scholarly journals Differential Ability of Pandemic and Seasonal H1N1 Influenza A Viruses To Alter the Function of Human Neutrophils

mSphere ◽  
2018 ◽  
Vol 3 (1) ◽  
Author(s):  
Natalia Malachowa ◽  
Brett Freedman ◽  
Daniel E. Sturdevant ◽  
Scott D. Kobayashi ◽  
Vinod Nair ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bactericidal Activity ◽  
Influenza A ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Fungal Infections ◽  
Neutrophil Function ◽  
Human Neutrophils ◽  
Influenza A Viruses ◽  
Content Type

ABSTRACTNeutrophils are essential cells of host innate immunity. Although the role of neutrophils in defense against bacterial and fungal infections is well characterized, there is a relative paucity of information about their role against viral infections. Influenza A virus (IAV) infection can be associated with secondary bacterial coinfection, and it has long been posited that the ability of IAV to alter normal neutrophil function predisposes individuals to secondary bacterial infections. To better understand this phenomenon, we evaluated the interaction of pandemic or seasonal H1N1 IAV with human neutrophils isolated from healthy persons. These viruses were ingested by human neutrophils and elicited changes in neutrophil gene expression that are consistent with an interferon-mediated immune response. The viability of neutrophils following coculture with either pandemic or seasonal H1N1 IAV was similar for up to 18 h of culture. Notably, neutrophil exposure to seasonal (but not pandemic) IAV primed these leukocytes for enhanced functions, including production of reactive oxygen species and bactericidal activity. Taken together, our results are at variance with the universal idea that IAV impairs neutrophil function directly to predispose individuals to secondary bacterial infections. Rather, we suggest that some strains of IAV prime neutrophils for enhanced bacterial clearance.IMPORTANCEA long-standing notion is that IAV inhibits normal neutrophil function and thereby predisposes individuals to secondary bacterial infections. Here we report that seasonal H1N1 IAV primes human neutrophils for enhanced killing ofStaphylococcus aureus. Moreover, we provide a comprehensive view of the changes in neutrophil gene expression during interaction with seasonal or pandemic IAV and report how these changes relate to functions such as bactericidal activity. This study expands our knowledge of IAV interactions with human neutrophils.

Efficient production of human neutrophils from iPSCs that prevent murine lethal infection with immune cell recruitment

Blood ◽  
2021 ◽  
Author(s):  
Miyauchi Masashi ◽  
Yusuke Ito ◽  
Fumio Nakahara ◽  
Toshiya Hino ◽  
Fumi Nakamura ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Immune Cell ◽  
Fungal Infections ◽  
Neutrophil Function ◽  
Human Neutrophils ◽  
Efficient Production ◽  
Clinical Settings ◽  
Forward Solution ◽  
Induced Pluripotent

Neutrophils play an essential role in innate immune responses to bacterial and fungal infections and loss of neutrophil function can increase the risk of acquiring lethal infections in clinical settings. Here, we show that engineered neutrophil-primed progenitors derived from human induced pluripotent stem cells (iPSCs) can produce functional neutrophil-like cells at a clinically applicable scale that can act rapidly in vivo against lethal bacterial infections. Using five different mouse models, we systematically demonstrated that these neutrophil-like cells migrate to sites of inflammation and infection and increase survival against bacterial infection. In addition, we found that these human neutrophil-like cells can recruit murine immune cells. This system potentially provides a straight-forward solution for patients with neutrophil deficiency-an off-the-shelf neutrophil transfusion. This platform should facilitate the administration of human neutrophils for a broad spectrum of physiological and pathological conditions.

Sepsis in Infants

1991 ◽  
Vol 12 (11) ◽  
pp. 330-351
Keyword(s):  
Influenza A ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Seasonal Pattern ◽  
Virus Detection ◽  
Patient Treatment ◽  
Causative Organism ◽  
Influenza A Viruses ◽  
Suspected Sepsis ◽  
A Prospective Study

A prospective study was conducted to determine the frequency and distribution of bacterial and viral pathogens in infants hospitalized with suspected sepsis and to evaluate the potential of virus detection for improving patient treatment. A causative organism was detected in 157 (67%) of 233 previously healthy infants aged less than 3 months who had been hospitalized for suspected sepsis: 19 (8%) had bacterial infections, 135 (58%) had viral infections, and 3 (1%) had mixed viral-bacterial infections. Viral infections occurred in a seasonal pattern: enteroviruses were responsible for most of the hospitalizations during summer and fall (65 of 110, 63%), and respiratory syncytial and influenza A viruses were responsible for most of the infections during winter (44 of 81, 55%).

scholarly journals Acute non-atopic late-onset asthma induced by respiratory infection

2005 ◽  
pp. 53-57
Author(s):  
S. A. Sobchenko ◽  
O. S. Schetchikova ◽  
N. V. Yakovleva
Keyword(s):  
Respiratory Infection ◽  
Influenza A ◽  
Viral Infections ◽  
Late Onset ◽  
Lavage Fluid ◽  
Atopic Asthma ◽  
Influenza A Viruses ◽  
Asthma Patients ◽  
Bacterial Associations ◽  
Autumn And Winter

The aim of the study was to investigate features of respiratory infection inducing acute non-atopic late-onset asthma (NLA). Virologic and microbiologic examinations of brash biopsy samples of rhinopharyngeal and bronchial mucosa and bronchial lavage fluid were performed in 116 NLA patients admitted to a hospital in autumn and winter. The leading cause of acute NLA was found to be respiratory viral infections. We noted that different clinical NLA types had different sensibility to various viruses: adenoviruses mainly caused exacerbations of aspirin-induced asthma, respiratory syncytial and influenza A viruses were prevalently determined in non-atopic asthma. Patients with posttuberculotic lesions of the lungs mostly had viral and bacterial associations. Such mixed infection resulted in more severe and prolonged exacerbations of NLA.

scholarly journals Endopeptidase PepO Regulates the SpeB Cysteine Protease and Is Essential for the Virulence of Invasive M1T1Streptococcus pyogenes

2018 ◽  
Vol 200 (8) ◽  
Author(s):  
Stephan Brouwer ◽  
Amanda J. Cork ◽  
Cheryl-Lynn Y. Ong ◽  
Timothy C. Barnett ◽  
Nicholas P. West ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Phase ◽  
Cysteine Protease ◽  
Genetic Regulation ◽  
Bacterial Pathogen ◽  
Targeted Mutagenesis ◽  
Human Neutrophils ◽  
Content Type ◽  
Wide Range ◽  
Human Infections

ABSTRACTStreptococcus pyogenes(group AStreptococcus[GAS]) causes a wide range of human infections. The pathogenesis of GAS infections is dependent on the temporal expression of numerous secreted and surface-associated virulence factors that interact with host proteins. Streptococcal pyrogenic exotoxin B (SpeB) is one of the most extensively studied toxins produced by GAS, and the coordinate growth phase-dependent regulation ofspeBexpression is linked to disease severity phenotypes. Here, we identified the endopeptidase PepO as a novel growth phase-dependent regulator of SpeB in the invasive GAS M1 serotype strain 5448. By using transcriptomics followed by quantitative reverse transcriptase PCR and Western blot analyses, we demonstrate through targeted mutagenesis that PepO influences growth phase-dependent induction ofspeBgene expression. Compared to wild-type and complemented mutant strains, we demonstrate that the 5448ΔpepOmutant strain is more susceptible to killing by human neutrophils and is attenuated in virulence in a murine model of invasive GAS infection. Our results expand the complex regulatory network that is operating in GAS to control SpeB production and suggest that PepO is a virulence requirement during GAS M1T1 strain 5448 infections.IMPORTANCEDespite the continuing susceptibility ofS. pyogenesto penicillin, this bacterial pathogen remains a leading infectious cause of global morbidity and mortality. A particular subclone of the M1 serotype (M1T1) has persisted globally for decades as the most frequently isolated serotype from patients with invasive and noninvasive diseases in Western countries. One of the key GAS pathogenicity factors is the potent broad-spectrum cysteine protease SpeB. Although there has been extensive research interest on the regulatory mechanisms that controlspeBgene expression, its genetic regulation is not fully understood. Here, we identify the endopeptidase PepO as a new regulator ofspeBgene expression in the globally disseminated M1T1 clone and as being essential for virulence.

Skin Infections

2018 ◽  
Author(s):  
Jan V. Hirschmann
Keyword(s):  
Bacterial Infections ◽  
Tinea Pedis ◽  
Viral Infections ◽  
Fungal Infections ◽  
Treatment Options ◽  
Tinea Corporis ◽  
Microsporum Canis ◽  
Plantar Surface ◽  
Fournier Gangrene ◽  
Tinea Versicolor

The skin can become infected by viruses, fungi, and bacteria, including some that ordinarily are harmless colonizing organisms. The most common fungal infections are caused by dermatophytes, which can involve the hair, nails, and skin. Potassium hydroxide (KOH) preparations of specimens from affected areas typically demonstrate hyphae, and either topical or systemic antifungal therapy usually cures or controls the process. The most common bacterial pathogens are Staphylococcus aureus and group A streptococci, which, alone or together, can cause a wide variety of disorders, including impetigo, ecthyma, and cellulitis. Topical antibiotics may suffice for impetigo, but ecthyma and cellulitis require systemic treatment. S. aureus, including methicillin-resistant strains, can also cause furuncles, carbuncles, and cutaneous abscesses. For these infections, incision and drainage without antibiotics are usually curative. Warts are the most common cutaneous viral infection, and eradication can be difficult, especially where the skin is thick, such as the palms and soles, or the patient is immunocompromised. Most therapies consist of trying to destroy the viruses by mechanical, chemical, or immune mechanisms. This review covers dermatophyte infections, yeast infections, bacterial infections, and viral infections of the skin. Figures show the classic annular lesion of tinea corporis, a typical kerion presenting as a zoophilic Microsporum canis infection of the scalp (tinea capitis), tinea corporis, tinea barbae, tinea pedis between and under the toes and on the plantar surface, inflammatory tinea pedis, tinea unguium, tinea manuum, angular cheilitis, prominent satellite lesions of discrete vesicles associated with candidiasis, facial candidiasis, Candida paronychia, tinea versicolor, nonbullous impetigo, bullous impetigo, ecthyma, leg cellulitis, erythema and edema on the cheeks, eyelids, and nose, furuncle, carbuncle, nasal folliculitis, pitted keratolysis, trichomycosis axillaris, necrotizing fasciitis, Fournier gangrene, folliculitis, plantar wart, condyloma acuminatum, and benign lesions of bowenoid papulosis. Tables list dermatophyte species, terminology of dermatophyte infections, topical agents for dermatophyte infections, treatment options for impetigo (adult doses), and treatment options for erythrasma.   This review contains 28 highly rendered figures, 5 tables, and 33 references

Microarray analysis of lipopolysaccharide-treated human neutrophils

2003 ◽  
Vol 284 (4) ◽  
pp. L663-L670 ◽  
Author(s):  
Kenneth C. Malcolm ◽  
Patrick G. Arndt ◽  
Elizabeth J. Manos ◽  
David A. Jones ◽  
G. Scott Worthen
Keyword(s):  
Gene Expression ◽  
Growth Regulation ◽  
Molecular Mechanisms ◽  
Neutrophil Function ◽  
Interferon Response ◽  
Human Neutrophils ◽  
Oxygen Intermediates ◽  
Microarray Gene Expression ◽  
Monocyte Chemoattractant Protein 1 ◽  
Cytokines And Chemokines

Neutrophils respond to infection by degranulation, release of reactive oxygen intermediates, and secretion of chemokines and cytokines; however, activation of neutrophil transcriptional machinery has been little appreciated. Recent findings suggest that gene expression may represent an additional neutrophil function after exposure to lipopolysaccharide (LPS). We performed microarray gene expression analysis of 4,608 mostly nonredundant genes on LPS-stimulated human neutrophils. Analysis of three donors indicated some variability but also a high degree of reproducibility in gene expression. Twenty-eight verifiable, distinct genes were induced by 4 h of LPS treatment, and 13 genes were repressed. Genes other than cytokines and chemokines are regulated; interestingly, genes involved in cell growth regulation and survival, transcriptional regulation, and interferon response are among those induced, whereas genes involved in cytoskeletal regulation are predominantly repressed. In addition, we identified monocyte chemoattractant protein-1 as a novel LPS-regulated chemokine in neutrophils. Included in these lists are five clones with no defined function. These data suggest molecular mechanisms by which neutrophils respond to infection and indicate that the transcriptional potential of neutrophils is greater than previously thought.

scholarly journals Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects

2020 ◽  
Vol 4 (23) ◽  
pp. 5888-5901
Author(s):  
Christopher McKinney ◽  
Michael Ellison ◽  
Natalie J. Briones ◽  
Angelina Baroffio ◽  
John Murphy ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Bacterial Infections ◽  
Neutrophil Function ◽  
Functional Improvement ◽  
Human Neutrophils ◽  
Compound Heterozygous ◽  
Cd11b Expression ◽  
Exon 2 ◽  
Metabolic Defects ◽  
Functional Defects

Abstract Severe congenital neutropenia type 4 (SCN-4) is an autosomal recessive condition in which mutations in the G6PC3 gene encoding for the catalytic 3 subunit of glucose-6-phosphatase-β result in neutropenia, neutrophil dysfunction, and other syndromic features. We report a child with SCN-4 caused by compound heterozygous mutations in G6PC3, a previously identified missense mutation in exon 6 (c.758G>A[p.R235H]), and a novel missense mutation in exon 2 (c.325G>A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony–stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient’s neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios >1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was <25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope–labeled tracers (U-13C-glucose, 13C,15N-glutamine, and U-13C-fructose) demonstrated dramatic impairments in early glycolysis (hexose phosphate levels), hexosemonophosphate shunt (required for the generation of the NADPH), and the total adenylate pool, which could explain the dramatic cell dysfunction displayed by the patient’s neutrophils. Preliminary experiments with fructose supplementation to bypass the enzyme block demonstrated that the metabolic profile could be reversed, but was not sustained long enough for functional improvement. In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.

scholarly journals Enhanced Influenza Virus-Like Particle Vaccines Containing the Extracellular Domain of Matrix Protein 2 and a Toll-Like Receptor Ligand

2012 ◽  
Vol 19 (8) ◽  
pp. 1119-1125 ◽  
Author(s):  
Bao-Zhong Wang ◽  
Harvinder S. Gill ◽  
Sang-Moo Kang ◽  
Li Wang ◽  
Ying-Chun Wang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Fusion Protein ◽  
Influenza A ◽  
Matrix Protein ◽  
Protective Efficacy ◽  
Extracellular Domain ◽  
Toll Like Receptor ◽  
Influenza A Viruses ◽  
Live Virus ◽  
Content Type

ABSTRACTThe extracellular domain of matrix protein 2 (M2e) is conserved among influenza A viruses. The goal of this project is to develop enhanced influenza vaccines with broad protective efficacy using the M2e antigen. We designed a membrane-anchored fusion protein by replacing the hyperimmunogenic region ofSalmonella entericaserovar Typhimurium flagellin (FliC) with four repeats of M2e (4.M2e-tFliC) and fusing it to a membrane anchor from influenza virus hemagglutinin (HA). The fusion protein was incorporated into influenza virus M1-based virus-like particles (VLPs). These VLPs retained Toll-like receptor 5 (TLR5) agonist activity comparable to that of soluble FliC. Mice immunized with the VLPs by either intramuscular or intranasal immunization showed high levels of systemic M2-specific antibody responses compared to the responses to soluble 4.M2e protein. High mucosal antibody titers were also induced in intranasally immunized mice. All intranasally immunized mice survived lethal challenges with live virus, while intramuscularly immunized mice showed only partial protection, revealing better protection by the intranasal route. These results indicate that a combination of M2e antigens and TLR ligand adjuvants in VLPs has potential for development of a broadly protective influenza A virus vaccine.

High IL-15 Serum Levels on Day 7 After Hematopoietic Cell Transplantation Are Associated with a Low Likelihood of Graft-Vs-Host Disease and a High Likelihood of Infections

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1271-1271
Author(s):  
Laura M Hagel ◽  
Yiping Liu ◽  
Alejandra Ugarte-Torres ◽  
Tyler S Williamson ◽  
James A Russell ◽  
...  
Keyword(s):  
Cd8 T Cells ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Multivariate Analyses ◽  
Fungal Infections ◽  
Subsequent Development ◽  
Serum Levels ◽  
High Likelihood ◽  
Infection Rates ◽  
Cytokine Levels

Abstract Abstract 1271 Background: High levels of soluble IL-2 receptor alpha, IL-5, IL-6, IL-7, IL-15, soluble TNF alpha receptor and vascular endothelial growth factor have been associated with a high likelihood of GVHD. The levels were typically measured during or shortly before the development of GVHD. As preemptive therapy of GVHD would likely be efficacious if started early posttransplant, we set out to determine whether the levels of the above cytokines/cytokine receptors (hereafter referred to as “cytokines”) on day 7 are associated with subsequent development of GVHD and, if yes, whether the levels are also associated with relapse or infections. Patients and Methods: In a cohort of 153 consecutive allogeneic transplant recipients in Calgary who gave consent we determined serum levels of the above cytokines. All patients were adults, received myeloablative conditioning including rabbit antithymocyte globulin and typically filgrastim-mobilized blood mononuclear cells from HLA-matched unrelated donors or siblings, typically for hematologic malignancy. Cytokine levels were measured using sandwich ELISA (R&D). For each cytokine, levels in patients with versus without aGVHD (grade 2–4), cGVHD (needing systemic therapy) or relapse were compared using Mann-Whitney-Wilcoxon test, and correlation between the cytokine level and infection rates (number of infections per number of days at risk) was evaluated using Spearman rank correlation test. For each cytokine for which the levels appeared to be significantly associated with aGVHD, cGVHD, relapse or an infection rate, multivariate analyses were performed (using log-binomial regression for aGVHD, cGVHD or relapse, and Poisson regression for infection rates) adjusting for recipient age (continuous), donor type (HLA-matched sibling versus other), donor/recipient sex (M/M versus other), stem cell source (marrow versus blood stem cells) and, for relapse, also disease/disease stage (good vs poor risk) and, for infections, also engraftment day (continuous) and aGVHD or cGVHD (yes/no) using days at risk as the offset. Results: In univariate analyses, the only cytokine levels significantly associated with subsequent development of aGVHD or cGVHD were IL-15 levels (median 29 vs 40 pg/mL in patients with vs without aGVHD, p=.02, and median 25 vs 40 pg/mL in patients with vs without cGVHD, p=.02). IL-15 levels were similar in patients who did vs did not develop relapse (30 vs 39 pg/mL, p=0.60). There was a significant or near-significant positive correlation between IL-15 levels and the rates of definite (microbiologically documented) infections (p=.008), total (definite or presumed) infections (p=.008), viral infections (p=.06), bacterial infections (p=.06) and fungal infections (p=0.03) occurring between day 7 and 83. In multivariate analyses, IL-15 levels above31.0 pg/mL were associated with a 0.38-fold risk of aGVHD (p=0.005), and levels above 31.3 pg/mL with a 0.35-fold risk of cGVHD (p<.008). For a unit increase of IL-15 level (change of 1 pg/mL), the rate of infections increased 1.02-fold (p<.001) for definite infections, 1.03-fold for total infections (p<.001), 1.03-fold for viral infections (p<.001), 1.02-fold for bacterial infections (p<.001) and 1.03-fold for fungal infections (p=.06). Conclusion: Unexpectedly, high IL-15 levels were associated with a low likelihood of GVHD. For this we do not have an explanation. High IL-15 levels were also associated with a high likelihood of infections. This may reflect the fact that the most lymphopenic patients (at the highest risk of infections) may have had the highest levels of IL-15, a homeostatic growth factor for CD8 T cells and NK cells. Consistent with that, post-hoc analyses showed negative correlations between day 7 IL-15 levels and day 28 counts of CD8 T cells (p=.0002), NK cells (p=.06) and total lymphocytes (p=.03). Disclosures: No relevant conflicts of interest to declare.

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