scholarly journals Mycobacterium tuberculosis evasion of Guanylate Binding Protein-mediated host defense in mice requires the ESX1 secretion system

2020 ◽  
Author(s):  
Andrew J. Olive ◽  
Clare M. Smith ◽  
Christina E. Baer ◽  
Jörn Coers ◽  
Christopher M. Sassetti
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Defense ◽  
Genetic Interaction ◽  
Mycobacterial Infection ◽  
Secretion System ◽  
Immune Defense ◽  
Chromosome 3 ◽  
Intracellular Pathogens ◽  
Potent Inducer ◽  
Defense Proteins

AbstractCell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen Mycobacterium tuberculosis (Mtb) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of IFNγ by T cells is essential to protect against Mtb, it is not capable of fully eradicating Mtb infection. This suggests that Mtb evades a subset of IFNγ-mediated antimicrobial responses, yet what mechanisms Mtb resists remains unclear. The IFNγ-inducible Guanylate binding proteins (GBPs) are key host defense proteins able to control infections with intracellular pathogens. GBPs were previously shown to directly restrict Mycobacterium bovis BCG yet their role during Mtb infection has remained unknown. Here, we examine the importance of a cluster of five GBPs on mouse chromosome 3 in controlling Mycobacterial infection. While M. bovis BCG is directly restricted by GBPs, we find that the GBPs on chromosome 3 do not contribute to the control of Mtb replication or the associated host response to infection. The differential effects of GBPs during Mtb versus M. bovis BCG infection is at least partially explained by the absence of the ESX1 secretion system from M. bovis BCG, since Mtb mutants lacking the ESX1 secretion system become similarly susceptible to GBP-mediated immune defense. Therefore, this specific genetic interaction between the murine host and Mycobacteria reveals a novel function for the ESX1 virulence system in the evasion of GBP-mediated immunity.

scholarly journals Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella

2010 ◽  
Vol 207 (8) ◽  
pp. 1745-1755 ◽  
Author(s):  
Petr Broz ◽  
Kim Newton ◽  
Mohamed Lamkanfi ◽  
Sanjeev Mariathasan ◽  
Vishva M. Dixit ◽  
...  
Keyword(s):  
Salmonella Typhimurium ◽  
Host Defense ◽  
Immune Defense ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Intracellular Pathogens ◽  
Danger Signals ◽  
Caspase 1 ◽  
Innate Immune Defense

Intracellular pathogens and endogenous danger signals in the cytosol engage NOD-like receptors (NLRs), which assemble inflammasome complexes to activate caspase-1 and promote the release of proinflammatory cytokines IL-1β and IL-18. However, the NLRs that respond to microbial pathogens in vivo are poorly defined. We show that the NLRs NLRP3 and NLRC4 both activate caspase-1 in response to Salmonella typhimurium. Responding to distinct bacterial triggers, NLRP3 and NLRC4 recruited ASC and caspase-1 into a single cytoplasmic focus, which served as the site of pro–IL-1β processing. Consistent with an important role for both NLRP3 and NLRC4 in innate immune defense against S. typhimurium, mice lacking both NLRs were markedly more susceptible to infection. These results reveal unexpected redundancy among NLRs in host defense against intracellular pathogens in vivo.

scholarly journals Mycobacterium tuberculosis Protein PE6 (Rv0335c), a Novel TLR4 Agonist, Evokes an Inflammatory Response and Modulates the Cell Death Pathways in Macrophages to Enhance Intracellular Survival

2021 ◽  
Vol 12 ◽  
Author(s):  
Neha Sharma ◽  
Mohd Shariq ◽  
Neha Quadir ◽  
Jasdeep Singh ◽  
Javaid A. Sheikh ◽  
...  
Keyword(s):  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Proinflammatory Cytokines ◽  
Intracellular Survival ◽  
Immune Defense ◽  
Innate Immune ◽  
Bafilomycin A1 ◽  
Potent Inducer ◽  
Cell Functions ◽  
Cell Death Pathways

Mycobacterium tuberculosis (M. tb) is an intracellular pathogen that exploits moonlighting functions of its proteins to interfere with host cell functions. PE/PPE proteins utilize host inflammatory signaling and cell death pathways to promote pathogenesis. We report that M. tb PE6 protein (Rv0335c) is a secretory protein effector that interacts with innate immune toll-like receptor TLR4 on the macrophage cell surface and promotes activation of the canonical NFĸB signaling pathway to stimulate secretion of proinflammatory cytokines TNF-α, IL-12, and IL-6. Using mouse macrophage TLRs knockout cell lines, we demonstrate that PE6 induced secretion of proinflammatory cytokines dependent on TLR4 and adaptor Myd88. PE6 possesses nuclear and mitochondrial targeting sequences and displayed time-dependent differential localization into nucleus/nucleolus and mitochondria, and exhibited strong Nucleolin activation. PE6 strongly induces apoptosis via increased production of pro-apoptotic molecules Bax, Cytochrome C, and pcMyc. Mechanistic details revealed that PE6 activates Caspases 3 and 9 and induces endoplasmic reticulum-associated unfolded protein response pathways to induce apoptosis through increased production of ATF6, Chop, BIP, eIF2α, IRE1α, and Calnexin. Despite being a potent inducer of apoptosis, PE6 suppresses innate immune defense strategy autophagy by inducing inhibitory phosphorylation of autophagy initiating kinase ULK1. Inversely, PE6 induces activatory phosphorylation of autophagy master regulator MtorC1, which is reflected by lower conversion of autophagy markers LC3BI to LC3BII and increased accumulation of autophagy substrate p62 which is also dependent on innate immune receptor TLR4. The use of pharmacological agents, rapamycin and bafilomycin A1, confirms the inhibitory effect of PE6 on autophagy, evidenced by the reduced conversion of LC3BI to LC3BII and increased accumulation of p62 in the presence of rapamycin and bafilomycin A1. We also observed that PE6 binds DNA, which could have significant implications in virulence. Furthermore, our analyses reveal that PE6 efficiently binds iron to likely aid in intracellular survival. Recombinant Mycobacterium smegmatis (M. smegmatis) containing pe6 displayed robust growth in iron chelated media compared to vector alone transformed cells, which suggests a role of PE6 in iron acquisition. These findings unravel novel mechanisms exploited by PE6 protein to subdue host immunity, thereby providing insights relevant to a better understanding of host–pathogen interaction during M. tb infection.

scholarly journals Mycoketide: A CD1c-Presented Antigen with Important Implications in Mycobacterial Infection

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Isamu Matsunaga ◽  
Masahiko Sugita
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Host Defense ◽  
Biosynthetic Pathway ◽  
Mycobacterial Infection ◽  
Acquired Immunity ◽  
Human Group ◽  
Unique Role ◽  
Lipid Antigens ◽  
Group 1

Mycobacterium tuberculosisand related mycobacteria species are unique in that the acid-fast bacilli possess a highly lipid-rich cell wall that not simply confers resistance to treatment with acid alcohol, but also controls their survival and virulence. It has recently been established that a fraction of the cell wall lipid components of mycobacteria can function as antigens targeted by the acquired immunity of the host. Human group 1 CD1 molecules (CD1a, CD1b, and CD1c) bind a pool of lipid antigens expressed by mycobacteria and present them to specific T cells, thereby mediating an effective pathway for host defense against tuberculosis. The contrasting and mutually complementary functions of CD1a and CD1b molecules in terms of the repertoire of antigens they bind have been well appreciated, but it remains to be established how CD1c may play a unique role. Nevertheless, recent advances in our understanding of the CD1c structure as well as the biosynthetic pathway of a CD1c-presented antigen, mannose-1, β-phosphomycoketide, expressed by pathogenic mycobacteria now unravel a new aspect of the group 1 CD1 biology that has not been appreciated in previous studies of CD1a and CD1b molecules.

scholarly journals The Contribution of the Airway Epithelial Cell to Host Defense

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Frauke Stanke
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cell ◽  
Ion Transport ◽  
Host Defense ◽  
Immune Defense ◽  
Bicarbonate Transport ◽  
Airway Epithelial ◽  
Defense Proteins ◽  
Inflammatory Conditions

In the context of cystic fibrosis, the epithelial cell has been characterized in terms of its ion transport capabilities. The ability of an epithelial cell to initiate CFTR-mediated chloride and bicarbonate transport has been recognized early as a means to regulate the thickness of the epithelial lining fluid and recently as a means to regulate the pH, thereby determining critically whether or not host defense proteins such as mucins are able to fold appropriately. This review describes how the epithelial cell senses the presence of pathogens and inflammatory conditions, which, in turn, facilitates the activation of CFTR and thus directly promotes pathogens clearance and innate immune defense on the surface of the epithelial cell. This paper summarizes functional data that describes the effect of cytokines, chemokines, infectious agents, and inflammatory conditions on the ion transport properties of the epithelial cell and relates these key properties to the molecular pathology of cystic fibrosis. Recent findings on the role of cystic fibrosis modifier genes that underscore the role of the epithelial ion transport in host defense and inflammation are discussed.

scholarly journals Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense

Science ◽  
2020 ◽  
Vol 370 (6514) ◽  
pp. eaay8085 ◽  
Author(s):  
Marta Bosch ◽  
Miguel Sánchez-Álvarez ◽  
Alba Fajardo ◽  
Ronan Kapetanovic ◽  
Bernhard Steiner ◽  
...  
Keyword(s):  
Host Defense ◽  
Lipid Droplets ◽  
Acid Metabolism ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Eukaryotic Cells ◽  
Metabolic Adaptation ◽  
Intracellular Pathogens ◽  
Defense Proteins ◽  
Danger Signals

Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and a source of nutrients for intracellular pathogens. We demonstrate that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated by danger signals. In response to lipopolysaccharide (LPS), multiple host defense proteins, including interferon-inducible guanosine triphosphatases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD-bacterial contacts. Thus, LDs actively participate in mammalian innate immunity at two levels: They are both cell-autonomous organelles that organize and use immune proteins to kill intracellular pathogens as well as central players in the local and systemic metabolic adaptation to infection.

scholarly journals Mycobacterium tuberculosisType VII Secretion System Effectors Differentially Impact the ESCRT Endomembrane Damage Response

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Ekansh Mittal ◽  
Michael L. Skowyra ◽  
Grace Uwase ◽  
Emir Tinaztepe ◽  
Alka Mehra ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Recent Work ◽  
Host Response ◽  
Membrane Damage ◽  
Secretion System ◽  
Intracellular Pathogens ◽  
Dependent Manner ◽  
Membrane Repair ◽  
Content Type ◽  
Endosomal Sorting

ABSTRACTIntracellular pathogens have varied strategies to breach the endolysosomal barrier so that they can deliver effectors to the host cytosol, access nutrients, replicate in the cytoplasm, and avoid degradation in the lysosome. In the case ofMycobacterium tuberculosis, the bacterium perforates the phagosomal membrane shortly after being taken up by macrophages. Phagosomal damage depends upon the mycobacterial ESX-1 type VII secretion system (T7SS). Sterile insults, such as silica crystals or membranolytic peptides, can also disrupt phagosomal and endolysosomal membranes. Recent work revealed that the host endosomal sorting complex required for transport (ESCRT) machinery rapidly responds to sterile endolysosomal damage and promotes membrane repair. We hypothesized that ESCRTs might also respond to pathogen-induced phagosomal damage and thatM. tuberculosiscould impair this host response. Indeed, we found that ESCRT-III proteins were recruited toM. tuberculosisphagosomes in anESX-1-dependent manner. We previously demonstrated that the mycobacterial effectors EsxG/TB9.8 and EsxH/TB10.4, both secreted by the ESX-3 T7SS, can inhibit ESCRT-dependent trafficking of receptors to the lysosome. Here, we additionally show that ESCRT-III recruitment to sites of endolysosomal damage is antagonized by EsxG and EsxH, both within the context ofM. tuberculosisinfection and sterile injury. Moreover, EsxG and EsxH themselves respond within minutes to membrane damage in a manner that is independent of calcium and ESCRT-III recruitment. Thus, our study reveals that T7SS effectors and ESCRT participate in a series of measures and countermeasures for control of phagosome integrity.IMPORTANCEMycobacterium tuberculosiscauses tuberculosis, which kills more people than any other infection.M. tuberculosisgrows in macrophages, cells that specialize in engulfing and degrading microorganisms. Like many intracellular pathogens, in order to cause disease,M. tuberculosisdamages the membrane-bound compartment (phagosome) in which it is enclosed after macrophage uptake. Recent work showed that when chemicals damage this type of intracellular compartment, cells rapidly detect and repair the damage, using machinery called the endosomal sorting complex required for transport (ESCRT). Therefore, we hypothesized that ESCRT might also respond to pathogen-induced damage. At the same time, our previous work showed that the EsxG-EsxH heterodimer ofM. tuberculosiscan inhibit ESCRT, raising the possibility thatM. tuberculosisimpairs this host response. Here, we show that ESCRT is recruited to damagedM. tuberculosisphagosomes and that EsxG-EsxH undermines ESCRT-mediated endomembrane repair. Thus, our studies demonstrate a battle between host and pathogen over endomembrane integrity.

scholarly journals Autophagy—A Story of Bacteria Interfering with the Host Cell Degradation Machinery

Pathogens ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 110
Author(s):  
Anna K. Riebisch ◽  
Sabrina Mühlen ◽  
Yan Yan Beer ◽  
Ingo Schmitz
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Listeria Monocytogenes ◽  
Salmonella Typhimurium ◽  
Innate Immune ◽  
Intracellular Pathogens ◽  
Response Mechanism ◽  
Pathogenic Escherichia Coli

Autophagy is a highly conserved and fundamental cellular process to maintain cellular homeostasis through recycling of defective organelles or proteins. In a response to intracellular pathogens, autophagy further acts as an innate immune response mechanism to eliminate pathogens. This review will discuss recent findings on autophagy as a reaction to intracellular pathogens, such as Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Staphylococcus aureus, and pathogenic Escherichia coli. Interestingly, while some of these bacteria have developed methods to use autophagy for their own benefit within the cell, others have developed fascinating mechanisms to evade recognition, to subvert the autophagic pathway, or to escape from autophagy.

scholarly journals Infection with Mycobacterium aviumDifferentially Regulates the Expression of Iron Transport Protein mRNA in Murine Peritoneal Macrophages

2001 ◽  
Vol 69 (11) ◽  
pp. 6618-6624 ◽  
Author(s):  
Wangjian Zhong ◽  
William P. Lafuse ◽  
Bruce S. Zwilling
Keyword(s):  
Host Defense ◽  
Transferrin Receptor ◽  
Iron Transport ◽  
Peritoneal Macrophages ◽  
Natural Resistance ◽  
Intracellular Pathogens ◽  
Mrna Levels ◽  
Iron Availability ◽  
Iron Transporter ◽  
Murine Peritoneal Macrophages

ABSTRACT Iron is an important element for the growth of microorganisms as well as in the defense of the host by serving as a catalyst for the generation of free radicals via the Fenton/Haber-Weiss reactions. The iron transporter natural resistance-associated macrophage protein 1 (Nramp1) confers resistance to the growth of a variety of intracellular pathogens including Mycobacterium avium. Recently several other proteins that are involved in iron transport, including the highly homologous iron transporter Nramp2 and the transferrin receptor-associated protein HFE (hereditary hemochromatosis protein), have been described. The relationship of these proteins to host defense and to the growth of intracellular pathogens is not known. Here, we report that infection with M. avium differentially regulates mRNA expression of the proteins associated with iron transport in murine peritoneal macrophages. Both Nramp1 and Nramp2 mRNA levels increase following infection, while the expression of transferrin receptor mRNA decreases. The level of expression of HFE mRNA remains unchanged. The difference in the expression of the mRNA of these proteins following infection or cytokine stimulation suggests that they may play an important role in host defense by maintaining a delicate balance between iron availability for host defense and at the same time limiting iron availability for microbial growth.

scholarly journals A Novel Tuberculosis DNA Vaccine in an HIV-1 p24 Protein Backbone Confers Protection against Mycobacterium tuberculosis and Simultaneously Elicits Robust Humoral and Cellular Responses to HIV-1

2012 ◽  
Vol 19 (5) ◽  
pp. 723-730 ◽  
Author(s):  
Xiaoman Li ◽  
Wei Xu ◽  
Sidong Xiong
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Dna Vaccine ◽  
Cellular Response ◽  
Mycobacterial Infection ◽  
T Cell Epitopes ◽  
Content Type ◽  
P24 Protein ◽  
Elevated Frequency ◽  
Hiv 1

ABSTRACTTuberculosis (TB) caused byMycobacterium tuberculosisremains a major infectious disease worldwide. Moreover, latentM. tuberculosisinfection is more likely to progress to active TB and eventually leads to death when HIV infection is involved. Thus, it is urgent to develop a novel TB vaccine with immunogenicity to bothM. tuberculosisand HIV. In this study, four uncharacterized T cell epitopes from MPT64, Ag85A, Ag85B, and TB10.4 antigens ofM. tuberculosiswere predicted, and HIV-1-derived p24, an immunodominant protein that can induce protective responses to HIV-1, was used as an immunogenic backbone.M. tuberculosisepitopes were incorporated separately into the gene backbone of p24, forming a pP24-Mtb DNA vaccine. We demonstrated that pP24-Mtb immunization induced a strongM. tuberculosis-specific cellular response as evidenced by T cell proliferation, cytotoxicity, and elevated frequency of gamma interferon (IFN-γ)-secreting T cells. Interestingly, a p24-specific cellular response and high levels of p24-specific IgG were also induced by pP24-Mtb immunization. When the protective effect was assessed after mycobacterial challenge, pP24-Mtb vaccination significantly reduced tissue bacterial loads and profoundly attenuated the mycobacterial infection-related lung inflammation and injury. Our findings demonstrated that the pP24-Mtb tuberculosis vaccine confers effective protection against mycobacterial challenge with simultaneously elicited robust immune responses to HIV-1, which may provide clues for developing novel vaccines to prevent dual infections.

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