Tasha Barr

Opposing effects of alcohol on the immune system.

Several studies have described a dose-dependent effect of alcohol on human health with light to moderate drinkers having a lower risk of all-cause mortality than abstainers, while heavy drinkers are at the highest risk. In the case of the immune system, moderate alcohol consumption is associated with reduced inflammation and improved responses to vaccination, while chronic heavy drinking is associated with a decreased frequency of lymphocytes and increased risk of both bacterial and viral infections. However, the mechanisms by which alcohol exerts a dose-dependent effect on the immune system remain poorly understood due to a lack of systematic studies that examine the effect of multiple doses and different time courses. This review will summarize our current understanding of the impact of moderate versus excessive alcohol consumption on the innate and adaptive branches of the immune system derived from both in vitro as well as in vivo studies carried out in humans and animal model studies.

Alcohol Consumption Modulates Host Defense in Rhesus Macaques by Altering Gene Expression in Circulating Leukocytes

Several lines of evidence indicate that chronic alcohol use disorder leads to increased susceptibility to several viral and bacterial infections, whereas moderate alcohol consumption decreases the incidence of colds and improves immune responses to some pathogens. In line with these observations, we recently showed that heavy ethanol intake (average blood ethanol concentrations > 80 mg/dl) suppressed, whereas moderate alcohol consumption (blood ethanol concentrations < 50 mg/dl) enhanced, T and B cell responses to modified vaccinia Ankara vaccination in a nonhuman primate model of voluntary ethanol consumption. To uncover the molecular basis for impaired immunity with heavy alcohol consumption and enhanced immune response with moderate alcohol consumption, we performed a transcriptome analysis using PBMCs isolated on day 7 post–modified vaccinia Ankara vaccination, the earliest time point at which we detected differences in T cell and Ab responses. Overall, chronic heavy alcohol consumption reduced the expression of immune genes involved in response to infection and wound healing and increased the expression of genes associated with the development of lung inflammatory disease and cancer. In contrast, chronic moderate alcohol consumption upregulated the expression of genes involved in immune response and reduced the expression of genes involved in cancer. To uncover mechanisms underlying the alterations in PBMC transcriptomes, we profiled the expression of microRNAs within the same samples. Chronic heavy ethanol consumption altered the levels of several microRNAs involved in cancer and immunity and known to regulate the expression of mRNAs differentially expressed in our data set.

microRNAs Regulate Host Immune Response and Pathogenesis During Influenza Infection in Rhesus Macaques

microRNAs (miRNAs) are small noncoding RNAs that are key regulators of biological processes, including the immune response to viral infections. Differential expression levels of cellular miRNAs and their predicted targets have been described in the lungs of H1N1-infected BALB/c mice, the lungs of H5N1 influenza-infected cynomolgus macaques, and in peripheral blood mononuclear cells (PBMCs) of critically ill patients infected with 2009 pandemic H1N1. However, a longitudinal analysis of changes in the expression of miRNAs and their targets during influenza infection and how they relate to viral replication and host response has yet to be carried out. In the present study, we conducted a comprehensive analysis of innate and adaptive immune responses as well as the expression of several miRNAs and their validated targets in both peripheral blood and bronchoalveolar lavage (BAL) collected from rhesus macaques over the course of infection with the 2009 H1N1 virus A/Mexico/4108/2009 (MEX4108). We describe a distinct set of differentially expressed miRNAs in BAL and PBMCs, which regulate the expression of genes involved in inflammation, immune response, and regulation of cell cycle and apoptosis.

Concurrent gut transcriptome and microbiota profiling following chronic ethanol consumption in nonhuman primates

ABSTRACT Alcohol use disorder (AUD) results in increased intestinal permeability, nutrient malabsorption, and increased risk of colorectal cancer (CRC). Our understanding of the mechanisms underlying these morbidities remains limited because studies to date have relied almost exclusively on short-term heavy/binge drinking rodent models and colonic biopsies/fecal samples collected from AUD subjects with alcoholic liver disease (ALD). Consequently, the dose- and site-dependent impact of chronic alcohol consumption in the absence of overt liver disease remains poorly understood. In this study, we addressed this knowledge gap using a nonhuman primate model of voluntary ethanol self-administration where rhesus macaques consume varying amounts of 4% ethanol in water for 12 months. Specifically, we performed RNA-Seq and 16S rRNA gene sequencing on duodenum, jejunum, ileum, and colon biopsies collected from 4 controls and 8 ethanol-consuming male macaques. Our analysis revealed that chronic ethanol consumption leads to changes in the expression of genes involved in protein trafficking, metabolism, inflammation, and CRC development. Additionally, we observed differences in the relative abundance of putatively beneficial bacteria as well as those associated with inflammation and CRC. Given that the animals studied in this manuscript did not exhibit signs of ALD or CRC, our data suggest that alterations in gene expression and bacterial communities precede clinical disease and could serve as biomarkers as well as facilitate future studies aimed at developing interventions to restore gut homeostasis.

Inflammatory Determinants of Pregravid Obesity in Placenta and Peripheral Blood

Pre-pregnancy (pregravid) obesity has been linked to several adverse health outcomes for both mother and offspring. Complications during pregnancy include increased risk for gestational diabetes, hypertension, preeclampsia, placental abruption, and difficulties during delivery. Several studies suggest that these negative outcomes are mediated by heightened systemic inflammation as well as changes in placental development and function. However, the molecular mechanisms by which pregravid obesity affects these processes are poorly understood. In this study, we aimed to address this question by carrying out a comprehensive analysis of the systemic maternal immune system coupled with placental gene expression and microbial profiling at term delivery (11 lean and 14 obese). Specifically, we examined the impact of pregravid obesity on circulating cytokines, chemokine, adipokines, and growth factors using multiplex Luminex assay. Innate and adaptive immune cell frequencies and their cytokine production in response to stimuli were measured using flow cytometry. Finally, changes in placental transcriptome and microbiome were profiled using RNA- and 16S-sequencing, respectively. Pregravid obesity is characterized by insulin and leptin resistance, high levels of circulating inflammatory markers IL-6 and CRP, in addition to chemokine IL-8 (p < 0.01). Moreover, pregravid obesity was associated with lower frequency of naïve CD4+ T-cells (p < 0.05), increased frequency of memory CD4+ T-cells (p < 0.01), and a shift towards Th2 cytokine production (p = 0.05). Myeloid cells from the obese cohort produced higher levels of pro-inflammatory cytokines but lower levels of chemokines following TLR stimulation (p < 0.05). Lastly, pregravid obesity is associated with increased abundance of Bacteroides and changes in the expression of genes important for nutrient transport and immunity (FDR < 0.05). Collectively, these data indicate that pregravid obesity is associated with heightened systemic inflammation and of dysregulated nutrient transport in the placenta and provide insight into the basis of fetal reprogramming.

Nonhuman Primate Models of Immunosenescence

Due to a dramatic increase in life expectancy, the number of individuals aged 65 and older is rapidly rising. This presents considerable challenges to our health care system since advanced age is associated with a higher susceptibility to infectious diseases due to immune senescence. However, the mechanisms underlying age-associated dysregulated immunity are still incompletely understood. Advancement in our comprehension of mechanisms of immune senescence and development of interventions to improve health span requires animal models that closely recapitulate the physiological changes that occur with aging in humans. Nonhuman primates (NHPs) are invaluable preclinical models to study the underlying causal mechanism of pathogenesis due to their outbred nature, high degree of genetic and physiological similarity to humans, and their susceptibility to human pathogens. In this chapter, we review NHP models available for biogerontology research, advantages and challenges they present, and advances they facilitated. Furthermore, we emphasize the utility of NHPs in characterizing immune senescence, evaluating interventions to reverse aging of the immune system, and development of vaccine strategies that are better suited for this vulnerable population.