scholarly journals Leptin Receptor Mutation Results in Defective Neutrophil Recruitment to the Colon during Entamoeba histolytica Infection

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Caitlin Naylor ◽  
Stacey Burgess ◽  
Rajat Madan ◽  
Erica Buonomo ◽  
Khadija Razzaq ◽  
...  
Keyword(s):  
Entamoeba Histolytica ◽  
Leptin Receptor ◽  
Neutrophil Infiltration ◽  
Neutrophil Function ◽  
Enteric Infection ◽  
Neutrophil Chemotaxis ◽  
Content Type ◽  
Innate Defense ◽  
The Impact ◽  
Increased Susceptibility

ABSTRACTAmebiasis is an enteric infection caused byEntamoeba histolytica, with symptoms ranging in severity from asymptomatic colonization to dysentery. Humans with the Q223R leptin receptor mutation have increased susceptibility to amebiasis, but the mechanism has been unclear. Using a mouse model expressing the mutation, we tested the impact of the Q223R mutation on the innate immune response toE. histolyticainfection. The 223R mutation resulted in delayed clearance of amebae from the cecum, as had been previously observed. We found that neutrophil influx to the site of the infection was reduced 12 h after infection in 223R mice. Depletion of neutrophils with anti-Ly6G monoclonal antibody increased susceptibility of wild-type mice to infection, supporting the importance of neutrophils in innate defense. Leptin expression was increased in the cecum byE. histolyticainfection, suggesting that leptin could serve as a homing signal for neutrophils to the gut. Interestingly, neutrophils from mice with the 223R mutation had diminished chemotaxis toward leptin. This impaired chemotaxis likely explained the reduced gut infiltration of neutrophils. The newly recognized effect of the leptin receptor Q223R mutation on neutrophil chemotaxis and the impact of this mutation on multiple infectious diseases suggest a broader impact of this mutation on susceptibility to disease.IMPORTANCEThe Q223R leptin receptor mutation results in increased susceptibility of children and adults toE. histolytica, one of the leading causes of diarrhea morbidity and mortality in children of the developing world. Here we show that the mutation results in reduced neutrophil infiltration to the site of infection. This decreased infiltration is likely due to the mutation’s impact on neutrophil chemotaxis toward leptin, an inflammatory agent upregulated in the cecum after infection. The significance of this work thus extends beyond understandingE. histolyticasusceptibility by also providing insight into the potential impact of leptin on neutrophil function in other states of altered leptin signaling, which include both malnutrition and obesity.

scholarly journals Short Palate, Lung, and Nasal Epithelial Clone 1 Has Antimicrobial and Antibiofilm Activities against the Burkholderia cepacia Complex

2016 ◽  
Vol 60 (10) ◽  
pp. 6003-6012 ◽  
Author(s):  
Saira Ahmad ◽  
Jean Tyrrell ◽  
William G. Walton ◽  
Ashutosh Tripathy ◽  
Matthew R. Redinbo ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Lung Disease ◽  
Biofilm Formation ◽  
Burkholderia Cepacia ◽  
Burkholderia Cepacia Complex ◽  
Upper Airways ◽  
Content Type ◽  
Innate Defense ◽  
Opportunistic Bacteria ◽  
The Impact

ABSTRACTThe opportunistic bacteria of theBurkholderia cepaciacomplex (Bcc) are extremely pathogenic to cystic fibrosis (CF) patients, and acquisition of Bcc bacteria is associated with a significant increase in mortality. Treatment of Bcc infections is difficult because the bacteria are multidrug resistant and able to survive in biofilms. Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) is an innate defense protein that is secreted by the upper airways and pharynx. While SPLUNC1 is known to have antimicrobial functions, its effects on Bcc strains are unclear. We therefore tested the hypothesis that SPLUNC1 is able to impair Bcc growth and biofilm formation. We found that SPLUNC1 exerted bacteriostatic effects against several Bcc clinical isolates, includingB. cenocepaciastrain J2315 (50% inhibitory concentration [IC50] = 0.28 μM), and reduced biofilm formation and attachment (IC50= 0.11 μM). We then determined which domains of SPLUNC1 are responsible for its antimicrobial activity. Deletions of SPLUNC1's N terminus and α6 helix did not affect its function. However, deletion of the α4 helix attenuated antimicrobial activity, while the corresponding α4 peptide displayed antimicrobial activity. Chronic neutrophilia is a hallmark of CF lung disease, and neutrophil elastase (NE) cleaves SPLUNC1. However, we found that the ability of SPLUNC1 to disrupt biofilm formation was significantly potentiated by NE pretreatment. While the impact of CF on SPLUNC1-Bcc interactions is not currently known, our data suggest that understanding this interaction may have important implications for CF lung disease.

scholarly journals Filifactor alocis Promotes Neutrophil Degranulation and Chemotactic Activity

2016 ◽  
Vol 84 (12) ◽  
pp. 3423-3433 ◽  
Author(s):  
Cortney L. Armstrong ◽  
Irina Miralda ◽  
Adam C. Neff ◽  
Shifu Tian ◽  
Aruna Vashishta ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Periodontal Pocket ◽  
Human Neutrophils ◽  
Neutrophil Chemotaxis ◽  
Granule Exocytosis ◽  
Content Type ◽  
Innate Defense ◽  
Random Migration ◽  
Neutrophil Degranulation ◽  
Filifactor Alocis

Filifactor alocis is a recently recognized periodontal pathogen; however, little is known regarding its interactions with the immune system. As the first-responder phagocytic cells, neutrophils are recruited in large numbers to the periodontal pocket, where they play a crucial role in the innate defense of the periodontium. Thus, in order to colonize, successful periodontal pathogens must devise means to interfere with neutrophil chemotaxis and activation. In this study, we assessed major neutrophil functions, including degranulation and cell migration, associated with the p38 mitogen-activated protein kinase (MAPK) signaling pathway upon challenge with F. alocis. Under conditions lacking a chemotactic gradient, F. alocis -challenged neutrophils had increased migration compared to uninfected cells, indicating that F. alocis increases chemokinesis in human neutrophils. In addition, neutrophil chemotaxis induced by interleukin-8 was significantly enhanced when cells were challenged with F. alocis , compared to noninfected cells. Similar to live bacteria, heat-killed F. alocis induced both random and directed migration of human neutrophils. The interaction of F. alocis with Toll-like receptor 2 induced granule exocytosis along with a transient ERK1/2 and sustained p38 MAPK activation. Moreover, F. alocis -induced secretory vesicle and specific granule exocytosis were p38 MAPK dependent. Blocking neutrophil degranulation with TAT-SNAP23 fusion protein significantly reduced the chemotactic and random migration induced by F. alocis . Therefore, we propose that induction of random migration by F. alocis will prolong neutrophil traffic time in the gingival tissue, and subsequent degranulation will contribute to tissue damage.

scholarly journals Vitamin D Deficiency Does Not Result in a Breach of Host Defense in Murine Models of Pneumonia

2016 ◽  
Vol 84 (11) ◽  
pp. 3097-3104 ◽  
Author(s):  
Julia Niederstrasser ◽  
Christian Herr ◽  
Lisa Wolf ◽  
Claus M. Lehr ◽  
Christoph Beisswenger ◽  
...  
Keyword(s):  
Vitamin D ◽  
Pseudomonas Aeruginosa ◽  
Streptococcus Pneumoniae ◽  
Host Defense ◽  
Murine Models ◽  
Deficient Diet ◽  
Content Type ◽  
Cell Counts ◽  
The Impact ◽  
Increased Susceptibility

Vitamin D (VitD) has a role in the regulation of calcium and phosphate metabolism and in addition impacts the activity of the immune system. VitD deficiency might be linked to increased susceptibility to respiratory tract infection. The aim of the present study was to characterize the impact of VitD deficiency on the susceptibility to bacterial infection in murine models. C57BL/6N mice were fed a diet with or without VitD for 10 weeks. The VitD-deficient or -sufficient mice were infected with Pseudomonas aeruginosa or Streptococcus pneumoniae . The colonization and inflammatory response in the lung were analyzed at defined time points. The serum 25-hydroxy-VitD concentration was significantly lower in mice on the VitD-deficient diet. In infection experiments with Pseudomonas aeruginosa or Streptococcus pneumoniae , no differences could be observed in the numbers of viable bacteria or in differential cell counts in the bronchoalveolar lavage fluids. Measurements of inflammatory cytokines (KC and interleukin-1β [IL-1β]) did not show significant differences between the groups. In conclusion, VitD-deficient animals did not show significantly increased susceptibility to infection or an altered course of infection. The immune systems of humans and mice likely respond differently to VitD. Murine models are likely not appropriate for drawing conclusions on the role of VitD in human pulmonary host defense.

scholarly journals Bone Marrow Dendritic Cells from Mice with an Altered Microbiota Provide Interleukin 17A-Dependent Protection against Entamoeba histolytica Colitis

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Stacey L. Burgess ◽  
Erica Buonomo ◽  
Maureen Carey ◽  
Carrie Cowardin ◽  
Caitlin Naylor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Entamoeba Histolytica ◽  
Murine Model ◽  
Inflammatory Diseases ◽  
Human Microbiome ◽  
Intestinal Bacteria ◽  
Enteric Infection ◽  
Content Type ◽  
Interleukin 17A

ABSTRACTThere is an emerging paradigm that the human microbiome is central to many aspects of health and may have a role in preventing enteric infection.Entamoeba histolyticais a major cause of amebic diarrhea in developing countries. It colonizes the colon lumen in close proximity to the gut microbiota. Interestingly, not all individuals are equally susceptible to E. histolytica infection. Therefore, as the microbiota is highly variable within individuals, we sought to determine if a component of the microbiota could regulate susceptibility to infection. In studies utilizing a murine model, we demonstrated that colonization of the gut with the commensalClostridia-related bacteria known as segmented filamentous bacteria (SFB) is protective during E. histolyticainfection. SFB colonization in this model was associated with elevated cecal levels of interleukin 17A (IL-17A), dendritic cells, and neutrophils. Bone marrow-derived dendritic cells (BMDCs) from SFB-colonized mice had higher levels of IL-23 production in response to stimulation with trophozoites. Adoptive transfer of BMDCs from an SFB+to an SFB−mouse was sufficient to provide protection againstE. histolytica. IL-17A induction during BMDC transfer was necessary for this protection. This work demonstrates that intestinal colonization with a specific commensal bacterium can provide protection during amebiasis in a murine model. Most importantly, this work demonstrates that the microbiome can mediate protection against an enteric infection via extraintestinal effects on bone marrow-derived dendritic cells.IMPORTANCEEntamoeba histolyticais the causative agent of amebiasis, an infectious disease that contributes significantly to morbidity and mortality due to diarrhea in the developing world. We showed in a murine model that colonization with the commensal members of theClostridiaknown as SFB provides protection againstE. histolyticaand that dendritic cells from SFB-colonized mice alone can recapitulate protection. Understanding interactions between enteropathogens, commensal intestinal bacteria, and the mucosal immune response, including dendritic cells, will help in the development of effective treatments for this disease and other infectious and inflammatory diseases. The demonstration of immune-mediated protection due to communication from the microbiome to the bone marrow represents an emerging field of study that will yield unique approaches to the development of these treatments.

scholarly journals Impact of Extracellular Nuclease Production on the Biofilm Phenotype of Staphylococcus aureus underIn VitroandIn VivoConditions

2012 ◽  
Vol 80 (5) ◽  
pp. 1634-1638 ◽  
Author(s):  
Karen E. Beenken ◽  
Horace Spencer ◽  
Linda M. Griffin ◽  
Mark S. Smeltzer
Keyword(s):  
Staphylococcus Aureus ◽  
Murine Model ◽  
Biofilm Formation ◽  
Extracellular Dna ◽  
Content Type ◽  
Extracellular Nuclease ◽  
The Impact ◽  
Increased Susceptibility

ABSTRACTRecent studies suggest that extracellular DNA promotes biofilm formation inStaphylococcus aureusand, conversely, that extracellular nucleases limit the ability to form a biofilm.S. aureusproduces at least two extracellular nucleases, and in the study described in this report, we examined the impact of each of these nucleases on biofilm formation under bothin vitroandin vivoconditions. Our results demonstrate that both nucleases impact biofilm formation in the clinical isolate UAMS-1. Under certainin vitroconditions, this impact is negative, with mutation of either or both of the nuclease genes (nuc1andnuc2) resulting in an enhanced capacity to form a biofilm. However, this effect was not apparentin vivoin a murine model of catheter-associated biofilm formation. Rather, mutation of either or both nuclease genes appeared to limit biofilm formation to a degree that could be correlated with increased susceptibility to daptomycin.

scholarly journals Entamoeba histolytica Induces Intestinal Cathelicidins but Is Resistant to Cathelicidin-Mediated Killing

2011 ◽  
Vol 80 (1) ◽  
pp. 143-149 ◽  
Author(s):  
Eduardo R. Cobo ◽  
Chen He ◽  
Ken Hirata ◽  
Grace Hwang ◽  
UyenPhuong Tran ◽  
...  
Keyword(s):  
Immune System ◽  
Entamoeba Histolytica ◽  
Cysteine Proteases ◽  
Host Immune System ◽  
Intestinal Epithelial ◽  
Cysteine Proteinases ◽  
Content Type ◽  
Amebic Colitis ◽  
Innate Defense ◽  
Essential Components

ABSTRACTThe enteric protozoan parasiteEntamoeba histolyticais the cause of potentially fatal amebic colitis and liver abscesses.E. histolyticatrophozoites colonize the colon, where they induce inflammation, penetrate the mucosa, and disrupt the host immune system. The early establishment ofE. histolyticain the colon occurs in the presence of antimicrobial human (LL-37) and murine (CRAMP [cathelin-related antimicrobial peptide]) cathelicidins, essential components of the mammalian innate defense system in the intestine. Studying this early step in the pathogenesis of amebic colitis, we demonstrate thatE. histolyticatrophozoites or their released proteinases, including cysteine proteinase 1 (EhCP1), induce intestinal cathelicidins in human intestinal epithelial cell lines and in a mouse model of amebic colitis. Despite induction,E. histolyticatrophozoites were found to be resistant to killing by these antimicrobial peptides, and LL-37 and CRAMP were rapidly cleaved by released amebic cysteine proteases. The cathelicidin fragments however, did maintain their antimicrobial activity against bacteria. Degradation of intestinal cathelicidins is a novel function ofE. histolyticacysteine proteinases in the evasion of the innate immune system in the bowel. Thus, early intestinal epithelial colonization of invasive trophozoites involves a complex interplay in which the ultimate outcome of infection depends in part on the balance between degradation of cathelicidins by amebic released cysteine proteinases and upregulation of proinflammatory mediators which trigger the inflammatory response.

scholarly journals Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome following Infection with Entamoeba histolytica

2013 ◽  
Vol 81 (5) ◽  
pp. 1460-1470 ◽  
Author(s):  
Nicole M. Mackey-Lawrence ◽  
Xiaoti Guo ◽  
Daniel E. Sturdevant ◽  
Kimmo Virtaneva ◽  
Matthew M. Hernandez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Entamoeba Histolytica ◽  
Mucosal Immunity ◽  
Cellular Proliferation ◽  
Leptin Receptor ◽  
Gene Expression Pattern ◽  
Differentially Expressed ◽  
Intestinal Infection ◽  
Content Type ◽  
Downstream Effects

ABSTRACTResistance to amebiasis is associated with a polymorphism in the leptin receptor. Previous studies demonstrated that humans with the ancestral Q223 leptin receptor allele were nearly four times less likely to be infected withEntamoeba histolyticathan those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected againstE. histolyticavia STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanizedLEPRQ or R allele at codon 223 were intracecally infected withE. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues were analyzed for changes in gene expression. By 72 h postchallenge, all Q223 mice had clearedE. histolytica, whereas 39% of 223R mice were infected. Thirty-seven genes were differentially expressed in response to infection at 72 h, including proinflammatory genes (CXCL2,S100A8/9,PLA2G7,ITBG2, andMMP9) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h postchallenge of infected Q223 versus R223 mice identified a subset of differentially expressed genes, many of which were closely linked to leptin signaling. Further analyses indicated that the Q223 gene expression pattern was consistent with a suppressed apoptotic response to infection, while 223R showed increased cellular proliferation and recruitment. These studies are the first to illuminate the downstream effects of leptin receptor polymorphisms on intestinal infection byE. histolytica. As such, they are important for the insight that they provide into this previously uncharacterized mechanism of mucosal immunity.

scholarly journals Depletion of Alveolar Macrophages Increases Pulmonary Neutrophil Infiltration, Tissue Damage, and Sepsis in a Murine Model of Acinetobacter baumannii Pneumonia

2020 ◽  
Vol 88 (7) ◽  
Author(s):  
Hiu Ham Lee ◽  
Lilit Aslanyan ◽  
Arjun Vidyasagar ◽  
Melissa B. Brennan ◽  
Maxine S. Tauber ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Alveolar Macrophages ◽  
Tissue Damage ◽  
Bacterial Pathogen ◽  
Neutrophil Infiltration ◽  
Pulmonary Tissue ◽  
Content Type ◽  
Systemic Dissemination ◽  
The Impact

ABSTRACT Acinetobacter baumannii has emerged as an important etiological agent of hospital-related infections, especially nosocomial pneumonia. The virulence factors of this bacterium and their interactions with the cells and molecules of the immune system just recently began to be extensively studied. Here, we investigated the impact of alveolar macrophages on A. baumannii pneumonia using a mouse model of infection and a flexible tissue culture system. We hypothesized that depletion of macrophages would enhance sepsis and severity of A. baumannii disease. We showed that macrophages are important for modulating the antibacterial function of neutrophils and play an important role in eradicating A. baumannii infection in vivo. Our findings suggest that in the absence of macrophages in the lungs, A. baumannii replicates significantly, and host proinflammatory cytokines are considerably reduced. Neutrophils are abundantly recruited to pulmonary tissue, releasing high amounts of reactive oxygen species and causing extensive tissue damage. The ability of A. baumannii to form biofilms and resist oxidative stress in the respiratory tract facilitates systemic dissemination and ultimately death of infected C57BL/6 mice. These results provide novel information regarding A. baumannii pathogenesis and may be important for the development of therapies aimed at reducing morbidity and mortality associated with this emerging bacterial pathogen.

The More Control, the Better?

2014 ◽  
Vol 26 (2) ◽  
pp. 81-91 ◽  
Author(s):  
Jeeyun Oh ◽  
Mun-Young Chung ◽  
Sangyong Han
Keyword(s):  
Mixed Design ◽  
Negative Effects ◽  
Story Structure ◽  
Content Type ◽  
High User ◽  
User Control ◽  
Rigorous Research ◽  
Control Versus ◽  
The Media ◽  
The Impact

Despite of the popularity of interactive movie trailers, rigorous research on one of the most apparent features of these interfaces – the level of user control – has been scarce. This study explored the effects of user control on users’ immersion and enjoyment of the movie trailers, moderated by the content type. We conducted a 2 (high user control versus low user control) × 2 (drama film trailer versus documentary film trailer) mixed-design factorial experiment. The results showed that the level of user control over movie trailer interfaces decreased users’ immersion when the trailer had an element of traditional story structure, such as a drama film trailer. Participants in the high user control condition answered that they were less fascinated with, absorbed in, focused on, mentally involved with, and emotionally affected by the movie trailer than participants in the low user control condition only with the drama movie trailer. The negative effects of user control on the level of immersion for the drama trailer translated into users’ enjoyment. The impact of user control over interfaces on immersion and enjoyment varies depending on the nature of the media content, which suggests a possible trade-off between the level of user control and entertainment outcomes.

Perceived workplace gender-bias and psychological impact

2019 ◽  
Vol 43 (3/4) ◽  
pp. 339-353 ◽  
Author(s):  
Siham Lekchiri ◽  
Cindy Crowder ◽  
Anna Schnerre ◽  
Barbara A.W. Eversole
Keyword(s):  
Gender Bias ◽  
Critical Incident ◽  
Psychological Impact ◽  
Working Women ◽  
Content Type ◽  
Treatment Bias ◽  
Male Dominated ◽  
The Impact ◽  
Organizational Mechanisms ◽  
Practical Implications

Purpose The purpose of this paper is to explore the experiences of working women in a male-dominated country (Morocco) and unveil the unique challenges and everyday gender-bias they face, the psychological impact of the perceived gender-bias and, finally, identify a variety of coping strategies or combatting mechanisms affecting their motivation and retention in the workplace. Design/methodology/approach Empirical evidence was obtained using a qualitative research method. The Critical Incident Technique (CIT) was used to collect incidents recalled by women in the select institution reflecting their perceptions of their managers’ ineffective behaviors towards them and the impact of these behaviors. The critical incidents were inductively coded, and behavioral statements were derived from the coded data. Findings The qualitative data analysis led them to structure the data according to two theme clusters: The perceived gender-bias behaviors (Covert and evident personal and organizational behaviors) and Psychological impacts resulting from the perceived bias. These behavioral practices included abusive behaviors, unfair treatment, bias and lack of recognition. The psychological impact elements involved decreased productivity, depression, anxiety and low self-esteem. Practical implications Understanding these experiences can facilitate the identification of strategies geared towards the retention of women in the workforce, and Moroccan organizations can develop and implement strategies and policies that are geared towards eliminating gender-bias in the workplace and to retaining and motivating women who remain ambitious to work in male-dominated environments and cultures. Originality/value This paper provides evidence that sufficient organizational mechanisms to support women in male-dominated environments are still unavailable, leaving them to find the proper coping mechanisms to persevere and resist.

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