Mycobacterium tuberculosis PE_PGRS19 Induces Pyroptosis through a Non-Classical Caspase-11/GSDMD Pathway in Macrophages

Qian, Jianing; Hu, Youwei; Zhang, Xiao; Chi, Mingzhe; Xu, Siyue; Wang, Honghai

doi:10.3390/microorganisms10122473

Cited by 13 publications

(7 citation statements)

References 41 publications

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“…These proteins constitute a unique subfamily which is usually found only in the pathogenic species of the Mycobacterium genus. Despite the fact that their function remains largely unclear, they are believed to be crucial actors in HPI during M. tb infection, being involved in many biological processes such as cell adhesion, phagocytosis, oxidative stress and apoptosis [48]. Among the most represented M.tb hubs in our networks is PE_PGRS18, a particularly interesting one, that displayed the ability to inhibit the apoptosis of infected macrophages, thus promoting bacterial intracellular survival [49].…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis-THP-1 like macrophages protein-protein interaction map revealed through dual RNA-seq analysis and a computational approach

Hkimi,

Kamoun,

Khamessi

et al. 2024

Journal of Medical Microbiology

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Introduction. Infection caused by Mycobacterium tuberculosis (M. tb) is still a leading cause of mortality worldwide with estimated 1.4 million deaths annually. Hypothesis/Gap statement. Despite macrophages' ability to kill bacterium, M. tb can grow inside these innate immune cells and the exploration of the infection has traditionally been characterized by a one-sided relationship, concentrating solely on the host or examining the pathogen in isolation. Aim. Because of only a handful of M. tb–host interactions have been experimentally characterized, our main goal is to predict protein–protein interactions during the early phases of the infection. Methodology. In this work, we performed an integrative computational approach that exploits differentially expressed genes obtained from Dual RNA-seq analysis combined with known domain–domain interactions. Results. A total of 2381 and 7214 genes were identified as differentially expressed in M. tb and in THP-1-like macrophages, respectively, revealing different transcriptional profiles in response to infection. Over 48 h of infection, the host–pathogen network revealed 25 016 PPIs. Analysis of the resulting predicted network based on cellular localization information of M. tb proteins, indicated the implication of interacting nodes including the bacterial PE/PPE/PE_PGRS family. In addition, M. tb proteins interacted with host proteins involved in NF-kB signalling pathway as well as interfering with the host apoptosis ability via the potential interaction of M. tb TB16.3 with human TAB1 and M. tb GroEL2 with host protein kinase C delta, respectively. Conclusion. The prediction of the full range of interactions between M. tb and host will contribute to better understanding of the pathogenesis of this bacterium and may provide advanced approaches to explore new therapeutic targets against tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis-THP-1 like macrophages protein-protein interaction map revealed through dual RNA-seq analysis and a computational approach

Hkimi,

Kamoun,

Khamessi

et al. 2024

Journal of Medical Microbiology

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“…One outstanding line of questions from our findings is the specificity of the genetic interaction between Cybb and Caspase1/11. Both Caspase1-and Caspase11-dependent pathways are activated during Mtb infection, yet the direct contribution of either Caspase1 or Caspase11 to our observed susceptibility remains to be investigated by individually generating either Cybb -/-Caspase1 -/-or Cybb -/-Caspase11 -/-animals (18,(42)(43)(44). Given the recent availability of clean Caspase1 and Caspase11 knockout mice, we are in the process of developing these models for the future (45)(46)(47).…”

Section: Discussionmentioning

confidence: 99%

Rapid lethality of mice lacking the phagocyte oxidase and Caspase1/11 followingMycobacterium tuberculosisinfection

Thomas

Olive

2023

Preprint

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Immune networks that control antimicrobial and inflammatory mechanisms have overlapping regulation and functions to ensure effective host responses. Genetic interaction studies of immune pathways that compare host responses in single and combined knockout backgrounds are a useful tool to identify new mechanisms of immune control during infection. For disease caused by pulmonaryMycobacterium tuberculosis(Mtb) infections, which currently lacks an effective vaccine, understanding genetic interactions between protective immune pathways may identify new therapeutic targets or disease-associated genes. Previous studies suggested a direct link between the activation of NLRP3-Caspase1 inflammasome and the NADPH-dependent phagocyte oxidase complex during Mtb infection. Loss of the phagocyte oxidase complex alone resulted in increased activation of Caspase1 and IL1β production during Mtb infection, resulting in failed disease tolerance during the chronic stages of disease. To better understand this interaction, we generated mice lacking bothCybb, a key subunit of the phagocyte oxidase, andCaspase1/11. We found thatex vivoMtb infection ofCybb-/-Caspase1/11-/-macrophages resulted in the expected loss of IL1β secretion but an unexpected change in other inflammatory cytokines and bacterial control. Mtb infectedCybb-/-Caspase1/11-/-mice rapidly progressed to severe TB, succumbing within four weeks to disease characterized by high bacterial burden, increased inflammatory cytokines, and the recruitment of granulocytes that associated with Mtb in the lungs. These results uncover a key genetic interaction between the phagocyte oxidase complex and Caspase1/11 that controls protection against TB and highlight the need for a better understanding of the regulation of fundamental immune networks during Mtb infection.

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“…For example, PPE13 activates the NLRP3 inflammasome, thereby inducing caspase‐1 cleavage and IL‐1β secretion in J774a.1, BMDMs, and THP‐1 macrophages 112 . Recent studies have shown for the first time that PE_PGRS19 induces pyroptosis through a non‐classical Caspase‐11/GSDMD pathway in macrophages and promotes the survival of the bacterium 113 …”

Section: Pyroptosismentioning

confidence: 99%

Host‐pathogen dialogues in different cell death modes during Mycobacterium tuberculosis infection

Ruan,

Lyu,

Lai

et al. 2024

Interdisciplinary Medicine

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Tuberculosis (TB) is a fatal infectious disease that continues to pose a serious public health threat. The emergence of drug‐resistant TB has further worsened the burden of the disease. The interaction between the host and the pathogen involves multiple modes of cell death, which play a role in determining immune outcomes. Several studies have established a strong correlation between cell death and TB progression. This review explores the molecular mechanisms of various cell death modes in Mycobacterium tuberculosis (Mtb) infection and how Mtb's virulence effectors regulate these pathways, including apoptosis, autophagy, pyroptosis, ferroptosis, and necrosis. Furthermore, therapeutic strategies targeting cell death pathways have shown promising results in TB treatment. Importantly, this review highlights the significant potential of mitochondria in mediating communication between different cell death modes and influencing the final outcomes. Overall, this work provides a comprehensive summary of the role of cell death in host immune responses and immune evasion by Mtb. It also offers valuable insights into the pathogenesis of TB and immune evasion strategies employed by Mtb and contributes to the development of more effective anti‐TB therapies.

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Mycobacterium tuberculosis PE_PGRS19 Induces Pyroptosis through a Non-Classical Caspase-11/GSDMD Pathway in Macrophages

Cited by 13 publications

References 41 publications

Mycobacterium tuberculosis-THP-1 like macrophages protein-protein interaction map revealed through dual RNA-seq analysis and a computational approach

Mycobacterium tuberculosis-THP-1 like macrophages protein-protein interaction map revealed through dual RNA-seq analysis and a computational approach

Rapid lethality of mice lacking the phagocyte oxidase and Caspase1/11 followingMycobacterium tuberculosisinfection

Host‐pathogen dialogues in different cell death modes during Mycobacterium tuberculosis infection

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