Tuberculosis and the art of macrophage manipulation

Upadhyay, Sandeep; Mittal, Ekansh; Philips, Jennifer A.

doi:10.1093/femspd/fty037

Cited by 140 publications

(119 citation statements)

References 159 publications

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“…The functional role of the ESX-1 system is to damage the phagosomal membrane following uptake by host phagocytes (21)(22)(23)(24)(25). Phagosomal damage allows M. marinum, as well as its secreted products, access to the host cell cytosol, where it triggers and combats the host cell response to infection (20). One measure of the lytic activity of the ESX-1 system is its activity against sheep red blood cells (sRBCs).…”

Section: Resultsmentioning

confidence: 99%

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

et al. 2019

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The ESX-1 (ESAT-6 system 1) secretion system plays a conserved role in the virulence of diverse mycobacterial pathogens, including the human pathogen Mycobacterium tuberculosis and M. marinum, an environmental mycobacterial species. The ESX-1 system promotes the secretion of protein virulence factors to the extracytoplasmic environment. The secretion of these proteins triggers the host response by lysing the phagosome during macrophage infection. Using proteomic analyses of the M. marinum secretome in the presence and absence of a functional ESX-1 system, we and others have hypothesized that MMAR_2894, a PE family protein, is a potential ESX-1 substrate in M. marinum. We used genetic and quantitative proteomic approaches to determine if MMAR_2894 is secreted by the ESX-1 system, and we defined the requirement of MMAR_2894 for ESX-1-mediated secretion and virulence. We show that MMAR_2894 is secreted by the ESX-1 system in M. marinum and is itself required for the optimal secretion of the known ESX-1 substrates in M. marinum. Moreover, we found that MMAR_2894 was differentially required for hemolysis and cytolysis of macrophages, two lytic activities ascribed to the M. marinum ESX-1 system. IMPORTANCE Both Mycobacterium tuberculosis, the cause of human tuberculosis (TB), and Mycobacterium marinum, a pathogen of ectotherms, use the ESX-1 secretion system to cause disease. There are many established similarities between the ESX-1 systems in M. tuberculosis and in M. marinum. Yet the two bacteria infect different hosts, hinting at species-specific functions of the ESX-1 system. Our findings demonstrate that MMAR_2894 is a PE protein secreted by the ESX-1 system of M. marinum. We show that MMAR_2894 is required for the optimal secretion of mycobacterial proteins required for disease. Because the MMAR_2894 gene is not conserved in M. tuberculosis, our findings demonstrate that MMAR_2894 may contribute to a species-specific function of the ESX-1 system in M. marinum, providing new insight into how the M. marinum and M. tuberculosis systems differ.

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Section: Resultsmentioning

confidence: 99%

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

et al. 2019

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“…miRNAs are a general class of endogenous noncoding RNAs of 22–25 nucleotides, widely existing in diverse species, and playing essential roles in cell proliferation, immune response, and maintaining homeostasis . miRNAs can control the expression of nearly 30% of protein‐coding genes by targeting a sequence located in the 3′‐untranslated region (3′‐UTR) of the target genes, resulting in cleavage or inhibition of translation and causing profound changes in protein levels .…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

et al. 2019

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Autophagy is a highly conserved catabolic process and fundamental biological process in eukaryotic cells. It recycles intracellular components to provide nutrients during starvation and maintains quality control of organelles and proteins. In addition, autophagy is a well‐organized homeostatic cellular process that is responsible for the removal of damaged organelles and intracellular pathogens. Moreover, it also modulates the innate and adaptive immune systems. Micro ribonucleic acids (microRNAs) are a mature class of post‐transcriptional modulators that are widely expressed in tissues and organs. And, it can suppress gene expression by targeting messenger RNAs for translational repression or, at a lesser extent, degradation. Research indicates that microRNAs regulate autophagy through different pathways, playing an essential role in the treatment of various diseases. It is an important regulator of fundamental cellular processes such as proliferation, autophagy, and cell apoptosis. In this review article, we first review the current knowledge of autophagy and the function of microRNAs. Then, we summarize the mechanism of autophagy and the signaling pathways related to autophagy by citing at least the main proteins involved in the different phases of the process. Second, we introduce other members of RNA and report some examples in various pathologies. Finally, we review the current literature regarding microRNA‐based therapies for cancer, atherosclerosis, cardiac disease, tuberculosis, and viral diseases. MicroRNAs can cause autophagy upregulation or downregulation by targeting genes or affecting autophagy‐related signaling pathways. Therefore, the microRNAs have a huge potential in autophagy regulation, and it is the function as diagnostic and prognostic markers.

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“…The ESX-1 system is functionally conserved between M. tuberculosis, the cause of human tuberculosis, and Mycobacterium marinum, a pathogen of poikilothermic fish and an established model for the ESX-1 system (14)(15)(16)(17)(18). Phagosomal lysis releases secreted bacterial factors and triggers the host response to infection (7,8,(19)(20)(21)(22)(23)(24)(25)(26)(27). In the absence of an ESX-1 system, both mycobacterial pathogens remain in the phagosome and are attenuated (7)(8)(9)22).…”

mentioning

confidence: 99%

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

Sanchez

Ferrell

Chirakos

et al. 2020

mBio

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Pathogenic mycobacteria encounter multiple environments during macrophage infection. Temporally, the bacteria are engulfed into the phagosome, lyse the phagosomal membrane, and interact with the cytosol before spreading to another cell. Virulence factors secreted by the mycobacterial ESX-1 (ESAT-6-system-1) secretion system mediate the essential transition from the phagosome to the cytosol. It was recently discovered that the ESX-1 system also regulates mycobacterial gene expression in Mycobacterium marinum (R. E. Bosserman, T. T. Nguyen, K. G. Sanchez, A. E. Chirakos, et al., Proc Natl Acad Sci U S A 114:E10772–E10781, 2017, https://doi.org/10.1073/pnas.1710167114), a nontuberculous mycobacterial pathogen, and in the human-pathogenic species M. tuberculosis (A. M. Abdallah, E. M. Weerdenburg, Q. Guan, R. Ummels, et al., PLoS One 14:e0211003, 2019, https://doi.org/10.1371/journal.pone.0211003). It is not known how the ESX-1 system regulates gene expression. Here, we identify the first transcription factor required for the ESX-1-dependent transcriptional response in pathogenic mycobacteria. We demonstrate that the gene divergently transcribed from the whiB6 gene and adjacent to the ESX-1 locus in mycobacterial pathogens encodes a conserved transcription factor (MMAR_5438, Rv3863, now espM). We prove that EspM from both M. marinum and M. tuberculosis directly and specifically binds the whiB6-espM intergenic region. We show that EspM is required for ESX-1-dependent repression of whiB6 expression and for the regulation of ESX-1-associated gene expression. Finally, we demonstrate that EspM functions to fine-tune ESX-1 activity in M. marinum. Taking the data together, this report extends the esx-1 locus, defines a conserved regulator of the ESX-1 virulence pathway, and begins to elucidate how the ESX-1 system regulates gene expression. IMPORTANCE Mycobacterial pathogens use the ESX-1 system to transport protein substrates that mediate essential interactions with the host during infection. We previously demonstrated that in addition to transporting proteins, the ESX-1 secretion system regulates gene expression. Here, we identify a conserved transcription factor that regulates gene expression in response to the ESX-1 system. We demonstrate that this transcription factor is functionally conserved in M. marinum, a pathogen of ectothermic animals; M. tuberculosis, the human-pathogenic species that causes tuberculosis; and M. smegmatis, a nonpathogenic mycobacterial species. These findings provide the first mechanistic insight into how the ESX-1 system elicits a transcriptional response, a function of this protein transport system that was previously unknown.

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Tuberculosis and the art of macrophage manipulation

Cited by 140 publications

References 159 publications

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

A New ESX-1 Substrate in Mycobacterium marinum That Is Required for Hemolysis but Not Host Cell Lysis

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

EspM Is a Conserved Transcription Factor That Regulates Gene Expression in Response to the ESX-1 System

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