scholarly journals Loss of Mitochondrial Protein Fus1 Augments Host Resistance to Acinetobacter baumannii Infection

2013 ◽  
Vol 81 (12) ◽  
pp. 4461-4469 ◽  
Author(s):  
M. Indriati Hood ◽  
Roman Uzhachenko ◽  
Kelli Boyd ◽  
Eric P. Skaar ◽  
Alla V. Ivanova
Keyword(s):  
Immune Response ◽  
Acinetobacter Baumannii ◽  
Immune Cell ◽  
Mitochondrial Protein ◽  
Mammalian Target Of Rapamycin ◽  
Sterile Inflammation ◽  
Interleukin 17 ◽  
Content Type ◽  
Rapid Clearance ◽  
Species Production

ABSTRACTFus1 is a tumor suppressor protein with recently described immunoregulatory functions. Although its role in sterile inflammation is being elucidated, its role in regulating immune responses to infectious agents has not been examined. We used here a murine model ofAcinetobacter baumanniipneumonia to identify the role of Fus1 in antibacterial host defenses. We found that the loss of Fus1 in mice results in significantly increased resistance toA. baumanniipneumonia. We observed earlier and more robust recruitment of neutrophils and macrophages to the lungs of infected Fus1−/−mice, with a concomitant increase in phagocytosis of invading bacteria and more rapid clearance. Such a prompt and enhanced immune response to bacterial infection in Fus1−/−mice stems from early activation of proinflammatory pathways (NF-κB and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin [mTOR]), most likely due to significantly increased mitochondrial membrane potential and mitochondrial reactive oxygen species production. Significant early upregulation of interleukin-17 (IL-17) in Fus1−/−immune cells was also observed, together with significant downregulation of IL-10. Depletion of neutrophils eliminates the enhanced antibacterial defenses of the Fus1−/−mice, suggesting that ultimately it is the enhanced immune cell recruitment that mediates the increased resistance of Fus1−/−mice toA. baumanniipneumonia. Taken together, our data define the novel role for Fus1 in the immune response toA. baumanniipneumonia and highlight new avenues for immune modulating therapeutic targets for this treatment-resistant nosocomial pathogen.

scholarly journals Tim-3 Induces Th2-Biased Immunity and Alternative Macrophage Activation during Schistosoma japonicum Infection

2015 ◽  
Vol 83 (8) ◽  
pp. 3074-3082 ◽  
Author(s):  
Nan Hou ◽  
Xianyu Piao ◽  
Shuai Liu ◽  
Chuang Wu ◽  
Qijun Chen
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Schistosoma Japonicum ◽  
Immune Cell ◽  
Nk Cell ◽  
Alternative Activation ◽  
Interleukin 12 ◽  
Content Type

T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected withSchistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response againstS. japonicuminfection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4+and CD8+T cells, NK1.1+cells, and CD11b+cells from the livers ofS. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8+T cells or CD11b+cells. The schistosome-induced upregulation of Tim-3 on natural killer (NK) cells was accompanied by reduced NK cell numbersin vitroandin vivo. Tim-3 antibody blockade led to upregulation of inducible nitric oxide synthase and interleukin-12 (IL-12) mRNA in CD11b+cells cocultured with soluble egg antigen and downregulation of Arg1 and IL-10, which are markers of M2 macrophages. In summary, we observed schistosome-induced expression of Tim-3 on critical immune cell populations, which may be involved in the Th2-biased immune response and alternative activation of macrophages during infection.

scholarly journals The Surface-Associated Exopolysaccharide of Bifidobacterium longum 35624 Plays an Essential Role in Dampening Host Proinflammatory Responses and Repressing Local TH17 Responses

2016 ◽  
Vol 82 (24) ◽  
pp. 7185-7196 ◽  
Author(s):  
Elisa Schiavi ◽  
Marita Gleinser ◽  
Evelyn Molloy ◽  
David Groeger ◽  
Remo Frei ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Essential Role ◽  
Inflammatory Responses ◽  
Bifidobacterium Longum ◽  
Molecular Characteristics ◽  
Interleukin 17 ◽  
Content Type ◽  
Exopolysaccharide Production

ABSTRACTThe immune-modulating properties of certain bifidobacterial strains, such asBifidobacterium longumsubsp.longum35624 (B. longum35624), have been well described, although the strain-specific molecular characteristics associated with such immune-regulatory activity are not well defined. It has previously been demonstrated thatB. longum35624 produces a cell surface exopolysaccharide (sEPS), and in this study, we investigated the role played by this exopolysaccharide in influencing the host immune response.B. longum35624 induced relatively low levels of cytokine secretion from human dendritic cells, whereas an isogenic exopolysaccharide-negative mutant derivative (termed sEPSneg) induced vastly more cytokines, including interleukin-17 (IL-17), and this response was reversed when exopolysaccharide production was restored in sEPSnegby genetic complementation. Administration ofB. longum35624 to mice of the T cell transfer colitis model prevented disease symptoms, whereas sEPSnegdid not protect against the development of colitis, with associated enhanced recruitment of IL-17+lymphocytes to the gut. Moreover, intranasal administration of sEPSnegalso resulted in enhanced recruitment of IL-17+lymphocytes to the murine lung. These data demonstrate that the particular exopolysaccharide produced byB. longum35624 plays an essential role in dampening proinflammatory host responses to the strain and that loss of exopolysaccharide production results in the induction of local TH17 responses.IMPORTANCEParticular gut commensals, such asB. longum35624, are known to contribute positively to the development of mucosal immune cells, resulting in protection from inflammatory diseases. However, the molecular basis and mechanisms for these commensal-host interactions are poorly described. In this report, an exopolysaccharide was shown to be decisive in influencing the immune response to the bacterium. We generated an isogenic mutant unable to produce exopolysaccharide and observed that this mutation caused a dramatic change in the response of human immune cellsin vitro. In addition, the use of mouse models confirmed that lack of exopolysaccharide production induces inflammatory responses to the bacterium. These results implicate the surface-associated exopolysaccharide of theB. longum35624 cell envelope in the prevention of aberrant inflammatory responses.

scholarly journals The Carbohydrate Lectin Receptor Dectin-1 Mediates the Immune Response to Exserohilum rostratum

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Jennifer L. Reedy ◽  
Paige E. Negoro ◽  
Marianela Feliu ◽  
Allison K. Lord ◽  
Nida S. Khan ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Wide Spectrum ◽  
Granulomatous Inflammation ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Macrophage Response ◽  
Lectin Receptor ◽  
Exserohilum Rostratum

ABSTRACT Dematiaceous molds are found ubiquitously in the environment and cause a wide spectrum of human disease, including infections associated with high rates of mortality. Despite this, the mechanism of the innate immune response has been less well studied, although it is key in the clearance of fungal pathogens. Here, we focus on Exserohilum rostratum, a dematiaceous mold that caused 753 infections during a multistate outbreak due to injection of contaminated methylprednisolone. We show that macrophages are incapable of phagocytosing Exserohilum. Despite a lack of phagocytosis, macrophage production of tumor necrosis factor alpha is triggered by hyphae but not spores and depends upon Dectin-1, a C-type lectin receptor. Dectin-1 is specifically recruited to the macrophage-hyphal interface but not the macrophage-spore interface due to differences in carbohydrate antigen expression between these two fungal forms. Corticosteroid and antifungal therapy perturb this response, resulting in decreased cytokine production. In vivo soft tissue infection in wild-type mice demonstrated that Exserohilum provokes robust neutrophilic and granulomatous inflammation capable of thwarting fungal growth. However, coadministration of methylprednisolone acetate results in robust hyphal tissue invasion and a significant reduction in immune cell recruitment. Our results suggest that Dectin-1 is crucial for macrophage recognition and the macrophage response to Exserohilum and that corticosteroids potently attenuate the immune response to this pathogen.

scholarly journals Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

2011 ◽  
Vol 79 (8) ◽  
pp. 3317-3327 ◽  
Author(s):  
Jessica M. Breslow ◽  
Joseph J. Meissler ◽  
Rebecca R. Hartzell ◽  
Phillip B. Spence ◽  
Allan Truant ◽  
...  
Keyword(s):  
Immune Responses ◽  
Acinetobacter Baumannii ◽  
Systemic Infection ◽  
Innate Immune ◽  
Mouse Strains ◽  
Multiple Drug ◽  
Interleukin 17 ◽  
Innate Immune Responses ◽  
Bacterial Strains ◽  
Content Type

ABSTRACTAcinetobacter baumanniiis a nosocomial pathogen with a high prevalence of multiple-drug-resistant strains, causing pneumonia and sepsis. The current studies further develop a systemic mouse model of this infection and characterize selected innate immune responses to the organism. Five clinical isolates, with various degrees of antibiotic resistance, were assessed for virulence in two mouse strains, and between male and female mice, using intraperitoneal infection. A nearly 1,000-fold difference in virulence was found between bacterial strains, but no significant differences between sexes or mouse strains were observed. It was found that microbes disseminated rapidly from the peritoneal cavity to the lung and spleen, where they replicated. A persistent septic state was observed. The infection progressed rapidly, with mortality between 36 and 48 h. Depletion of neutrophils with antibody to Ly-6G decreased mean time to death and increased mortality. Interleukin-17 (IL-17) promotes the response of neutrophils by inducing production of the chemokine keratinocyte-derived chemoattractant (KC/CXCL1), the mouse homolog of human IL-8.Acinetobacterinfection resulted in biphasic increases in both IL-17 and KC/CXCL1. Depletion of neither IL-17 nor KC/CXCL1, using specific antibodies, resulted in a difference in bacterial burdens in organs of infected mice at 10 h postinfection. Comparison of bacterial burdens between IL-17a−/−and wild-type mice confirmed that the absence of this cytokine did not sensitize mice toAcinetobacterinfection. These studies definitely demonstrate the importance of neutrophils in resistance to systemicAcinetobacterinfection. However, neither IL-17 nor KC/CXCL1 alone is required for effective host defense to systemic infection with this organism.

scholarly journals A Phenome-Wide Association Study Uncovers a Pathological Role of Coagulation Factor X duringAcinetobacter baumanniiInfection

2019 ◽  
Vol 87 (5) ◽  
Author(s):  
Jacob E. Choby ◽  
Andrew J. Monteith ◽  
Lauren E. Himmel ◽  
Paris Margaritis ◽  
Jana K. Shirey-Rice ◽  
...  
Keyword(s):  
Immune Response ◽  
Association Study ◽  
Immune Cell ◽  
Coagulation Factor ◽  
Factor X ◽  
Human Pathogens ◽  
Chemokine Production ◽  
Content Type ◽  
Factor X Deficiency ◽  
Deficient Mice

ABSTRACTCoagulation and inflammation are interconnected, suggesting that coagulation plays a key role in the inflammatory response to pathogens. A phenome-wide association study (PheWAS) was used to identify clinical phenotypes of patients with a polymorphism in coagulation factor X. Patients with this single nucleotide polymorphism (SNP) were more likely to be hospitalized with hemostatic and infection-related disorders, suggesting that factor X contributes to the immune response to infection. To investigate this, we modeled infections by human pathogens in a mouse model of factor X deficiency. Factor X-deficient mice were protected from systemicAcinetobacter baumanniiinfection, suggesting that factor X plays a role in the immune response toA. baumannii. Factor X deficiency was associated with reduced cytokine and chemokine production and alterations in immune cell population during infection: factor X-deficient mice demonstrated increased abundance of neutrophils, macrophages, and effector T cells. Together, these results suggest that factor X activity is associated with an inefficient immune response and contributes to the pathology ofA. baumanniiinfection.

scholarly journals The Polysaccharide Capsule of Campylobacter jejuni Modulates the Host Immune Response

2012 ◽  
Vol 81 (3) ◽  
pp. 665-672 ◽  
Author(s):  
Alexander C. Maue ◽  
Krystle L. Mohawk ◽  
David K. Giles ◽  
Frédéric Poly ◽  
Cheryl P. Ewing ◽  
...  
Keyword(s):  
Immune Response ◽  
Campylobacter Jejuni ◽  
Diarrheal Disease ◽  
Host Immune Response ◽  
Interleukin 17 ◽  
Wild Type ◽  
Content Type ◽  
Polysaccharide Capsule ◽  
Colonization Model

ABSTRACTCampylobacter jejuniis a major cause of bacterial diarrheal disease worldwide. The organism is characterized by a diversity of polysaccharide structures, including a polysaccharide capsule. MostC. jejunicapsules are known to be decorated nonstoichiometrically with methyl phosphoramidate (MeOPN). The capsule ofC. jejuni81-176 has been shown to be required for serum resistance, but here we show that an encapsulated mutant lacking the MeOPN modification, anmpnCmutant, was equally as sensitive to serum killing as the nonencapsulated mutant. A nonencapsulated mutant, akpsMmutant, exhibited significantly reduced colonization compared to that of wild-type 81-176 in a mouse intestinal colonization model, and thempnCmutant showed an intermediate level of colonization. Both mutants were associated with higher levels of interleukin 17 (IL-17) expression from lamina propria CD4+cells than from cells from animals infected with 81-176. In addition, reduced levels of Toll-like receptor 4 (TLR4) and TLR2 activation were observed followingin vitrostimulation of human reporter cell lines with thekpsMandmpnCmutants compared to those with wild-type 81-176. The data suggest that the capsule polysaccharide ofC. jejuniand the MeOPN modification modulate the host immune response.

scholarly journals LL-37 Immunomodulatory Activity during Mycobacterium tuberculosis Infection in Macrophages

2015 ◽  
Vol 83 (12) ◽  
pp. 4495-4503 ◽  
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.

scholarly journals Control of Giardiasis by Interleukin-17 in Humans and Mice—Are the Questions All Answered?

2015 ◽  
Vol 23 (1) ◽  
pp. 2-5 ◽  
Author(s):  
Steven M. Singer
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Giardia Lamblia ◽  
Antigenic Variation ◽  
Interleukin 17 ◽  
Content Type ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Key Factor

ABSTRACTFor years, studies of the immune response toGiardia lambliainfection focused on the production of IgA by infected hosts and antigenic variation by the parasite to escape destruction by this IgA. A new study by Hanevik and colleagues (C. S. Saghaug, S. Sørnes, D. Peirasmaki, S. Svärd, N. Langeland, and K. Hanevik, Clin Vaccine Immunol 23:11–18, 2016,http://dx.doi.org/10.1128/CVI.00419-15) highlights the emerging role of interleukin-17 (IL-17) in immunity to this parasite. Along with recent studies ofGiardiainfections of animals, this work shows that IL-17 appears to be essential for the control of these infections and to be a key factor linking cellular and humoral immune responses.

scholarly journals Caspase-11 Plays a Protective Role in Pulmonary Acinetobacter baumannii Infection

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Wei Wang ◽  
Yue Shao ◽  
Shengjun Li ◽  
Na Xin ◽  
Tingxian Ma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Acinetobacter Baumannii ◽  
Pulmonary Infection ◽  
Protective Role ◽  
Innate Immune ◽  
Gram Negative Bacteria ◽  
Pathological Changes ◽  
Gram Negative ◽  
Content Type

ABSTRACT Activation of caspase-11 by some Gram-negative bacteria triggers the caspase-1/interleukin 1β (IL-1β) pathway, independent of canonical inflammasomes. Acinetobacter baumannii is a Gram-negative, conditionally pathogenic bacterium that can cause severe pulmonary infection in hospitalized patients. A. baumannii was revealed to activate canonical and noncanonical inflammasome pathways in bone marrow-derived macrophages (BMDMs). Pulmonary infection of caspase-11−/− mice with A. baumannii showed that caspase-11 deficiency impaired A. baumannii clearance, exacerbated pulmonary pathological changes, and enhanced susceptibility to A. baumannii. These data indicate that the caspase-11-mediated innate immune response plays a crucial role in defending against A. baumannii.

scholarly journals Therapeutic Efficacy of Lysophosphatidylcholine in Severe Infections Caused by Acinetobacter baumannii

2015 ◽  
Vol 59 (7) ◽  
pp. 3920-3924 ◽  
Author(s):  
Younes Smani ◽  
Juan Domínguez-Herrera ◽  
José Ibáñez-Martínez ◽  
Jerónimo Pachón
Keyword(s):  
Acinetobacter Baumannii ◽  
Therapeutic Efficacy ◽  
Immune Cell ◽  
Early Time ◽  
Experimental Models ◽  
Antimicrobial Treatment ◽  
Enzyme Linked Immunosorbent Assay ◽  
Preemptive Therapy ◽  
Necrosis Factor Alpha ◽  
Content Type

ABSTRACTDue to the significant increase in antimicrobial resistance ofAcinetobacter baumannii, immune system stimulation to block infection progression may be a therapeutic adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC), a major component of phospholipids in eukaryotic cells, is involved in immune cell recruitment and modulation. The aim of this study was to show if LPC could be useful for treating infections caused byA. baumannii. A. baumanniiATCC 17978 was used in this study. Levels of serum LPC and levels of the inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-1β, and IL-10 were determined by spectrophotometric assay and enzyme-linked immunosorbent assay (ELISA), respectively, using a murine peritoneal sepsis model in which mice were inoculated with 5.3 log CFU/ml ofA. baumannii. The therapeutic efficacy of LPC againstA. baumanniiin murine peritoneal sepsis and pneumonia models was assessed for 48 h after bacterial infection. At early time points in the murine model of peritoneal sepsis caused byA. baumannii, LPC was depleted and was associated with an increase of inflammatory cytokine release. Preemptive therapy with LPC in murine peritoneal sepsis and pneumonia models markedly enhanced spleen and lung bacterial clearance and reduced the numbers of positive blood cultures and the mouse mortality rates. Moreover, treatment with LPC reduced proinflammatory cytokine production. These data demonstrate that LPC is efficacious as a preemptive treatment in experimental models of peritoneal sepsis and pneumonia caused byA. baumannii.

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