Publications by authors named "Ryan K Nelson"

4 Publications

  • Page 1 of 1

Eosinophilic Asthma.

J Allergy Clin Immunol Pract 2020 02 28;8(2):465-473. Epub 2019 Nov 28.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, Calif. Electronic address:

Asthma endotypes are constantly evolving. Currently, there are no universally accepted criteria to define endotypes. The T2-high endotype can have either allergic or nonallergic underpinnings and is typically characterized by some degree of eosinophilic airway inflammation. Unbiased clustering analyses have led to the identification of pediatric and adult phenotypes characterized by T2 inflammation and associated endotypes with eosinophilic inflammation. Aspirin-exacerbated respiratory disease has also long been recognized as a unique asthma phenotype. An approach to identify these groups with biomarkers and subsequently choose a targeted therapeutic modality, particularly in severe disease requiring biologic agents, is outlined.
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http://dx.doi.org/10.1016/j.jaip.2019.11.024DOI Listing
February 2020

E-cigarette use increases susceptibility to bacterial infection by impairment of human neutrophil chemotaxis, phagocytosis, and NET formation.

Am J Physiol Cell Physiol 2020 01 30;318(1):C205-C214. Epub 2019 Oct 30.

Pulmonary and Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, California.

E-cigarettes are portrayed as safer relative to conventional tobacco. However, burgeoning evidence suggests that E-cigarettes may adversely affect host defenses. However, the precise mechanisms by which E-cigarette vapor alters innate immune cell function have not been fully elucidated. We determined the effects of E-cigarette exposure on the function and responses to infectious challenge of the most abundant innate immune cell, the neutrophil, using isolated human neutrophils and a mouse model of gram-negative infection. Our results revealed that human neutrophils exposed to E-cigarette vapor had 4.2-fold reductions in chemotaxis toward the bacterial cell-well component f-Met-Leu-Phe ( < 0.001). F-actin polarization and membrane fluidity were also adversely affected by E-cigarette vapor exposure. E-cigarette-exposed human neutrophils exhibited a 48% reduction in production of reactive oxygen species (ROS; < 0.001). Given the central role of ROS in neutrophil extracellular trap (NET) production, NET production was quantified, and E-cigarette vapor exposure was found to reduce NETosis by 3.5-fold ( < 0.01); formulations with and without nicotine containing propylene glycol exhibiting significant suppressive effects. However, noncanonical NETosis was unaffected. In addition, exposure to E-cigarette vapor lowered the rate of phagocytosis of bacterial bioparticles by 47% ( < 0.05). In our physiological mouse model of chronic E-cigarette exposure and sepsis, E-cigarette vapor inhalation led to reduced neutrophil migration in infected spaces and a higher burden of . These findings provide evidence that E-cigarette use adversely impacts the innate immune system and may place E-cigarette users at higher risk for dysregulated inflammatory responses and invasive bacterial infections.
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http://dx.doi.org/10.1152/ajpcell.00045.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985828PMC
January 2020

Human Eosinophils Express a Distinct Gene Expression Program in Response to IL-3 Compared with Common β-Chain Cytokines IL-5 and GM-CSF.

J Immunol 2019 07 7;203(2):329-337. Epub 2019 Jun 7.

Division of Pulmonary, Critical Care, and Sleep Medicine, University of California San Diego, La Jolla, CA 92037;

Despite recent advances in asthma management with anti-IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common β subunit receptor with both IL-5 and GM-CSF but, through α-subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed ( = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the β-chain receptor cytokines. IL-3-upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies.
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http://dx.doi.org/10.4049/jimmunol.1801668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616007PMC
July 2019

Effect of dietary monosaccharides on Pseudomonas aeruginosa virulence.

Surg Infect (Larchmt) 2013 Feb 1;14(1):35-42. Epub 2013 Mar 1.

Department of Surgery, University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637, USA.

Background: Pseudomonas aeruginosa is an opportunistic, gram-negative pathogen associated with many hospital-acquired infections and disease states. In particular, P. aeruginosa has been identified as a crucial factor in the pathogenesis of neonatal necrotizing enterocolitis (NEC). This condition presents more frequently in infants fed a formula-based diet, which may be a result of the specific monosaccharide content of this diet. We hypothesized that P. aeruginosa would express virulence genes differentially when exposed to monosaccharides present in formula versus those in human milk.

Methods: Using the results of a metabolomics study on infant diets and their resulting fecal samples, we identified several monosaccharides that distinguished milk from formula diets. Of these compounds, four were found to be metabolized by P. aeruginosa. We subsequently grew P. aeruginosa in tryptic soy broth (TSB) supplemented with these four monosaccharides and used quantitative reverse transcriptase-polymerase chain reaction to measure the expression of 59 major P. aeruginosa virulence genes. The results were standardized to an external control of P. aeruginosa grown in TSB alone.

Results: P. aeruginosa did not respond differentially to the monosaccharides after 6 h of growth. However, after 24 h, the organism grown in arabinose (present in formula), xylose (present in human milk), and galactose (present in both formula and feces from milk-fed infants) displayed a significant increase in the expression of virulence genes in all categories. In contrast, P. aeruginosa grown in mannose (present in the feces of milk-fed infants) displayed a significant decrease in virulence gene expression.

Conclusion: These results demonstrate the importance of nutrient content on the relative expression of virulence genes in pathogens that colonize commonly the gut of infants. Understanding the effect of current dietary formulas on virulence gene expression in various gut-colonizing pathogens may present a new approach to elucidating the differences between human milk and formula in the development of NEC.
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http://dx.doi.org/10.1089/sur.2011.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601807PMC
February 2013
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