Abstract
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.
Highlights
We examined whether bacterial aggregation could differentially modulate the early host cell transcriptional response
We determined the range of fluorescence per single Mycobacterium tuberculosis (Mtb) (Supplementary Figure 1) and we used sorting gates, which corresponded to zero Mtb per macrophage (Figure 1A, sorting gate P1), one Mtb per macrophage (Figure 1A, sorting gate P2), or more than one Mtb per macrophage (Figure 1A, sorting gate P3)
Sorted macrophages were classified as multiply infected by single Mtb if single Mtb was used as the source of infection, or as having internalized an Mtb aggregate if aggregated Mtb was used as the source of infection
Summary
Mycobacterium tuberculosis (Mtb) infection of a human lung results in either a latent disease state, in which an individual remains asymptomatic, or active tuberculosis (TB) disease, manifesting as hemoptysis, lung damage, weight loss, and other severe systemic effects (Russell, 2001, 2007; Barry et al, 2009; Ramakrishnan, 2012; Martin et al, 2017). In active TB, Mtb infection leads to necrosis of the granuloma, the structure which contains Mtb infection, attempting to isolate it from the surrounding lung (Kaplan et al, 2003; Barry et al, 2009; Lin et al, 2014; Lenaerts et al, 2015) This in turn results in the necrotic granuloma undergoing liquefaction that can breach the alveoli, Mtb Aggregates Elicit More Inflammation entering the airway and is followed by expectoration of bacilli out of the lung and transmission to other hosts (Russell, 2001, 2007; Barry et al, 2009; Ramakrishnan, 2012). Mtb aggregates have recently been shown to be transmitted in bio-aerosols (Dinkele et al, 2021)
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