The host tropism of viral infection is determined by a variety of factors, from cell surface receptors to innate immune signaling. Many viruses encode proteins that interfere with host innate immune ...recognition in order to promote infection. STAT2 is divergent between species and therefore has a role in species restriction of some viruses. To understand the role of STAT2 in human metapneumovirus (HMPV) infection of human and murine tissues, we first infected STAT2
mice and found that HMPV could be serially passaged in STAT2
, but not WT, mice. We then used in vitro methods to show that HMPV inhibits expression of both STAT1 and STAT2 in human and primate cells, but not in mouse cells. Transfection of the murine form of STAT2 into STAT2-deficient human cells conferred resistance to STAT2 inhibition. Finally, we sought to understand the in vivo role of STAT2 by infecting hSTAT2 knock-in mice with HMPV, and found that mice had increased weight loss, inhibition of type I interferon signaling, and a Th2-polarized cytokine profile compared to WT mice. These results indicate that STAT2 is a target of HMPV in human infection, while the murine version of STAT2 restricts tropism of HMPV for murine cells and tissue.
Exposure to nitrogen dioxide (NO2), a byproduct of combustion, is associated with poor asthma control in children. We sought to determine whether gas-fueled kitchen appliance use is associated with ...24-h indoor NO2 concentrations and whether these concentrations are associated with asthma morbidity in children. Children aged 5–12 years old with asthma were eligible. Mean 24-h NO2 concentration was measured in the kitchen over a four-day sampling period and gas stove use was captured in time activity diaries. The relationship between stove and oven use and daily NO2 concentration was analyzed. Longitudinal analysis assessed the effect of daily NO2 exposure on symptoms, inhaler use, and lung function. Multivariate models were adjusted for age, sex, season, and maternal education. Thirty children contributed 126 participant days of sampling. Mean indoor 24-h NO2 concentration was 58(48)ppb with a median (range) of 45(12–276)ppb. All homes had gas stoves and furnaces. Each hour of kitchen appliance use was associated with an 18ppb increase in 24-h NO2 concentration. In longitudinal multivariate analysis, each ten-fold increase in previous-day NO2 was associated with increased nighttime inhaler use (OR = 4.9, p = 0.04). There were no associations between NO2 and lung function or asthma symptoms. Higher previous-day 24-h concentration of NO2 is associated with increased nighttime inhaler use in children with asthma.
•Nitrogen dioxide (NO2) exposure is associated with poor childhood asthma control.•Indoor sources of NO2 include gas cooking stoves.•Gas stove use is associated with higher indoor 24-h NO2 concentration.•Higher 24-h NO2 concentration is associated with increased rescue inhaler use.
Our goal was to investigate whether obesity increases susceptibility to the adverse effects of indoor particulate matter on respiratory morbidity among individuals with chronic obstructive pulmonary ...disease (COPD). Participants with COPD were studied at baseline, 3 and 6 months. Obesity was defined as a body mass index ≥30 kg·m(-2). At each time point, indoor air was sampled for 5-7 days and particulate matter (PM) with an aerodynamic size ≤2.5 μm (PM2.5) and 2.5-10 μm (PM2.5-10) was measured. Respiratory symptoms, health status, rescue medication use, exacerbations, blood biomarkers and exhaled nitric oxide were assessed simultaneously. Of the 84 participants enrolled, 56% were obese and all were former smokers with moderate-to-severe COPD. Obese participants tended to have less severe disease as assessed by Global Initiative for Chronic Obstructive Pulmonary Disease stage and fewer pack-years of smoking. There was evidence that obesity modified the effects of indoor PM on COPD respiratory outcomes. Increases in PM2.5 and PM2.5-10 were associated with greater increases in nocturnal symptoms, dyspnoea and rescue medication use among obese versus non-obese participants. The impact of indoor PM on exacerbations, respiratory status and wheeze also tended to be greater among obese versus non-obese participants, as were differences in airway and systemic inflammatory responses to indoor PM. We found evidence that obesity was associated with exaggerated responses to indoor fine and coarse PM exposure among individuals with COPD.
Background: The effect of indoor nitrogen dioxide concentrations on asthma morbidity among inner-city preschool children is uncertain. Objectives: Our goal was to estimate the effect of indoor ${\rm ...NO}_{2}$ concentrations on asthma morbidity in an inner-city population while adjusting for other indoor pollutants. Methods: We recruited 150 children (2-6 years of age) with physician-diagnosed asthma from inner-city Baltimore, Maryland. Indoor air was monitored over a 72-hr period in the children's bedrooms at baseline and 3 and 6 months. At each visit, the child's caregiver completed a questionnaire assessing asthma symptoms over the previous 2 weeks and recent health care utilization. Results: Children were 58% male, 91% African American, and 42% from households with annual income < $25,000; 63% had persistent asthma symptoms. The mean (± SD) in-home ${\rm NO}_{2}$ concentration was 30.0 ± 33.7 (range, 2.9-394.0) ppb. The presence of a gas stove and the use of a space heater or oven/stove for heat were independently associated with higher ${\rm NO}_{2}$ concentrations. Each 20-ppb increase in ${\rm NO}_{2}$ exposure was associated significantly with an increase in the number of days with limited speech incidence rate ratio (IRR) = 1.15; 95% confidence interval (CI), 1.05-1.25, cough (IRR = 1.10; 95% CI, 1.02-1.18), and nocturnal symptoms (IRR = 1.09; 95% CI, 1.02-1.16), after adjustment for potential confounders. ${\rm NO}_{2}$ concentrations were not associated with increased health care utilization. Conclusions: Higher indoor ${\rm NO}_{2}$ concentrations were associated with increased asthma symptoms in preschool inner-city children. Interventions aimed at lowering ${\rm NO}_{2}$ concentrations in inner-city homes may reduce asthma morbidity in this vulnerable population.
Reinfections with respiratory viruses are common and cause significant clinical illness, yet precise mechanisms governing this susceptibility are ill defined. Lung Ag-specific CD8(+) T cells (T(CD8)) ...are impaired during acute viral lower respiratory infection by the inhibitory receptor programmed death-1 (PD-1). To determine whether PD-1 contributes to recurrent infection, we first established a model of reinfection by challenging B cell-deficient mice with human metapneumovirus (HMPV) several weeks after primary infection, and found that HMPV replicated to high titers in the lungs. A robust secondary effector lung TCD8 response was generated during reinfection, but these cells were more impaired and more highly expressed the inhibitory receptors PD-1, LAG-3, and 2B4 than primary T(CD8). In vitro blockade demonstrated that PD-1 was the dominant inhibitory receptor early after reinfection. In vivo therapeutic PD-1 blockade during HMPV reinfection restored lung T(CD8) effector functions (i.e., degranulation and cytokine production) and enhanced viral clearance. PD-1 also limited the protective efficacy of HMPV epitope-specific peptide vaccination and impaired lung T(CD8) during heterotypic influenza virus challenge infection. Our results indicate that PD-1 signaling may contribute to respiratory virus reinfection and evasion of vaccine-elicited immune responses. These results have important implications for the design of effective vaccines against respiratory viruses.
Background: Although outdoor particulate matter (PM) has been linked to mortality and asthma morbidity, the impact of indoor PM on asthma has not been well established. Objective: This study was ...designed to investigate the effect of in-home PM on asthma morbidity. Methods: For a cohort of 150 asthmatic children (2-6 years of age) from Baltimore, Maryland, a technician deployed environmental monitoring equipment in the children's bedrooms for 3-day intervals at baseline and at 3 and 6 months. Caregivers completed questionnaires and daily diaries during air sampling. Longitudinal data analyses included regression models with generalized estimating equations. Results: Children were primarily African Americans (91%) from lower socioeconomic backgrounds and spent most of their time in the home. Mean (± SD) indoor${\rm PM}_{2.5-10}$(PM with aerodynamic diameter 2.5-10 μm) and${\rm PM}_{2.5}$(aerodynamic diameter < 2.5 μm) concentrations were 17.4 ± 21.0 and 40.3 ± 35.4 μg/m³. In adjusted models, 10-μg/m³ increases in indoor${\rm PM}_{2.5-10}$and${\rm PM}_{2.5}$were associated with increased incidences of asthma symptoms: 6% 95% confidence interval (CI), 1 to 12% and 3% (95% CI, -1 to 7%), respectively; symptoms causing children to slow down: 8% (95% CI, 2 to 14%) and 4% (95% CI, 0 to 9%), respectively; nocturnal symptoms: 8% (95% CI, 1 to 14%) and 6% (95% CI, 1 to 10%), respectively; wheezing that limited speech: 11% (95% CI, 3 to 19%) and 7% (95% CI, 0 to 14%), respectively; and use of rescue medication: 6% (95% CI, 1 to 10%) and 4% (95% CI, 1 to 8%), respectively. Increases of 10 μg/m³ in indoor and ambient${\rm PM}_{2.5}$were associated with 7% (95% CI, 2 to 11%) and 26% (95% CI, 1 to 52%) increases in exercise-related symptoms, respectively. Conclusions: Among preschool asthmatic children in Baltimore, increases in in-home${\rm PM}_{2.5-10}$and${\rm PM}_{2.5}$were associated with respiratory symptoms and rescue medication use. Increases in in-home and ambient${\rm PM}_{2.5}$were associated with exercise-related symptoms. Although reducing PM outdoors may decrease asthma morbidity, reducing PM indoors, especially in homes of inner-city children, may lead to improved asthma health.
Viruses are frequent causes of lower respiratory infection (LRI). Programmed cell death-1 (PD-1) signaling contributes to pulmonary CD8(+) T cell (TCD8) functional impairment during acute viral LRI, ...but the role of TCD8 impairment in viral clearance and immunopathology is unclear. We now find that human metapneumovirus infection induces virus-specific lung TCD8 that fail to produce effector cytokines or degranulate late postinfection, with minimally increased function even in the absence of PD-1 signaling. Impaired lung TCD8 upregulated multiple inhibitory receptors, including PD-1, lymphocyte activation gene 3 (LAG-3), T cell Ig mucin 3, and 2B4. Moreover, coexpression of these receptors continued to increase even after viral clearance, with most virus-specific lung TCD8 expressing three or more inhibitory receptors on day 14 postinfection. Viral infection also increased expression of inhibitory ligands by both airway epithelial cells and APCs, further establishing an inhibitory environment. In vitro Ab blockade revealed that multiple inhibitory receptors contribute to TCD8 impairment induced by either human metapneumovirus or influenza virus infection. In vivo blockade of T cell Ig mucin 3 signaling failed to enhance TCD8 function or reduce viral titers. However, blockade of LAG-3 in PD-1-deficient mice restored TCD8 effector functions but increased lung pathology, indicating that LAG-3 mediates lung TCD8 impairment in vivo and contributes to protection from immunopathology during viral clearance. These results demonstrate that an orchestrated network of pathways modifies lung TCD8 functionality during viral LRI, with PD-1 and LAG-3 serving prominent roles. Lung TCD8 impairment may prevent immunopathology but also contributes to recurrent lung infections.
Viral lung infections are leading causes of morbidity and mortality. Effective immune responses to these infections require precise immune regulation to preserve lung function after viral clearance. ...One component of airway pathophysiology and lung injury associated with acute respiratory virus infection is effector T cells, yet these are the primary cells required for viral clearance. Accordingly, multiple immune mechanisms exist to regulate effector T cells, limiting immunopathology while permitting clearance of infection. Much has been learned in recent years about regulation of T cell function during chronic infection and cancer, and it is now clear that many of these mechanisms also control inflammation in acute lung infection. In this review, we focus on regulatory T cells, inhibitory receptors, and other cells and molecules that regulate cell-mediated immunity in the context of acute respiratory virus infection.
Compared with atopic asthma, fewer environmental modifications are recommended for non-atopic asthma in children.
To better understand the role of indoor pollutants in provoking non-atopic asthma, we ...investigated the effect of in-home particulate matter on asthma symptoms among non-atopic and atopic children living in inner-city Baltimore.
A cohort of 150 children ages 2 to 6 years with asthma underwent home environmental monitoring for 3-day intervals at baseline, 3, and 6 months. Children were classified as non-atopic if they were skin test negative to a panel of 14 aeroallergens. Caregivers completed questionnaires assessing symptoms and rescue medication use. Longitudinal data analysis included regression models with generalized estimating equations.
Children were primarily African American from lower socioeconomic backgrounds and spent most of their time in the home. Thirty-one percent were non-atopic, and 69% were atopic. Among non-atopic and atopic children, increased in-home fine (PM2.5) and coarse (PM2.5-10) particle concentrations were associated with significant increases in asthma symptoms and rescue medication use ranging from 7% (95% confidence interval CI, 0-15) to 14% (95% CI, 1-27) per 10 μg/m(3) increase in particle concentration after adjustment for confounders.
In-home particles similarly cause increased symptoms of asthma in non-atopic and atopic children. Environmental control strategies that reduce particle concentrations may prove to be an effective means of improving asthma outcomes, especially for non-atopic asthma, for which there are few environmental control practice recommendations.
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