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 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 NF-κB translocation prevents host cell death after low-dose challenge by Legionella pneumophila

2006 ◽  
Vol 203 (9) ◽  
pp. 2177-2189 ◽  
Author(s):  
Vicki P. Losick ◽  
Ralph R. Isberg
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Legionella Pneumophila ◽  
Low Dose ◽  
Plasminogen Activator Inhibitor ◽  
Nuclear Factor Κb ◽  
Human Macrophage ◽  
Dependent Manner ◽  
Host Cell Response ◽  
Host Cell Death

Legionella pneumophila, the causative agent of Legionnaires' disease, grows within macrophages and manipulates target cell signaling. Formation of a Legionella-containing replication vacuole requires the function of the bacterial type IV secretion system (Dot/Icm), which transfers protein substrates into the host cell cytoplasm. A global microarray analysis was used to examine the response of human macrophage-like U937 cells to low-dose infections with L. pneumophila. The most striking change in expression was the Dot/Icm-dependent up-regulation of antiapoptotic genes positively controlled by the transcriptional regulator nuclear factor κB (NF-κB). Consistent with this finding, L. pneumophila triggered nuclear localization of NF-κB in human and mouse macrophages in a Dot/Icm-dependent manner. The mechanism of activation at low-dose infections involved a signaling pathway that occurred independently of the Toll-like receptor adaptor MyD88 and the cytoplasmic sensor Nod1. In contrast, high multiplicity of infection conditions caused a host cell response that masked the unique Dot/Icm-dependent activation of NF-κB. Inhibition of NF-κB translocation into the nucleus resulted in premature host cell death and termination of bacterial replication. In the absence of one antiapoptotic protein, plasminogen activator inhibitor–2, host cell death increased in response to L. pneumophila infection, indicating that induction of antiapoptotic genes is critical for host cell survival.

scholarly journals Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death

2012 ◽  
Vol 8 (2) ◽  
pp. e1002507 ◽  
Author(s):  
Roxane Simeone ◽  
Alexandre Bobard ◽  
Juliane Lippmann ◽  
Wilbert Bitter ◽  
Laleh Majlessi ◽  
...  
Keyword(s):  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Host Cell Death

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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