Bacterial Nucleotidyl Cyclase Inhibits the Host Innate Immune Response by Suppressing TAK1 Activation

ABSTRACT Exoenzyme Y (ExoY) is a type III secretion system effector found in 90% of the Pseudomonas aeruginosa isolates. Although it is known that ExoY is a soluble nucleotidyl cyclase that increases the cytoplasmic levels of nucleoside 3′,5′-cyclic monophosphates (cNMPs) to mediate endothelial Tau phosphorylation and permeability, its functional role in the innate immune response is still poorly understood. Transforming growth factor β-activated kinase 1 (TAK1) is critical for mediating Toll-like receptor (TLR) signaling and subsequent activation of NF-κB and AP-1, which are transcriptional activators of innate immunity. Here, we report that ExoY inhibits proinflammatory cytokine production through suppressing the activation of TAK1 as well as downstream NF-κB and mitogen-activated protein (MAP) kinases. Mice infected with ExoY-deficient P. aeruginosa had higher levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6), more neutrophil recruitment, and a lower bacterial load in lung tissue than mice infected with wild-type P. aeruginosa. Taken together, our findings identify a previously unknown mechanism by which P. aeruginosa ExoY inhibits the host innate immune response.

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Leptospira interrogans Catalase Is Required for Resistance to H2O2and for Virulence

Infection and Immunity ◽

10.1128/iai.00466-12 ◽

2012 ◽

Vol 80 (11) ◽

pp. 3892-3899 ◽

Cited By ~ 64

Author(s):

Azad Eshghi ◽

Kristel Lourdault ◽

Gerald L. Murray ◽

Thanatchaporn Bartpho ◽

Rasana W. Sermswan ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Immune Response ◽

Innate Immune Response ◽

Reactive Oxygen ◽

Innate Immune ◽

Leptospira Interrogans ◽

Oxygen Species ◽

Content Type ◽

Host Innate Immune Response

ABSTRACTPathogenicLeptospiraspp. are likely to encounter higher concentrations of reactive oxygen species induced by the host innate immune response. In this study, we characterizedLeptospira interroganscatalase (KatE), the only annotated catalase found within pathogenicLeptospiraspecies, by assessing its role in resistance to H2O2-induced oxidative stress and during infection in hamsters. PathogenicL. interrogansbacteria had a 50-fold-higher survival rate under H2O2-induced oxidative stress than did saprophyticL. biflexabacteria, and this was predominantly catalase dependent. We also characterized KatE, the only annotated catalase found within pathogenicLeptospiraspecies. Catalase assays performed with recombinant KatE confirmed specific catalase activity, while protein fractionation experiments localized KatE to the bacterial periplasmic space. The insertional inactivation ofkatEin pathogenicLeptospirabacteria drastically diminished leptospiral viability in the presence of extracellular H2O2and reduced virulence in an acute-infection model. Combined, these results suggest thatL. interrogansKatE confersin vivoresistance to reactive oxygen species induced by the host innate immune response.

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Exogenous Gamma and Alpha/Beta Interferon Rescues Human Macrophages from Cell Death Induced by Bacillus anthracis

Infection and Immunity ◽

10.1128/iai.72.3.1291-1297.2004 ◽

2004 ◽

Vol 72 (3) ◽

pp. 1291-1297 ◽

Cited By ~ 35

Author(s):

Jeffrey A. Gold ◽

Yoshihiko Hoshino ◽

Satomi Hoshino ◽

Marcus B. Jones ◽

Anna Nolan ◽

...

Keyword(s):

Immune Response ◽

Bacillus Anthracis ◽

Innate Immune Response ◽

Innate Immune ◽

Mitogen Activated Protein Kinase ◽

Human Macrophages ◽

Mitogen Activated Protein ◽

Host Innate Immune Response ◽

Alpha Beta ◽

Early Effects

ABSTRACT During the recent bioterrorism-related outbreaks, inhalational anthrax had a 45% mortality in spite of appropriate antimicrobial therapy, underscoring the need for better adjuvant therapies. The variable latency between exposure and development of disease suggests an important role for the host's innate immune response. Alveolar macrophages are likely the first immune cells exposed to inhalational anthrax, and the interferon (IFN) response of these cells comprises an important arm of the host innate immune response to intracellular infection with Bacillus anthracis. Furthermore, IFNs have been used as immunoadjuvants for treatment of another intracellular pathogen, Mycobacterium tuberculosis. We established a model of B. anthracis infection with the Sterne strain (34F2) which contains lethal toxin (LeTx). 34F2 was lethal to murine and human macrophages. Treatment with IFNs significantly improved cell viability and reduced the number of germinated intracellular spores. Infection with 34F2 failed to induce the latent transcription factors signal transducer and activators of transcription 1 (STAT1) and ISGF-3, which are central to the IFN response. Furthermore, 34F2 reduced STAT1 activation in response to exogenous alpha/beta IFN, suggesting direct inhibition of IFN signaling. Even though 34F2 has LeTx, there was no mitogen-activated protein kinase kinase 3 cleavage and p38 was normally induced, suggesting that these early effects of B. anthracis infection in macrophages are independent of LeTx. These data suggest an important role for both IFNs in the control of B. anthracis and the potential benefit of using exogenous IFN as an immunoadjuvant therapy.

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LL-37 Immunomodulatory Activity during Mycobacterium tuberculosis Infection in Macrophages

Infection and Immunity ◽

10.1128/iai.00936-15 ◽

2015 ◽

Vol 83 (12) ◽

pp. 4495-4503 ◽

Cited By ~ 32

Author(s):

Flor Torres-Juarez ◽

Albertina Cardenas-Vargas ◽

Alejandra Montoya-Rosales ◽

Irma González-Curiel ◽

Mariana H. Garcia-Hernandez ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Cytokines ◽

Innate Immune Response ◽

Transforming Growth Factor ◽

Innate Immune ◽

Immunomodulatory Activity ◽

Interleukin 17 ◽

Host Defense Peptides ◽

Content Type ◽

Anti Inflammatory

Tuberculosis is one of the most important infectious diseases worldwide. The susceptibility to this disease depends to a great extent on the innate immune response against mycobacteria. Host defense peptides (HDP) are one of the first barriers to counteract infection. Cathelicidin (LL-37) is an HDP that has many immunomodulatory effects besides its weak antimicrobial activity. Despite advances in the study of the innate immune response in tuberculosis, the immunological role of LL-37 duringM. tuberculosisinfection has not been clarified. Monocyte-derived macrophages were infected withM. tuberculosisstrain H37Rv and then treated with 1, 5, or 15 μg/ml of exogenous LL-37 for 4, 8, and 24 h. Exogenous LL-37 decreased tumor necrosis factor alpha (TNF-α) and interleukin-17 (IL-17) while inducing anti-inflammatory IL-10 and transforming growth factor β (TGF-β) production. Interestingly, the decreased production of anti-inflammatory cytokines did not reduce antimycobacterial activity. These results are consistent with the concept that LL-37 can modulate the expression of cytokines during mycobacterial infection and this activity was independent of the P2X7 receptor. Thus, LL-37 modulates the response of macrophages during infection, controlling the expression of proinflammatory and anti-inflammatory cytokines.

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PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence

Infection and Immunity ◽

10.1128/iai.05249-11 ◽

2011 ◽

Vol 80 (1) ◽

pp. 43-54 ◽

Cited By ~ 51

Author(s):

Dandan Dong ◽

Decheng Wang ◽

Ming Li ◽

Hui Wang ◽

Jia Yu ◽

...

Keyword(s):

Immune Response ◽

Cell Surface ◽

Glutamic Acid ◽

Innate Immune Response ◽

Mycobacterium Marinum ◽

Innate Immune ◽

Uncharacterized Protein ◽

Content Type ◽

Host Innate Immune Response ◽

Mycobacterial Pathogenesis

ABSTRACTThe proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) family proteins are prevalent in pathogenic mycobacteria and play a diverse role in mycobacterial pathogenesis. While some members have been studied, the function of most PE/PPE proteins remains unknown. In this study, we isolated a transposon-inactivatedPPE38mutant ofMycobacterium marinumand characterized its phenotype. We found that the PPE38 protein is associated with the cell wall and exposed on the cell surface. The inactivation ofPPE38altered the bacterial cell surface properties and led to deficiencies in cord formation, sliding motility, and biofilm formation. ThePPE38mutant was defective in phagocytosis by macrophages and exhibited reduced virulence in adult zebrafish. We also found that PPE38 is involved in the induction of proinflammatory cytokines in infected macrophages. Together, our results indicate that PPE38, a previously uncharacterized protein, plays a role in mycobacterial virulence, presumably by modulating the host innate immune response.

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Bifidobacterium bifidum PRL2010 Modulates the Host Innate Immune Response

Applied and Environmental Microbiology ◽

10.1128/aem.03313-13 ◽

2013 ◽

Vol 80 (2) ◽

pp. 730-740 ◽

Cited By ~ 44

Author(s):

Francesca Turroni ◽

Valentina Taverniti ◽

Patricia Ruas-Madiedo ◽

Sabrina Duranti ◽

Simone Guglielmetti ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Transcriptome Profiling ◽

Bifidobacterium Bifidum ◽

Innate Immune ◽

Intestinal Cells ◽

Content Type ◽

Transcription Profiles ◽

Enhanced Production ◽

Host Innate Immune Response

ABSTRACTHere, we describe data obtained from transcriptome profiling of human cell lines and intestinal cells of a murine model upon exposure and colonization, respectively, withBifidobacterium bifidumPRL2010. Significant changes were detected in the transcription of genes that are known to be involved in innate immunity. Furthermore, results from enzyme-linked immunosorbent assays (ELISAs) showed that exposure toB. bifidumPRL2010 causes enhanced production of interleukin 6 (IL-6) and IL-8 cytokines, presumably through NF-κB activation. The obtained global transcription profiles strongly suggest thatBifidobacterium bifidumPRL2010 modulates the innate immune response of the host.

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