4.6 Article

Aggregated Mycobacterium tuberculosis Enhances the Inflammatory Response

Journal

FRONTIERS IN MICROBIOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fmicb.2021.757134

Keywords

Mycobacterium tuberculosis; TB pathogenesis; aggregation; inflammation; TNF-alpha; phagocytosis

Categories

Funding

  1. Bill and Melinda Gates Foundation [OPP1116944]
  2. Sub-Saharan African Network for TB/HIV Research Excellence [SANTHE, a DELTAS Africa Initiative] fellowship [DEL-15-006]
  3. Searle Scholars Program
  4. Beckman Young Investigator Program
  5. Sloan Fellowship in Chemistry
  6. Bill and Melinda Gates Foundation [OPP1116944] Funding Source: Bill and Melinda Gates Foundation

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Aggregated Mtb infection leads to upregulation of pro-inflammatory genes and enhanced TNF alpha signaling via the NF kappa B pathway in human macrophages. Phagocytosis of Mtb aggregates leads to decreased acidification and increased cell death, suggesting a potential mechanism for TB pathogenesis. Detection of Mtb aggregates in patient granulomas raises the possibility of increased inflammation, bacterial growth, and macrophage death, leading to active disease and transmission cycles.
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 TNF alpha signaling via the NF kappa B 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.

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