scholarly journals Characterization of a Distinct Host Response Profile to Pneumocystis murina Asci during Clearance of Pneumocystis Pneumonia

2013 ◽  
Vol 81 (3) ◽  
pp. 984-995 ◽  
Author(s):  
Michael J. Linke ◽  
Alan Ashbaugh ◽  
Margaret S. Collins ◽  
Keeley Lynch ◽  
Melanie T. Cushion
Keyword(s):  
Life Cycle ◽  
Inflammatory Response ◽  
Immune Responses ◽  
Host Response ◽  
Cellular Response ◽  
Pneumocystis Pneumonia ◽  
Lung Damage ◽  
Th17 Response ◽  
Content Type ◽  
Chronic Lung Diseases

ABSTRACTPneumocystisspp. are yeast-like fungi that cause pneumocystis pneumonia (PcP) in immunocompromised individuals and exacerbate chronic lung diseases in immunocompetent individuals. ThePneumocystislife cycle includes trophic forms and asci (cyst forms). The cell walls ofPneumocystisasci contain β-1,3-d-glucan, and treatment of PcP with β-1,3-d-glucan synthase inhibitors, such as anidulafungin, results in depletion of asci, but not trophic forms. The pulmonary host response during immune reconstitution (IR)-mediated clearance of PcP in anidulafungin-treated and untreated mice was characterized to identify ascus-specific responses. During IR, similar numbers of trophic forms were present in the anidulafungin-treated and untreated mice; however, asci were only present in the untreated mice. IR resulted in a significant reduction of trophic forms from the lungs in both groups and asci in the untreated group. The presence of asci in untreated mice correlated with increased β-glucan content in the lungs. The untreated mice mounted immune responses associated with a deleterious host inflammatory response, including increased CD8+T cell influx and expression of macrophage inflammatory response markers. A more robust cellular response was also observed in the untreated mice, with increased numbers of macrophages and neutrophils that were associated with greater lung damage. Markers of a Th17 response were also elevated in the untreated mice. These results suggest that the host mounts unique responses to asci and trophic forms. That these 2 life cycle stages provoked distinct host response profiles has significant implications for clearance and interpretation of the host immune responses to PcP.

scholarly journals Enterococcus faecalisDemonstrates Pathogenicity through Increased Attachment in anEx VivoPolymicrobial Pulpal Infection

2018 ◽  
Vol 86 (5) ◽  
Author(s):  
Wayne Nishio Ayre ◽  
Genevieve Melling ◽  
Camille Cuveillier ◽  
Madhan Natarajan ◽  
Jessica L. Roberts ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Host Response ◽  
Ex Vivo ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Streptococcus Anginosus ◽  
Cell Counts ◽  
Tnf Α ◽  
Factor Alpha ◽  
Infection Types

ABSTRACTThis study investigated the host response to a polymicrobial pulpal infection consisting ofStreptococcus anginosusandEnterococcus faecalis, bacteria commonly implicated in dental abscesses and endodontic failure, using a validatedex vivorat tooth model. Tooth slices were inoculated with planktonic cultures ofS. anginosusorE. faecalisalone or in coculture atS. anginosus/E. faecalisratios of 50:50 and 90:10. Attachment was semiquantified by measuring the area covered by fluorescently labeled bacteria. Host response was established by viable histological cell counts, and inflammatory response was measured using reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemistry. A significant reduction in cell viability was observed for single and polymicrobial infections, with no significant differences between infection types (∼2,000 cells/mm2for infected pulps compared to ∼4,000 cells/mm2for uninfected pulps).E. faecalisdemonstrated significantly higher levels of attachment (6.5%) thanS. anginosusalone (2.3%) and mixed-species infections (3.4% for 50:50 and 2.3% for 90:10), with a remarkable affinity for the pulpal vasculature. Infections withE. faecalisdemonstrated the greatest increase in tumor necrosis factor alpha (TNF-α) (47.1-fold forE. faecalis, 14.6-fold forS. anginosus, 60.1-fold for 50:50, and 25.0-fold for 90:10) and interleukin 1β (IL-1β) expression (54.8-fold forE. faecalis, 8.8-fold forS. anginosus, 54.5-fold for 50:50, and 39.9-fold for 90:10) compared to uninfected samples. Immunohistochemistry confirmed this, with the majority of inflammation localized to the pulpal vasculature and odontoblast regions. Interestingly,E. faecalissupernatant and heat-killedE. faecalistreatments were unable to induce the same inflammatory response, suggestingE. faecalispathogenicity in pulpitis is linked to its greater ability to attach to the pulpal vasculature.

scholarly journals The Toll Interleukin-1 Receptor (IL-1R) 8/Single Ig Domain IL-1R-Related Molecule Modulates the Renal Response to Bacterial Infection

2012 ◽  
Vol 80 (11) ◽  
pp. 3812-3820 ◽  
Author(s):  
Jaklien C. Leemans ◽  
Loes M. Butter ◽  
Gwendoline J. D. Teske ◽  
Ingrid Stroo ◽  
Wilco P. Pulskens ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Response ◽  
Host Response ◽  
Interleukin 1 ◽  
Negative Regulator ◽  
Tubular Epithelial Cells ◽  
Content Type ◽  
Related Molecule ◽  
E Coli ◽  
Ig Domain

ABSTRACTOur immune system has to constantly strike a balance between activation and inhibition of an inflammatory response to combat invading pathogens and avoid inflammation-induced collateral tissue damage. Toll interleukin-1 receptor 8 (IL-1R-8)/single Ig domain IL-1R-related molecule (TIR8/SIGIRR) is an inhibitor of Toll-like receptor (TLR)/IL-1R signaling, which is predominantly expressed in the kidney. The biological role of renal TIR8 during infection is, however, unknown. We therefore evaluated renal TIR8 expression duringEscherichia colipyelonephritis and explored its role in host defense using TIR8−/−versus TIR8+/+mice. We found that TIR8 protein is abundantly present in the majority of cortical tubular epithelial cells. Pyelonephritis resulted in a significant downregulation of TIR8 mRNA in kidneys of TIR8+/+mice. TIR8 inhibited an effective host response againstE. coli, as indicated by diminished renal bacterial outgrowth and dysfunction in TIR8−/−mice. This correlated with increased amounts of circulating and intrarenal neutrophils at the early phase of infection. TIR8−/−tubular epithelial cells had increased cytokine/chemokine production when stimulated with lipopolysaccharide (LPS) or heat-killedE. coli, suggesting that TIR8 played an anti-inflammatory role during pathogen stimulation by inhibiting LPS signaling. These data suggest that TIR8 is an important negative regulator of an LPS-mediated inflammatory response in tubular epithelial cells and dampens an effective antibacterial host response during pyelonephritis caused by uropathogenicE. coli.

scholarly journals Intranasal Vaccination with the Recombinant Listeria monocytogenes ΔactA prfA*Mutant Elicits Robust Systemic and Pulmonary Cellular Responses and Secretory Mucosal IgA

2011 ◽  
Vol 18 (4) ◽  
pp. 640-646 ◽  
Author(s):  
Jin Qiu ◽  
Lin Yan ◽  
Jianbo Chen ◽  
Crystal Y. Chen ◽  
Ling Shen ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Immune Responses ◽  
Cellular Response ◽  
Cellular Responses ◽  
Broth Culture ◽  
Intravenous Route ◽  
Content Type ◽  
Vaccine Candidates ◽  
Ifn Γ ◽  
Subcutaneous Immunization

ABSTRACTWe previously showed that recombinant (r)Listeria monocytogenescarrying ΔactAand a selectedprfA*mutation (r-ListeriaΔactA prfA*) secreted >100-fold more immunogen in broth culture than wild-type r-Listeriaor r-ListeriaΔactAand elicited much greater cellular and humoral immune responses than r-ListeriaΔactAafter intravenous vaccination of mice. Here, we conducted comparative studies evaluating vaccine-elicited immune responses in systemic and mucosal sites after intranasal, intravenous, intraperitoneal, or subcutaneous immunization of mice with r-ListeriaΔactA prfA*vaccine candidates. Intranasal vaccination of mice with r-ListeriaΔactA prfA* vaccine candidates elicited a robust gamma interferon-positive (IFN-γ+) cellular response in systemic sites, although intravenous or intraperitoneal immunization was more efficient. Surprisingly, intranasal vaccination elicited an appreciable pulmonary IFN-γ+cellular response that was nonstatistically higher than the magnitude induced by the intravenous route but was significantly greater than that elicited by subcutaneous immunization. Furthermore, although intranasal r-ListeriaΔactA prfA*delivery induced poor systemic IgG responses, intranasal vaccination elicited appreciable secretory immunogen-specific IgA titers that were similar to or higher in mucosal fluid than those induced by subcutaneous and intravenous immunizations. Thus, intranasal vaccination with r-ListeriaΔactA prfA*appears to be a useful approach for eliciting robust systemic and pulmonary cellular responses and measurable secretory mucosal IgA titers.

scholarly journals Transcriptomic and Proteomic Analyses Reveal Key Innate Immune Signatures in the Host Response to the Gastrointestinal Pathogen Campylobacter concisus

2014 ◽  
Vol 83 (2) ◽  
pp. 832-845 ◽  
Author(s):  
Nadeem O. Kaakoush ◽  
Nandan P. Deshpande ◽  
Si Ming Man ◽  
Jose A. Burgos-Portugal ◽  
Faisal A. Khattak ◽  
...  
Keyword(s):  
Immune Responses ◽  
Host Response ◽  
Innate Immune ◽  
Colorectal Carcinogenesis ◽  
Host Recognition ◽  
Major Advance ◽  
Innate Immune Responses ◽  
Ongoing Research ◽  
Campylobacter Concisus ◽  
Content Type

Pathogenic species within the genusCampylobacterare responsible for a considerable burden on global health.Campylobacter concisusis an emergent pathogen that plays a role in acute and chronic gastrointestinal disease. Despite ongoing research onCampylobactervirulence mechanisms, little is known regarding the immunological profile of the host response toCampylobacterinfection. In this study, we describe a comprehensive global profile of innate immune responses toC. concisusinfection in differentiated THP-1 macrophages infected with an adherent and invasive strain ofC. concisus. Using RNA sequencing (RNA-seq), quantitative PCR (qPCR), mass spectrometry, and confocal microscopy, we observed differential expression of pattern recognition receptors and robust upregulation of DNA- and RNA-sensing molecules. In particular, we observed IFI16 inflammasome assembly inC. concisus-infected macrophages. Global profiling of the transcriptome revealed the significant regulation of a total of 8,343 transcripts upon infection withC. concisus, which included the activation of key inflammatory pathways involving CREB1, NF-κB, STAT, and interferon regulatory factor signaling. Thirteen microRNAs and 333 noncoding RNAs were significantly regulated upon infection, including MIR221, which has been associated with colorectal carcinogenesis. This study represents a major advance in our understanding of host recognition and innate immune responses to infection byC. concisus.

scholarly journals The Life Cycle Stages of Pneumocystis murina Have Opposing Effects on the Immune Response to This Opportunistic Fungal Pathogen

2016 ◽  
Vol 84 (11) ◽  
pp. 3195-3205 ◽  
Author(s):  
Heather M. Evans ◽  
Grady L. Bryant ◽  
Beth A. Garvy
Keyword(s):  
Cell Wall ◽  
Life Cycle ◽  
Immune Responses ◽  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Content Type ◽  
Life Cycle Stages ◽  
Ifn Γ

The cell wall β-glucans of Pneumocystis cysts have been shown to stimulate immune responses in lung epithelial cells, dendritic cells, and alveolar macrophages. Little is known about how the trophic life forms, which do not have a fungal cell wall, interact with these innate immune cells. Here we report differences in the responses of both neonatal and adult mice to the trophic and cystic life cycle stages of Pneumocystis murina . The adult and neonatal immune responses to infection with Pneumocystis murina trophic forms were less robust than the responses to infection with a physiologically normal mixture of cysts and trophic forms. Cysts promoted the recruitment of nonresident innate immune cells and T and B cells into the lungs. Cysts, but not trophic forms, stimulated increased concentrations of the cytokine gamma interferon (IFN-γ) in the alveolar spaces and an increase in the percentage of CD4 + T cells that produce IFN-γ. In vitro , bone marrow-derived dendritic cells (BMDCs) stimulated with cysts produced the proinflammatory cytokines interleukin 1β (IL-1β) and IL-6. In contrast, trophic forms suppressed antigen presentation to CD4 + T cells, as well as the β-glucan-, lipoteichoic acid (LTA)-, and lipopolysaccharide (LPS)-induced production of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) by BMDCs. The negative effects of trophic forms were not due to ligation of mannose receptor. Our results indicate that optimal innate and adaptive immune responses to Pneumocystis species are dependent on stimulation with the cyst life cycle stage. Conversely, trophic forms suppress β-glucan-induced proinflammatory responses in vitro , suggesting that the trophic forms dampen cyst-induced inflammation in vivo .

scholarly journals Vitamin D as Supplemental Therapy for Pneumocystis Pneumonia

2015 ◽  
Vol 60 (3) ◽  
pp. 1289-1297 ◽  
Author(s):  
Guang-Sheng Lei ◽  
Chen Zhang ◽  
Michelle K. Zimmerman ◽  
Chao-Hung Lee
Keyword(s):  
Vitamin D ◽  
Retinoic Acid ◽  
Alternative Therapy ◽  
Inflammatory Cells ◽  
Pneumocystis Pneumonia ◽  
Lung Damage ◽  
High Concentration ◽  
Macrophage Population ◽  
Content Type ◽  
Flow Cytometric

The combination of all-transretinoic acid (ATRA) and primaquine (PMQ) has been shown to be effective for therapy ofPneumocystispneumonia (PCP). Since a high concentration of ATRA has significant adverse effects, the possibility that vitamin D can be used to replace ATRA for PCP therapy was investigated. C57BL/6 mice were immunosuppressed by depleting CD4+cells and infected withPneumocystismurina1 week after initiation of immunosuppression. Three weeks after infection, the mice were treated orally for 3 weeks with vitamin D3(VitD3) alone, PMQ alone, a combination of VitD3 and PMQ (VitD3-PMQ), or a combination of trimethoprim and sulfamethoxazole (TMP-SMX). Results showed that VitD3 (300 IU/kg/day) had a synergistic effect with PMQ (5 mg/kg/day) for therapy of PCP. Flow cytometric studies showed that this VitD3-PMQ combination recovered the CD11blowCD11chighalveolar macrophage population in mice with PCP as effectively as TMP-SMX. The VitD3-PMQ combination also reduced the massive infiltration of inflammatory cells into the lungs and the severity of lung damage. VitD3 was also shown to reduce the dose of TMP-SMX required for effective treatment of PCP. Taken together, results of this study suggest that a VitD3-PMQ combination can be used as an alternative therapy for PCP.

scholarly journals Activation of Human and Chicken Toll-Like Receptors by Campylobacter spp.

2009 ◽  
Vol 78 (3) ◽  
pp. 1229-1238 ◽  
Author(s):  
Marcel R. de Zoete ◽  
A. Marijke Keestra ◽  
Paula Roszczenko ◽  
Jos P. M. van Putten
Keyword(s):  
Cell Wall ◽  
Inflammatory Response ◽  
Immune Responses ◽  
Host Response ◽  
The Body ◽  
Toll Like Receptors ◽  
Differential Host ◽  
Live Bacteria ◽  
Sense And Respond ◽  
Campylobacter Spp

ABSTRACT Campylobacter infection in humans is accompanied by severe inflammation of the intestinal mucosa, in contrast to colonization of chicken. The basis for the differential host response is unknown. Toll-like receptors (TLRs) sense and respond to microbes in the body and participate in the induction of an inflammatory response. Thus far, the interaction of Campylobacter with chicken TLRs has not been studied. Here, we investigated the potential of four Campylobacter strains to activate human TLR1/2/6, TLR4, TLR5, and TLR9 and chicken TLR2t2/16, TLR4, TLR5, and TLR21. Live bacteria showed no or very limited potential to activate TLR2, TLR4, and TLR5 of both the human and chicken species, with minor but significant differences between Campylobacter strains. In contrast, lysed bacteria induced strong NF-κB activation through human TLR1/2/6 and TLR4 and chicken TLR2t2/16 and TLR4 but not via TLR5 of either species. Interestingly, C. jejuni induced TLR4-mediated beta interferon in human but not chicken cells. Furthermore, isolated chromosomal Campylobacter DNA was unable to activate human TLR9 in our system, whereas chicken TLR21 was activated by DNA from all of the campylobacters tested. Our data are the first comparison of TLR-induced immune responses in humans and chickens. The results suggest that differences in bacterial cell wall integrity and in TLR responses to Campylobacter LOS and/or DNA may contribute to the distinct clinical manifestation between the species.

scholarly journals Immune Response in Pneumocystis Infections According to the Host Immune System Status

2021 ◽  
Vol 7 (8) ◽  
pp. 625
Author(s):  
Eléna Charpentier ◽  
Sandie Ménard ◽  
Catherine Marques ◽  
Antoine Berry ◽  
Xavier Iriart
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Immune Status ◽  
Pneumocystis Pneumonia ◽  
Favourable Outcome ◽  
Lung Damage ◽  
Host Immune System ◽  
M1 Macrophage ◽  
Immune Deficiencies ◽  
The Impact

The host immune response is critical in Pneumocystis pneumonia (PCP). Immunocompetent hosts can eliminate the fungus without symptoms, while immunodeficient hosts develop PCP with an unsuitable excessive inflammatory response leading to lung damage. From studies based on rodent models or clinical studies, this review aimed to better understand the pathophysiology of Pneumocystis infection by analysing the role of immune cells, mostly lymphocytes, according to the immune status of the infected host. Hence, this review first describes the immune physiological response in infected immunocompetent hosts that are able to eliminate the fungus. The objective of the second part is to identify the immune elements required for the control of the fungus, focusing on specific immune deficiencies. Finally, the third part concentrates on the effect of the different immune elements in immunocompromised subjects during PCP, to better understand which cells are detrimental, and which, on the contrary, are beneficial once the disease has started. This work highlights that the immune response associated with a favourable outcome of the infection may differ according to the immune status of the host. In the case of immunocompetency, a close communication between B cells and TCD4 within tertiary lymphocyte structures appears critical to activate M2 macrophages without much inflammation. Conversely, in the case of immunodeficiency, a pro-inflammatory response including Th1 CD4, cytotoxic CD8, NK cells, and IFNγ release seems beneficial for M1 macrophage activation, despite the impact of inflammation on lung tissue.

scholarly journals Dectin Immunoadhesins and Pneumocystis Pneumonia

2013 ◽  
Vol 81 (9) ◽  
pp. 3451-3462 ◽  
Author(s):  
David M. Ricks ◽  
Kong Chen ◽  
Mingquan Zheng ◽  
Chad Steele ◽  
Jay K. Kolls
Keyword(s):  
Inflammatory Response ◽  
Opportunistic Pathogen ◽  
Pneumocystis Pneumonia ◽  
Carbohydrate Binding ◽  
Content Type ◽  
Specificity Of Binding ◽  
Inflammatory Syndrome ◽  
Dependent Mechanism

ABSTRACTThe opportunistic pathogenPneumocystis jiroveciiis a significant cause of disease in HIV-infected patients and others with immunosuppressive conditions.Pneumocystiscan also cause complications in treatment following antiretroviral therapy or reversal of immunosuppressive therapy, as the newly reconstituted immune system can develop a pathological inflammatory response to remaining antigens or a previously undetected infection. To target β-(1,3)-glucan, a structural component of thePneumocystiscell wall with immune-stimulating properties, we have developed immunoadhesins consisting of the carbohydrate binding domain of Dectin-1 fused to the Fc regions of the 4 subtypes of murine IgG (mIgG). These immunoadhesins bind β-glucan with high affinity, and precoating the surface of zymosan with Dectin-1:Fc can reduce cytokine production by macrophages in anin vitrostimulation assay. All Dectin-1:Fc variants showed specificity of binding to the asci ofPneumocystis murina, but effector activity of the fusion molecules varied depending on Fc subtype. Dectin-1:mIgG2a Fc was able to reduce the viability ofP. murinain culture through a complement-dependent mechanism, whereas previous studies have shown the mIgG1 Fc fusion to increase macrophage-dependent killing. In anin vivochallenge model, systemic expression of Dectin-1:mIgG1 Fc significantly reduced ascus burden in the lung. When administered postinfection in a model of immune reconstitution inflammatory syndrome (IRIS), both Dectin-1:mIgG1 and Dectin-1:mIgG2a Fc reduced hypoxemia despite minimal effects on fungal burden in the lung. Taken together, these data indicate that molecules targeting β-glucan may provide a mechanism for treatment of fungal infection and for modulation of the inflammatory response toPneumocystisand other pathogens.

scholarly journals Myeloid-Derived Suppressor Cells Impair Alveolar Macrophages through PD-1 Receptor Ligation during Pneumocystis Pneumonia

2014 ◽  
Vol 83 (2) ◽  
pp. 572-582 ◽  
Author(s):  
Guang-Sheng Lei ◽  
Chen Zhang ◽  
Chao-Hung Lee
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
Alveolar Macrophages ◽  
Suppressor Cells ◽  
Pneumocystis Pneumonia ◽  
Lung Damage ◽  
Myeloid Derived Suppressor Cells ◽  
Content Type ◽  
Histone 3 ◽  
Receptor Ligation

Myeloid-derived suppressor cells (MDSCs) were recently found to accumulate in the lungs duringPneumocystispneumonia (PcP). Adoptive transfer of these cells caused lung damage in recipient mice, suggesting that MDSC accumulation is a mechanism of pathogenesis in PcP. In this study, the phagocytic activity of alveolar macrophages (AMs) was found to decrease by 40% when they were incubated with MDSCs fromPneumocystis-infected mice compared to those incubated with Gr-1+cells from the bone marrow of uninfected mice. The expression of the PU.1 gene in AMs incubated with MDSCs also was decreased. This PU.1 downregulation was due mainly to decreased histone 3 acetylation and increased DNA methylation caused by MDSCs. MDSCs were found to express high levels of PD-L1, and alveolar macrophages (AMs) were found to express high levels of PD-1 during PcP. Furthermore, PD-1 expression in AMs from uninfected mice was increased by 18-fold when they were incubated with MDSCs compared to those incubated with Gr-1+cells from the bone marrow of uninfected mice. The adverse effects of MDSCs on AMs were diminished when the MDSCs were pretreated with anti-PD-L1 antibody, suggesting that MDSCs disable AMs through PD-1/PD-L1 ligation during PcP.

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