke Schmidt ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Legionella Pneumophila ◽  
Severe Pneumonia ◽  
Human Monocyte ◽  
Dependent Manner ◽  
Delayed Cell Death ◽  
Mitochondrial Functions ◽  
Infected Cells ◽  
Bacterial Replication

Legionella pneumophila, the causative agent of Legionnaires'; disease, a severe pneumonia, injects via a type-IV-secretion-system (T4SS) more than 300 proteins into macrophages, its main host cell in humans. Certain of these proteins are implicated in reprogramming the metabolism of infected cells by reducing mitochondrial oxidative phosphorylation (OXPHOS) early after infection. Here we show that despite reduced OXPHOS, the mitochondrial membrane potential (Δψm) is maintained during infection of primary human monocyte-derived macrophages (hMDMs). We reveal that L. pneumophila reverses the ATP-synthase activity of the mitochondrial FOF1-ATPase to ATP-hydrolase activity in a T4SS-dependent manner, which leads to a conservation of the Δψm, preserves mitochondrial polarization and prevents macrophage cell death. Analyses of T4SS effectors known to target mitochondrial functions revealed that LpSpl is partially involved in conserving the Δψm, but not LncP and MitF. The inhibition of the L. pneumophila-induced 'reverse mode' of the FOF1-ATPase collapsed the Δψm and caused cell death in infected cells. Single-cell analyses suggested that bacterial replication occurs preferentially in hMDMs that conserved the Δψm and showed delayed cell death. This direct manipulation of the mode of activity of the FOF1-ATPase is a newly identified feature of L. pneumophila allowing to delay host cell death and thereby to preserve the bacterial replication niche during infection.

scholarly journals Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Deeqa Mahamed ◽  
Mikael Boulle ◽  
Yashica Ganga ◽  
Chanelle Mc Arthur ◽  
Steven Skroch ◽  
...  
Keyword(s):  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Host Cells ◽  
Intracellular Growth ◽  
Pathogen Virulence ◽  
Host Cell Death ◽  
A Cell ◽  
Infected Cells ◽  
Serial Killing ◽  
Cell Death Cascade

A hallmark of pulmonary tuberculosis is the formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states.

scholarly journals Involvement of Caspase-9 in the Inhibition of Necrosis of RAW 264 Cells Infected with Mycobacterium tuberculosis

2007 ◽  
Vol 75 (6) ◽  
pp. 2894-2902 ◽  
Author(s):  
Ryosuke Uchiyama ◽  
Ikuo Kawamura ◽  
Takao Fujimura ◽  
Michiko Kawanishi ◽  
Kohsuke Tsuchiya ◽  
...  
Keyword(s):  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Specific Inhibitor ◽  
Host Cells ◽  
Ros Generation ◽  
Caspase 9 ◽  
Host Cell Death ◽  
Intracellular Ros ◽  
Infected Cells

ABSTRACT In order to know how caspases contribute to the intracellular fate of Mycobacterium tuberculosis and host cell death in the infected macrophages, we examined the effect of benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethane (z-VAD-fmk), a broad-spectrum caspase inhibitor, on the growth of M. tuberculosis H37Rv in RAW 264 cells. In the cells treated with z-VAD-fmk, activation of caspase-8, caspase-3/7, and caspase-9 was clearly suppressed, and DNA fragmentation of the infected cells was also reduced. Under this experimental condition, it was found that the treatment markedly inhibited bacterial growth inside macrophages. The infected cells appeared to undergo cell death of the necrosis type in the presence of z-VAD-fmk. We further found that z-VAD-fmk treatment resulted in the generation of intracellular reactive oxygen species (ROS) in the infected cells. By addition of a scavenger of ROS, the host cell necrosis was inhibited and the intracellular growth of H37Rv was significantly restored. Among inhibitors specific for each caspase, only the caspase-9-specific inhibitor enhanced the generation of ROS and induced necrosis of the infected cells. Furthermore, we found that severe necrosis was induced by infection with H37Rv but not H37Ra in the presence of z-VAD-fmk. Caspase-9 activation was also detected in H37Rv-infected cells, but H37Ra never induced such caspase-9 activation. These results indicated that caspase-9, which was activated by infection with virulent M. tuberculosis, contributed to the inhibition of necrosis of the infected host cells, presumably through suppression of intracellular ROS generation.

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