Virulent Mycobacterium bovis Beijing Strain Activates the NLRP7 Inflammasome in THP-1 Macrophages

Zhou, Yang; Shah, Syed Qaiser; Yang, Lifeng; Zhang, Zhongqiu; Zhou, Xiangmei; Zhao, Deming

doi:10.1371/journal.pone.0152853

Cited by 30 publications

(35 citation statements)

References 40 publications

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“…The protein level of AIM2, the cytoplasmic sensor molecule, was elevated over time after infection of THP-1 cells despite the fact that AIM2 mRNA increased only at 6 hours post EBV incubation and subsequently decreased. Sustainment of the protein level of PRRs after peak expression of their mRNAs was also observed in another study [26]. Furthermore, the AIM2 mRNA level was significantly increased in primary human monocytes after EBV infection.…”

Section: Discussionsupporting

confidence: 71%

Epstein-Barr virus infection-induced inflammasome activation in human monocytes

et al. 2017

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Inflammasomes are cytoplasmic sensors that regulate the activity of caspase-1 and the secretion of interleukin-1β (IL-1β) or interleukin-18 (IL-18) in response to foreign molecules, including viral pathogens. They are considered to be an important link between the innate and adaptive immune responses. However, the mechanism by which inflammasome activation occurs during primary Epstein-Barr virus (EBV) infection remains unknown. Human B lymphocytes and epithelial cells are major targets of EBV, although it can also infect a variety of other cell types. In this study, we found that EBV could infect primary human monocytes and the monocyte cell line, THP-1, inducing inflammasome activation. We incubated cell-free EBV with THP-1 cells or primary human monocytes, then confirmed EBV infection using confocal microscopy and flow cytometry. Lytic and latent EBV genes were detected by real-time RT-PCR in EBV-infected monocytes. EBV infection of THP-1 cells and primary human monocytes induced caspase-dependent IL-1β production, while EBV infection of B-cell or T-cell lines did not induce IL-1β production. To identify the sensor molecule responsible for inflammasome activation during EBV infection, we examined the mRNA and the protein levels of NLR family pyrin domain-containing 3 (NLRP3), absent in melanoma 2 (AIM2), and interferon-inducible protein 16 (IFI16). Increased AIM2 levels were observed in EBV-infected THP-1 cells and primary human monocytes, whereas levels of IFI16 and NLRP3 did not show remarkable change. Furthermore, knockdown of AIM2 by small interfering RNA attenuated caspase-1 activation. Taken together, our results suggest that EBV infection of human monocytes induces caspase-1-dependent IL-1β production, and that AIM2, acting as an inflammasome, is involved in this response.

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Section: Discussionsupporting

confidence: 71%

Epstein-Barr virus infection-induced inflammasome activation in human monocytes

et al. 2017

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“…We also found residual caspase-1-dependent IL-1β maturation in cells lacking NLRP3 and AIM2, pointing towards the involvement of other inflammasome sensors. A recent study identified the NLRP7 inflammasome as a mediator of caspase-1 activation during Mycobacterium bovis infection 49 . Microbial lipopeptides signalling via TLR2 have also been shown to activate the NLRP7 inflammasome 50 .…”

Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological inhibition of inflammasomes reduces the survival of Mycobacterium tuberculosis strains in macrophages

Subbarao

Sanchez‐Garrido

Krishnan

et al. 2020

Sci Rep

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Mycobacterium tuberculosis infection causes high rates of morbidity and mortality. Host-directed therapy may enhance the immune response, reduce tissue damage and shorten treatment duration. The inflammasome is integral to innate immune responses but over-activation has been described in tuberculosis (TB) pathology and TB-immune reconstitution syndrome. Here we explore how clinical isolates differentially activate the inflammasome and how inflammasome inhibition can lead to enhanced bacterial clearance. Wild-type, Nlrp3 −/− /Aim2 −/− , Casp1/11 −/− and Asc −/− murine bonemarrow derived macrophages (BMDMs) were infected with laboratory strain M. tuberculosis H37Rv or clinical isolates from various lineages. Inflammasome activation and bacterial numbers were measured, and pharmacological inhibition of NLRP3 was achieved using MCC950. Clinical isolates of M. tuberculosis differed in their ability to activate inflammasomes. Beijing isolates had contrasting effects on IL-1β and caspase-1 activation, but all clinical isolates induced lower IL-1β release than H37Rv. Our studies suggest the involvement of NLRP3, AIM2 and an additional unknown sensor in IL-1β maturation. Pharmacological blockade of NLRP3 with MCC950 reduced bacterial survival, and combined treatment with the antimycobacterial drug rifampicin enhanced the effect. Modulating the inflammasome is an attractive adjunct to current anti-mycobacterial therapy that warrants further investigation. Although significant strides have been made in reducing the disease burden attributed to TB, it remains a considerable cause of mortality. Current figures estimate that 1.6 million people died from TB in 2017 1. Progress has been impeded by the rise in drug resistance and the HIV-epidemic. However, it is the ability of the bacterium to modulate its metabolism within the host environment 2 , enter non-replicating persistence 3 and form biofilms 4 in order to facilitate its own survival that leads to treatment difficulties 2. Treatment of M. tuberculosis necessitates a prolonged multi-drug regimen 5. Anti-microbials target actively replicating bacteria, but the intracellular population is composed of a mixed phenotype, requiring extended therapy to eradicate those bacterial populations that transiently and stochastically leave the slowly replicating state to enter an actively replicating state 5. However, the extended treatment is associated with non-compliance and selection of resistant mutations. To identify alternative anti-mycobacterial therapies efforts have been directed at altering the host immune response through host-directed therapy (HDT), which is to be used as an adjunct to standard quadruple therapy. Deregulated host immune responses may be counter-productive to bacterial killing and lead to tissue destruction, such that half of TB-survivors have some degree of persisting lung damage following successful microbiological cure 6. Thus, the host response may be manipulated in two ways; firstly by augmenting bacterial killing and secondly by rebalancing the inflamm...

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“…IL-1β has been found to play an important role in the anti-mycobacterial response by aiding in macrophage destruction of mycobacteria [58, 59]; however, its expression by γδ T cells has not been previously characterized during M. bovis infection. One caveat to our transcriptomics analysis is the approach used to prepare our γδ T cells.…”

Section: Discussionmentioning

confidence: 99%

Measuring bovine γδ T cell function at the site of Mycobacterium bovis infection

Rusk

Palmer

Waters

et al. 2017

Veterinary Immunology and Immunopathology

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Bovine γδ T cells are amongst the first cells to accumulate at the site of Mycobacterium bovis infection; however, their role in the developing lesion remains unclear. We utilized transcriptomics analysis, in situ hybridization, and a macrophage/γδ T cell co-culture system to elucidate the role of γδ T cells in local immunity to M. bovis infection. Transcriptomics analysis revealed that γδ T cells upregulated expression of several novel, immune-associated genes in response to stimulation with M. bovis antigen. BCG-infected macrophage/γδ T cell co-cultures confirmed the results of our RNAseq analysis, and revealed that γδ T cells from M. bovis-infected animals had a significant impact on bacterial viability. Analysis of γδ T cells within late-stage M. bovis granulomas revealed significant expression IFN-γ and CCL2, but not IL-10, IL-22, or IL-17. Our results suggest γδ T cells influence local immunity to M. bovis through cytokine secretion and direct effects on bacterial burden.

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Virulent Mycobacterium bovis Beijing Strain Activates the NLRP7 Inflammasome in THP-1 Macrophages

Cited by 30 publications

References 40 publications

Epstein-Barr virus infection-induced inflammasome activation in human monocytes

Epstein-Barr virus infection-induced inflammasome activation in human monocytes

Genetic and pharmacological inhibition of inflammasomes reduces the survival of Mycobacterium tuberculosis strains in macrophages

Measuring bovine γδ T cell function at the site of Mycobacterium bovis infection

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