It is well known that alcoholics have an increased incidence of respiratory diseases. Furthermore, chronic alcoholism predisposes for severe disease following respiratory infections. Indeed, bacterial pneumonias, among the best-studied examples of this increased predisposition, result in a 2 to 7-fold greater incidence in mortality i alcoholics compared to non-alcoholic pneumonia patients. Alcohol abuse additionally increases the morbidity associated with such infections. While many studies have detailed the increase in disease severity during respiratory infections in alcoholics, much less is understood about the underlying mechanisms through which chronic ethanol (EtOH) consumption mediates this increase in disease severity or how alcohol alters pulmonary adaptive immune responses. Influenza A virus (IAV) infections represent a serious challenge to human health and are known to predispose individuals to an increased incidence of pneumonia. Interestingly, our prior studies indicate that chronic consumption of EtOH increases both influenza associated morbidity and mortality. Further, our results suggest that this increased severity of disease is related to defects or alterations in both respiratory dendritic cells (rDC) as well as influenza- specific CD8 T cell responses. Given the current threat of both epidemic and pandemic influenza as well as the ongoing threat of Streptococcal infections in alcoholics a better understanding of the alcohol induced lesions within the pulmonary adaptive immune response could lead to methodologies to boost immunity to these important human pathogens in these individuals. Therefore our long-range goal is to determine what lesions chronic EtOH induces within the respiratory adaptive immune response and determine methodologies to overcome these lesions to protect from severe and fatal disease. Within this application we will continue to use the Meadow-Cook chronic EtOH model as well as our mouse models of influenza virus (IAV) and Streptococcus (GAS) infection toward this goal. Our central hypothesis is that defects within CD8 T cells are responsible for the increased severity of respiratory infections in chronic EtOH mice. We propose the following Specific Aims:
Aim 1. Determine if vaccination against IAV can enhance CD8 T cell immunity and prevent the enhanced disease associated with IAV infections during chronic EtOH consumption;
Aim 2. Determine how ethanol alters the kinetics, magnitude, character of pulmonary inflammation, and CD8 T cell immunity during GAS or IAV+GAS infections. This application will not only define the defects that chronic EtOH creates in pulmonary adaptive immunity during infections with IAV and GAS but should also increase our general understanding of immunity in the presence of chronic EtOH during other respiratory infections. Furthermore, the insights learned from this application hold the potential to suggest methodologies to restore and/or boost immunity in chronic alcoholics during these diseases.
While many studies have detailed the increase in disease severity during respiratory infections in alcoholics, much less is understood about the underlying mechanisms through which chronic ethanol (EtOH) consumption mediates this increase in disease severity or how alcohol alters pulmonary adaptive immune responses. This project will detail the lesions within and the mechanisms controlling the respiratory adaptive immune responses to influenza virus (IAV), Streptococcus (GAS), and IAV+GAS infections and determine methodologies to overcome these lesions to protect from severe and fatal disease during chronic EtOH. A better understanding of the alcohol induced lesions within the pulmonary adaptive immune response could lead to methodologies to boost immunity to these important human pathogens in these individuals.
|Zhang, Jing; Quan, Cong; Wang, Cheng et al. (2016) Systematic manipulation of glutathione metabolism in Escherichia coli for improved glutathione production. Microb Cell Fact 15:38|
|Wang, Yongkang; Song, Xiaodan; Zhang, Yongjun et al. (2016) Effects of nitrogen availability on polymalic acid biosynthesis in the yeast-like fungus Aureobasidium pullulans. Microb Cell Fact 15:146|
|Tan, Zaigao; Chen, Jing; Zhang, Xueli (2016) Systematic engineering of pentose phosphate pathway improves Escherichia coli succinate production. Biotechnol Biofuels 9:262|
|Wu, You-Duo; Xue, Chuang; Chen, Li-Jie et al. (2015) Transcriptional analysis of micronutrient zinc-associated response for enhanced carbohydrate utilization and earlier solventogenesis in Clostridium acetobutylicum. Sci Rep 5:16598|
|Hemann, Emily A; McGill, Jodi L; Legge, Kevin L (2014) Chronic ethanol exposure selectively inhibits the influenza-specific CD8 T cell response during influenza a virus infection. Alcohol Clin Exp Res 38:2403-13|
|Hemann, Emily A; Kang, Sang-Moo; Legge, Kevin L (2013) Protective CD8 T cell-mediated immunity against influenza A virus infection following influenza virus-like particle vaccination. J Immunol 191:2486-94|