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 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 Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response

2016 ◽  
Vol 84 (12) ◽  
pp. 3458-3470 ◽  
Author(s):  
Mike Khan ◽  
Jerome S. Harms ◽  
Fernanda M. Marim ◽  
Leah Armon ◽  
Cherisse L. Hall ◽  
...  
Keyword(s):  
Immune Response ◽  
Second Messenger ◽  
Host Immune Response ◽  
Vital Role ◽  
Host Cells ◽  
Content Type ◽  
Type Iv

Brucella species are facultative intracellular bacteria that cause brucellosis, a chronic debilitating disease significantly impacting global health and prosperity. Much remains to be learned about how Brucella spp. succeed in sabotaging immune host cells and how Brucella spp. respond to environmental challenges. Multiple types of bacteria employ the prokaryotic second messenger cyclic di-GMP (c-di-GMP) to coordinate responses to shifting environments. To determine the role of c-di-GMP in Brucella physiology and in shaping host- Brucella interactions, we utilized c-di-GMP regulatory enzyme deletion mutants. Our results show that a Δ bpdA phosphodiesterase mutant producing excess c-di-GMP displays marked attenuation in vitro and in vivo during later infections. Although c-di-GMP is known to stimulate the innate sensor STING, surprisingly, the Δ bpdA mutant induced a weaker host immune response than did wild-type Brucella or the low-c-di-GMP guanylate cyclase Δ cgsB mutant. Proteomics analysis revealed that c-di-GMP regulates several processes critical for virulence, including cell wall and biofilm formation, nutrient acquisition, and the type IV secretion system. Finally, Δ bpdA mutants exhibited altered morphology and were hypersensitive to nutrient-limiting conditions. In summary, our results indicate a vital role for c-di-GMP in allowing Brucella to successfully navigate stressful and shifting environments to establish intracellular infection.

scholarly journals Characterization of Host and Microbial Determinants in Individuals with Latent Tuberculosis Infection Using a Human Granuloma Model

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Evelyn Guirado ◽  
Uchenna Mbawuike ◽  
Tracy L. Keiser ◽  
Jesus Arcos ◽  
Abul K. Azad ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Immune Status ◽  
Host Immune Response ◽  
Granuloma Formation ◽  
Content Type ◽  
Transcriptional Signature ◽  
Latent Tb ◽  
Latent Tb Infection

ABSTRACTGranulomas sit at the center of tuberculosis (TB) immunopathogenesis. Progress in biomarkers and treatment specific to the human granuloma environment is hindered by the lack of a relevant and tractable infection model that better accounts for the complexity of the host immune response as well as pathogen counterresponses that subvert host immunity in granulomas. Here we developed and characterized anin vitrogranuloma model derived from human peripheral blood mononuclear cells (PBMCs) and autologous serum. Importantly, we interrogated this model for its ability to discriminate between host and bacterial determinants in individuals with and without latent TB infection (LTBI). By the use of this model, we provide the first evidence that granuloma formation, bacterial survival, lymphocyte proliferation, pro- and anti-inflammatory cytokines, and lipid body accumulation are significantly altered in LTBI individuals. Moreover, we show a specific transcriptional signature ofMycobacterium tuberculosisassociated with survival within human granuloma structures depending on the host immune status. Our report provides fundamentally new information on how the human host immune status and bacterial transcriptional signature may dictate early granuloma formation and outcome and provides evidence for the validity of the granuloma model and its potential applications.IMPORTANCEIn 2012, approximately 1.3 million people died from tuberculosis (TB), the highest rate for any single bacterial pathogen. The long-term control of TB requires a better understanding ofMycobacterium tuberculosispathogenesis in appropriate research models. Granulomas represent the characteristic host tissue response to TB, controlling the bacilli while concentrating the immune response to a limited area. However, complete eradication of bacteria does not occur, sinceM. tuberculosishas its own strategies to adapt and persist. Thus, theM. tuberculosis-containing granuloma represents a unique environment for dictating both the host immune response and the bacterial response. Here we developed and characterized anin vitrogranuloma model derived from blood cells of individuals with latent TB infection that more accurately defines the human immune response and metabolic profiles ofM. tuberculosiswithin this uniquely regulated immune environment. This model may also prove beneficial for understanding other granulomatous diseases.

scholarly journals Immune Recognition of the Epidemic Cystic Fibrosis Pathogen Burkholderia dolosa

2017 ◽  
Vol 85 (6) ◽  
Author(s):  
Damien Roux ◽  
Molly Weatherholt ◽  
Bradley Clark ◽  
Mihaela Gadjeva ◽  
Diane Renaud ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Immune Response ◽  
Cytokine Production ◽  
Cultured Cells ◽  
Host Immune Response ◽  
Host Cells ◽  
Burkholderia Cenocepacia ◽  
Immune Recognition ◽  
Content Type

ABSTRACT Burkholderia dolosa caused an outbreak in the cystic fibrosis (CF) clinic at Boston Children's Hospital from 1998 to 2005 and led to the infection of over 40 patients, many of whom died due to complications from infection by this organism. To assess whether B. dolosa significantly contributes to disease or is recognized by the host immune response, mice were infected with a sequenced outbreak B. dolosa strain, AU0158, and responses were compared to those to the well-studied CF pathogen Pseudomonas aeruginosa. In parallel, mice were also infected with a polar flagellin mutant of B. dolosa to examine the role of flagella in B. dolosa lung colonization. The results showed a higher persistence in the host by B. dolosa strains, and yet, neutrophil recruitment and cytokine production were lower than those with P. aeruginosa. The ability of host immune cells to recognize B. dolosa was then assessed, B. dolosa induced a robust cytokine response in cultured cells, and this effect was dependent on the flagella only when bacteria were dead. Together, these results suggest that B. dolosa can be recognized by host cells in vitro but may avoid or suppress the host immune response in vivo through unknown mechanisms. B. dolosa was then compared to other Burkholderia species and found to induce similar levels of cytokine production despite being internalized by macrophages more than Burkholderia cenocepacia strains. These data suggest that B. dolosa AU0158 may act differently with host cells and is recognized differently by immune systems than are other Burkholderia strains or species.

scholarly journals The Campylobacter jejuni Dps Homologue Is Important forIn VitroBiofilm Formation and Cecal Colonization of Poultry and May Serve as a Protective Antigen for Vaccination

2012 ◽  
Vol 19 (9) ◽  
pp. 1426-1431 ◽  
Author(s):  
James R. Theoret ◽  
Kerry K. Cooper ◽  
Bereket Zekarias ◽  
Kenneth L. Roland ◽  
Bibiana F. Law ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Biofilm Formation ◽  
Protective Antigen ◽  
Vaccine Antigen ◽  
Pcr Analysis ◽  
Wild Type ◽  
Content Type ◽  
Unit Reduction ◽  
Dps Protein

ABSTRACTIn this work, we investigated theCampylobacter jejuni dps(DNA binding protein from starved cells) gene for a role in biofilm formation and cecal colonization in poultry.In vitrobiofilm formation assays were conducted with stationary-phase cells in cell culture plates under microaerophilic conditions. These studies demonstrated a significant (>50%) reduction in biofilm formation by theC. jejuni dpsmutant compared to that by the wild-type strain. Studies in poultry also demonstrated the importance of thedpsgene in host colonization byC. jejuni. Real-time PCR analysis of mRNA extracted from the cecal contents of poultry infected with wild-typeC. jejuniindicated that thedpsgene is upregulated 20-fold during poultry colonization. Cecal colonization was greater than 5 log CFU lower in chicks infected with thedpsmutant than chicks infected with the wild-typeC. jejunistrain. Moreover, thedpsmutant failed to colonize 75% of the chicks following challenge with 105CFU. Preliminary studies were conducted in chicks by parenteral vaccination with a recombinant Dps protein or through oral vaccination with a recombinant attenuatedSalmonella entericastrain synthesizing theC. jejuniDps protein. No reduction inC. jejuniwas noted in chicks vaccinated with the parenteral recombinant protein, whereas, a 2.5-log-unit reduction ofC. jejuniwas achieved in chicks vaccinated with the attenuatedSalmonellavector after homologous challenge. Taken together, this work demonstrated the importance of Dps for biofilm formation and poultry colonization, and the study also provides a basis for continued work using the Dps protein as a vaccine antigen when delivered through aSalmonellavaccine vector.

scholarly journals Contribution of Laccase Expression to Immune Response against Cryptococcus gattii Infection

2019 ◽  
Vol 88 (3) ◽  
Author(s):  
Adithap Hansakon ◽  
Popchai Ngamskulrungroj ◽  
Pornpimon Angkasekwinai
Keyword(s):  
Immune Response ◽  
Virulence Factor ◽  
Laccase Activity ◽  
Early Stage ◽  
Cryptococcus Gattii ◽  
Interleukin 17 ◽  
Neutrophil Accumulation ◽  
Content Type ◽  
Important Virulence Factor

ABSTRACT Cryptococcosis is an infectious disease caused by two fungal species, Cryptococcus neoformans and Cryptococcus gattii. While C. neoformans affects mainly immunocompromised patients, C. gattii infects both immunocompetent and immunocompromised individuals. Laccase is an important virulence factor that contributes to the virulence of C. neoformans by promoting pulmonary growth and dissemination to the brain. The presence of laccase in C. neoformans can shift the host immune response toward a nonprotective Th2-type response. However, the role of laccase in the immune response against C. gattii remains unclear. In this study, we characterized laccase activity in C. neoformans and C. gattii isolates from Thailand and investigated whether C. gattii that is deficient in laccase might modulate immune responses during infection. C. gattii was found to have higher laccase activity than C. neoformans, indicating the importance of laccase in the pathogenesis of C. gattii infection. The expression of laccase promoted intracellular proliferation in macrophages and inhibited in vitro fungal clearance. Mice infected with a lac1Δ mutant strain of C. gattii had reduced lung burdens at the early but not the late stage of infection. Without affecting type-1 and type-2 responses, the deficiency of laccase in C. gattii induced cryptococcus-specific interleukin-17 (IL-17) cytokine, neutrophil accumulation, and expression of the neutrophil-associated cytokine gene Csf3 and chemokine genes Cxcl1, Cxcl2, and Cxcl5 in vivo, as well as enhanced neutrophil-mediated phagocytosis and killing in vitro. Thus, our data suggest that laccase constitutes an important virulence factor of C. gattii that plays roles in attenuating Th17-type immunity, neutrophil recruitment, and function during the early stage of infection.

The Host Immune Response to Clostridium Difficile and the Immunomodulatory Effects of Probiotic Bacteria in Vitro

Endoscopy ◽  
2006 ◽  
Vol 38 (11) ◽  
Author(s):  
JA Ryan ◽  
A Fanning ◽  
B Sheil ◽  
L O'Mahony ◽  
F Shanahan
Keyword(s):  
Immune Response ◽  
Clostridium Difficile ◽  
Host Immune Response ◽  
Probiotic Bacteria ◽  
Immunomodulatory Effects

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals Pharmacodynamics of Itraconazole against Aspergillus fumigatus in anIn VitroModel of the Human Alveolus: Perspectives on the Treatment of Triazole-Resistant Infection and Utility of Airway Administration

2012 ◽  
Vol 56 (8) ◽  
pp. 4146-4153 ◽  
Author(s):  
Zaid Al-Nakeeb ◽  
Ajay Sudan ◽  
Adam R. Jeans ◽  
Lea Gregson ◽  
Joanne Goodwin ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Therapeutic Strategies ◽  
Wild Type ◽  
Content Type ◽  
Exposure Response ◽  
Prevention And Treatment ◽  
Resistant Infection ◽  
Resistant Strains ◽  
Type Strains

ABSTRACTItraconazole is used for the prevention and treatment of infections caused byAspergillus fumigatus. An understanding of the pharmacodynamics of itraconazole against wild-type and triazole-resistant strains provides a basis for innovative therapeutic strategies for treatment of infections. Anin vitromodel of the human alveolus was used to define the pharmacodynamics of itraconazole. Galactomannan was used as a biomarker. The effect of systemic and airway administration of itraconazole was assessed, as was a combination of itraconazole administered to the airway and systemically administered 5FC. Systemically administered itraconazole against the wild type induced a concentration-dependent decline in galactomannan in the alveolar and endothelial compartments. No exposure-response relationships were apparent for the L98H, M220T, or G138C mutant. The administration of itraconazole to the airway resulted in comparable exposure-response relationships to those observed with systemic therapy. This was achieved without detectable concentrations of drug within the endothelial compartment. The airway administration of itraconazole resulted in a definite but submaximal effect in the endothelial compartment against the L98H mutant. The administration of 5FC resulted in a concentration-dependent decline in galactomannan in both the alveolar and endothelial compartments. The combination of airway administration of itraconazole and systemically administered 5FC was additive. Systemic administration of itraconazole is ineffective against Cyp51 mutants. The airway administration of itraconazole is effective for the treatment of wild-type strains and appears to have some activity against the L98H mutants. Combination with other agents, such as 5FC, may enable the attainment of near-maximal antifungal activity.

scholarly journals Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

2011 ◽  
Vol 80 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Chen Li ◽  
Kurniyati ◽  
Bo Hu ◽  
Jiang Bian ◽  
Jianlan Sun ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Biofilm Formation ◽  
Adult Population ◽  
Transcriptional Analysis ◽  
Wild Type ◽  
Content Type ◽  
Multiple Organs ◽  
Biochemical Analyses

ABSTRACTThe oral bacteriumPorphyromonas gingivalisis a key etiological agent of human periodontitis, a prevalent chronic disease that affects up to 80% of the adult population worldwide.P. gingivalisexhibits neuraminidase activity. However, the enzyme responsible for this activity, its biochemical features, and its role in the physiology and virulence ofP. gingivalisremain elusive. In this report, we found thatP. gingivalisencodes a neuraminidase, PG0352 (SiaPg). Transcriptional analysis showed thatPG0352is monocistronic and is regulated by a sigma70-like promoter. Biochemical analyses demonstrated that SiaPgis an exo-α-neuraminidase that cleaves glycosidic-linked sialic acids. Cryoelectron microscopy and tomography analyses revealed that thePG0352deletion mutant (ΔPG352) failed to produce an intact capsule layer. Compared to the wild type,in vitrostudies showed that ΔPG352 formed less biofilm and was less resistant to killing by the host complement.In vivostudies showed that while the wild type caused a spreading type of infection that affected multiple organs and all infected mice were killed, ΔPG352 only caused localized infection and all animals survived. Taken together, these results demonstrate that SiaPgis an important virulence factor that contributes to the biofilm formation, capsule biosynthesis, and pathogenicity ofP. gingivalis, and it can potentially serve as a new target for developing therapeutic agents againstP. gingivalisinfection.

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