scholarly journals Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome

2007 ◽  
Vol 204 (13) ◽  
pp. 3235-3245 ◽  
Author(s):  
Fayyaz S. Sutterwala ◽  
Lilia A. Mijares ◽  
Li Li ◽  
Yasunori Ogura ◽  
Barbara I. Kazmierczak ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Death ◽  
Host Cell ◽  
Proinflammatory Cytokine ◽  
Opportunistic Infections ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Immune Recognition ◽  
Independent Manner ◽  
Caspase 1

Pseudomonas aeruginosa is a Gram-negative bacterium that causes opportunistic infections in immunocompromised individuals. P. aeruginosa employs a type III secretion system to inject effector molecules into the cytoplasm of the host cell. This interaction with the host cell leads to inflammatory responses that eventually result in cell death. We show that infection of macrophages with P. aeruginosa results in activation of caspase-1 in an IPAF-dependent, but flagellin-independent, manner. Macrophages deficient in IPAF or caspase-1 were markedly resistant to P. aeruginosa–induced cell death and release of the proinflammatory cytokine interleukin (IL)-1β. A subset of P. aeruginosa isolates express the effector molecule exoenzyme U (ExoU), which we demonstrate is capable of inhibiting caspase-1–driven proinflammatory cytokine production. This study shows a key role for IPAF and capase-1 in innate immune responses to the pathogen P. aeruginosa, and also demonstrates that virulent ExoU-expressing strains of P. aeruginosa can circumvent this innate immune response.

scholarly journals Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

2014 ◽  
Vol 82 (10) ◽  
pp. 4204-4211 ◽  
Author(s):  
Khatoun Al Moussawi ◽  
Barbara I. Kazmierczak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Immune Responses ◽  
Bacterial Pathogen ◽  
Innate Immune ◽  
Immune Recognition ◽  
Content Type ◽  
Caspase 1 ◽  
Rapid Responses ◽  
Subsequent Activation ◽  
Deficient Mice

ABSTRACTThe bacterial pathogenPseudomonas aeruginosacauses acute infections associated with significant morbidity and mortality.P. aeruginosaelicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance.P. aeruginosalipopolysaccharide and flagellin are recognized by extracellular Toll-like receptors, but the most rapid responses to infection occur when cytosolic receptors sense flagellin or type 3 secretion system (T3SS) structural proteins. The subsequent activation of the NLRC4 inflammasome and caspase-1 generates an interleukin-1β (IL-1β) signal that is required for the rapid neutrophilic response. A T3SS effector, exotoxin U (ExoU), can inhibit activation of the NLRC4 inflammasome and caspase-1. Thus, our observation that IL-1 receptor (IL-1R)-mediated signals were still required to initiate a response to ExoU-producing bacteria was unexpected. As both IL-1α and IL-1β signal via the IL-1R, we examined immune responses in mice lacking either of these cytokines. IL-1β-deficient mice responded to ExoU-producingP. aeruginosabacteria similarly to wild-type animals; however, IL-1α-deficient mice had an attenuated immune response. The situation was reversed following infections by ExoU-negative bacteria: here, IL-1α was dispensable for neutrophil recruitment, while IL-1β was required. IL-1α secretion by macrophages infected with ExoU-producingP. aeruginosaisolates was independent of both caspase-1 and caspase-11. This study documents distinct roles for IL-1α and IL-1β in the response toP. aeruginosainfection as a function of the T3SS effectors produced by the infecting strain. The redundancy of these two cytokines nonetheless allows the infected host to mount a response to ExoU-positive and -negative bacterial isolates.

scholarly journals Viral Cell Death Inhibitor MC159 Enhances Innate Immunity against Vaccinia Virus Infection

2010 ◽  
Vol 84 (20) ◽  
pp. 10467-10476 ◽  
Author(s):  
Sreerupa Challa ◽  
Melissa Woelfel ◽  
Melissa Guildford ◽  
David Moquin ◽  
Francis Ka-Ming Chan
Keyword(s):  
Cell Death ◽  
Vaccinia Virus ◽  
Host Cell ◽  
Inflammatory Responses ◽  
Γδ T Cells ◽  
Innate Immune ◽  
Dual Function ◽  
Death Domain ◽  
Peripheral Tissues ◽  
Host Cell Death

ABSTRACT Viral inhibitors of host programmed cell death (PCD) are widely believed to promote viral replication by preventing or delaying host cell death. Viral FLIPs (Fas-linked ICE-like protease [FLICE; caspase-8]-like inhibitor proteins) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. Surprisingly, transgenic expression of the viral FLIP MC159 from molluscum contagiosum virus (MCV) in mice enhanced rather than inhibited the innate immune control of vaccinia virus (VV) replication. This effect of MC159 was specifically manifested in peripheral tissues such as the visceral fat pad, but not in the spleen. VV-infected MC159 transgenic mice mounted an enhanced innate inflammatory reaction characterized by increased expression of the chemokine CCL-2/MCP-1 and infiltration of γδ T cells into peripheral tissues. Radiation chimeras revealed that MC159 expression in the parenchyma, but not in the hematopoietic compartment, is responsible for the enhanced innate inflammatory responses. The increased inflammation in peripheral tissues was not due to resistance of lymphocytes to cell death. Rather, we found that MC159 facilitated Toll-like receptor 4 (TLR4)- and tumor necrosis factor (TNF)-induced NF-κB activation. The increased NF-κB responses were mediated in part through increased binding of RIP1 to TNFRSF1A-associated via death domain (TRADD), two crucial signal adaptors for NF-κB activation. These results show that MC159 is a dual-function immune modulator that regulates host cell death as well as NF-κB responses by innate immune signaling receptors.

scholarly journals SERINC5 Can Enhance Proinflammatory Cytokine Production by Primary Human Myeloid Cells in Response to Challenge with HIV-1 Particles

2021 ◽  
Vol 95 (9) ◽  
Author(s):  
Virginia Pierini ◽  
Lara Gallucci ◽  
Christina M. Stürzel ◽  
Frank Kirchhoff ◽  
Oliver T. Fackler
Keyword(s):  
T Lymphocytes ◽  
Host Cell ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Innate Immune ◽  
Target Cells ◽  
Immune Recognition ◽  
Proinflammatory Cytokine Production ◽  
Virion Incorporation ◽  
Hiv 1

ABSTRACT HIV-1 has to overcome physical barriers posed by host cell restriction factors (RFs) for efficient replication. Some RFs, including Trim5α and tetherin, trigger antiviral signaling in addition to directly impairing HIV replication. SERINC5 (S5) is an RF that is incorporated into HIV-1 particles to potently impair their infectivity and is efficiently antagonized by the viral pathogenesis factor Nef. Since effects of S5 on HIV-1 infectivity were mostly studied in reporter cell lines, we analyzed the effects of S5 during infection of primary HIV-1 target cells. In activated CD4+ T lymphocytes, virion incorporation of S5 only moderately impaired virion infectivity and was not associated with altered innate immune recognition. In contrast, in monocyte-derived macrophages, S5 virion incorporation potentiated the production of proinflammatory cytokines with very potent but donor-dependent effects on virion infectivity. Nef counteracted effects of S5 on both cytokine production and virion infectivity. Similar S5-induced cytokine production was observed in immature monocyte-derived dendritic cells. Notably, S5-mediated enhancement of cytokine production was not linked to the efficacy of productive infection and could be overcome by using vesicular stomatitis virus glycoprotein (VSV-G) but not infectivity restriction-insensitive HIV-1 Env for cell entry. Moreover, inhibiting entry of S5-negative HIV-1 ΔNef particles increased proinflammatory cytokine production comparably to virion incorporation of S5. Together, these results describe the sensitization of noninfectious HIV-1 particles to proinflammatory cytokine production by myeloid target cells as an additional and Nef-sensitive activity of S5. Moreover, the study reveals important cell-type and donor-dependent differences in the sensitivity of HIV target cells for antiviral effects of S5. IMPORTANCE SERINC5 (S5) is a host cell restriction factor (RF) that impairs the infectivity of HIV-1 particles in target cell lines. To assess the potential physiological relevance of this restriction, we assessed the effects of S5 on HIV-1 infection of relevant primary human target cells. We found that effects of S5 on infection of CD4+ T lymphocytes were negligible. In myeloid target cells, however, virion incorporation of S5 potently suppressed infectivity and promoted innate immune recognition of HIV-1 particles characterized by proinflammatory cytokine production. Both effects were not observed in cells of all donors analyzed, were exerted independently of one another, and were counteracted by the HIV-1 pathogenesis factor Nef. These results identify the sensitization of HIV-1 particles for innate immune recognition by myeloid target cells as a novel activity of S5 and emphasize the need to study RF function in the context of primary target cells and taking donor variabilities into account.

scholarly journals Chlamydia muridarumInfection of Macrophages Stimulates IL-1βSecretion and Cell Death via Activation of Caspase-1 in an RIP3-Independent Manner

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Lixiang Chen ◽  
Xue Liu ◽  
Xin Yu ◽  
Rongrong Ren ◽  
Chao Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Innate Immune ◽  
Host Cells ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Independent Manner ◽  
Chlamydia Muridarum ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Chlamydiae are Gram-negative bacteria, which replicate exclusively in the infected host cells. Infection of the host cells by Chlamydiae stimulates the innate immune system leading to an inflammatory response, which is manifested not only by secretion of proinflammatory cytokines such as IL-1βfrom monocytes, macrophages, and dendritic cells, but also possibly by cell death mediated by Caspase-1 pyroptosis. RIP3 is a molecular switch that determines the development of necrosis or inflammation. However, the involvement of RIP3 in inflammasome activation byChlamydia muridaruminfection has not been clarified. Here, we assessed the role of RIP3 in synergy with Caspase-1 in the induction of IL-1βproduction in BMDM after either LPS/ATP orChlamydia muridarumstimulation. The possibility of pyroptosis and necroptosis interplays and the role of RIP3 in IL-1βproduction duringChlamydia muridaruminfection in BMDM was investigated as well. The data indicated that RIP3 is involved in NLRP3 inflammasome activation in LPS/ATP-stimulated BMDMs but not inChlamydia muridaruminfection. Pyroptosis occurred in BMDM after LPS/ATP stimulation orChlamydia muridaruminfection. Moreover, the results also illuminated the important role of the Caspase-1-mediated pyroptosis process which does not involve RIP3. Taken together, these observations may help shed new light on details in inflammatory signaling pathways activated byChlamydia muridaruminfection.

scholarly journals In Vivo Discrimination of Type 3 Secretion System-Positive and -Negative Pseudomonas aeruginosa via a Caspase-1-Dependent Pathway

2010 ◽  
Vol 78 (11) ◽  
pp. 4744-4753 ◽  
Author(s):  
Tamding Wangdi ◽  
Lilia A. Mijares ◽  
Barbara I. Kazmierczak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Immune System ◽  
Innate Immune System ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Secretion Systems ◽  
Caspase 1 ◽  
Molecular Patterns ◽  
Type 3

ABSTRACT Microbe-associated molecular patterns are recognized by Toll-like receptors of the innate immune system. This recognition enables a rapid response to potential pathogens but does not clearly provide a way for the innate immune system to discriminate between virulent and avirulent microbes. We find that pulmonary infection of mice with type 3 translocation-competent Pseudomonas aeruginosa triggers a rapid inflammatory response, while infection with isogenic translocation-deficient mutants does not. Discrimination between translocon-positive and -negative bacteria requires caspase-1 activity in bone marrow-derived cells and interleukin-1 receptor signaling. Thus, the activation of caspase-1 by bacteria expressing type 3 secretion systems allows for rapid recognition of bacteria expressing conserved functions associated with virulence.

scholarly journals Mycobacterium PPE31 Contributes to Host Cell Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Siyuan Feng ◽  
Zhongsi Hong ◽  
Guoliang Zhang ◽  
Jiachen Li ◽  
Guo-Bao Tian ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Acid Medium ◽  
Mutant Strain ◽  
Mycobacterial Infection ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Jnk Signaling ◽  
Host Cell Death ◽  
Genome Scale

Genome scale mutagenesis identifies many genes required for mycobacterial infectivity and survival, but their contributions and mechanisms of action within the host are poorly understood. Using CRISPR interference, we created a knockdown of ppe31Mm gene in Mycobacterium marinum (M. marinum), which reduced the resistance to acid medium. To further explore the function of PPE31, the ppe31 mutant strain was generated in M. marinum and Mycobacterium tuberculosis (M. tuberculosis), respectively. Macrophages infected with the ppe31Mm mutant strain caused a reduced inflammatory mediator expressions. In addition, macrophages infected with M. marinum Δppe31Mm had decreased host cell death dependent on JNK signaling. Consistent with these results, deletion of ppe31Mtb from M. tuberculosis increased the sensitivity to acid medium and reduced cell death in macrophages. Furthermore, we demonstrate that both ppe31 mutants from M. marinum and M. tuberculosis resulted in reduced survival in macrophages, and the survivability of M. marinum was deceased in zebrafish due to loss of ppe31Mm. Our findings confirm that PPE31 as a virulence associated factor that modulates innate immune responses to mycobacterial infection.

scholarly journals Coxiella burnetii Avirulent Nine Mile Phase II Induces Caspase-1-Dependent Pyroptosis in Murine Peritoneal B1a B Cells

2016 ◽  
Vol 84 (12) ◽  
pp. 3638-3654 ◽  
Author(s):  
Laura Schoenlaub ◽  
Rama Cherla ◽  
Yan Zhang ◽  
Guoquan Zhang
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Phase Ii ◽  
Coxiella Burnetii ◽  
Content Type ◽  
Apoptotic Signaling ◽  
Caspase 1 ◽  
B1a Cells ◽  
Dependent Cell ◽  
Toll Like Receptor 2

Our recent study demonstrated that virulentCoxiella burnetiiNine Mile phase I (NMI) is capable of infecting and replicating within peritoneal B1a cells and that B1a cells play an important role in host defense againstC. burnetiiinfection in mice. However, it remains unknown if avirulent Nine Mile phase II (NMII) can infect and replicate in B1a cells and whether NMI and NMII can differentially interact with B1a cells. In this study, we examined if NMI and NMII can differentially modulate host cell apoptotic signaling in B1a cells. The results showed that NMII induced dose-dependent cell death in murine peritoneal B1a cells but NMI did not, suggesting that NMI and NMII may differentially activate host cell apoptotic signaling in B1a cells. Western blotting indicated that NMII-induced B1a cell death was not dependent on either caspase-3 or PARP-1 cleavage, but cleavage of caspase-1 was detected in NMII-infected B1a cells. In addition, inhibition or deficiency of caspase-1 activity blocked NMII-induced B1a cell death. These results suggest that NMII induces a caspase-1-dependent pyroptosis in murine peritoneal B1a cells. We also found that heat-killed NMII and type 4 secretion system (T4SS) mutant NMII were unable to induce B1a cell death and that NMII infection did not induce cell death in peritoneal B1a cells from Toll-like receptor 2 (TLR-2)- or NLRP3 inflammasome-deficient mice. These data suggest that NMII-induced caspase-1-dependent pyroptosis may require its T4SS and activation of the TLR-2 and NLRP3 signaling pathways.

scholarly journals Peptidoglycan mediates Leptospira outer membrane protein Loa22 to toll-like receptor 2 for inflammatory interaction: a novel innate immune recognition

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shen-Hsing Hsu ◽  
Ming-Yang Chang ◽  
Shih-Ming Lin ◽  
Yi-Ching Ko ◽  
Li-Feng Chou ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Outer Membrane ◽  
Outer Membrane Protein ◽  
Inflammatory Responses ◽  
Protein A ◽  
Innate Immune ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immune Recognition ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2

AbstractLeptospirosis is an overlooked zoonotic disease caused by pathogenic Leptospira depended on virulence of Leptospira and the host–pathogen interaction. Kidney is the major organ infected by Leptospira which causes tubulointerstitial nephritis. Leptospira outer membrane contains several virulence factors and an outer membrane protein A (OmpA) like protein (Loa22) is essential for virulence. Pull-down assays suggested that Loa22 was a potential Toll-Like Receptor 2 (TLR2) binding candidates from pathogenic Leptospira. Confocal microscopy was employed to observe the co-localization of TLR2 and Loa22-LPGN (Leptospira peptidoglycan) complexes. Atomic force microscopy (AFM), side-directed mutagenesis, and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the affinity between rLoa22, LPGN, and TLR2. Real time PCR was applied to measure the cytokines expression. Downstream signal transduction components were verified by western blot to evaluate the gene regulations. Mutation of two Loa22 key residues (Asp122 and Arg143) attenuated the affinities for LPGN. rLoa22-LPGN complexes were observed to co-localize with TLR2 and provoked inflammatory responses including CXCL8/IL8, hCCL2/MCP-1, and hTNF-α. Affinity studies suggested that Loa22-LPGN complexes elevated the affinity to TLR2 as compared to Loa22 protein. Downstream signals from TLR2 including p38, ERK, and JNK were regulated under rLoa22-LPGN complexes treatments. This study identified LPGN mediates interactions between Loa22 and TLR2 and induces downstream signals to trigger inflammatory responses. rLoa22-LPGN-TLR2 complexes reveal a novel binding mechanism for the innate immune system.

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