Chronic Ethanol Exposure Selectively Inhibits the Influenza‐Specific CD8 T Cell Response During Influenza A Virus Infection

Abstract

Background It is well established that chronic ethanol (EtOH) consumption is associated with increased incidence and disease severity of respiratory infections. Our recent work demonstrates this increase in disease severity to influenza virus (IAV) infections is due, in part, to a failure to mount a robust IAV-specific CD8 T cell response along with a specific impairment in the ability of these T cells to produce IFNγ. However, the full extent of the lesion in the effector CD8 T cell compartment during chronic EtOH consumption remains unknown. Methods Utilizing the Meadows-Cook murine model of chronic alcohol consumption, mice received EtOH in their drinking water for 8 or 12 weeks. Mice were challenged intranasally with IAV and the activation and effector functions of IAV specific CD8 T cells were determined in both the lung-draining lymph nodes and lungs. Results Our results confirm the defect in interferon γ (IFNγ) production, however, the ability of IAV-specific T cells to produce tumor necrosis factor α (TNFα) and interleukin-2 (IL-2) in EtOH-consuming mice remains unaltered while interferon γ (IFNγ) production. In contrast, EtOH consumption significantly reduces the ability of CD8 T cells to degranulate and kill IAV-specific targets. Finally, our findings suggest the lesion begins during the initial activation of CD8 T cells, as we observe early defects in proliferation in the lung-draining lymph nodes (dLN) of IAV-infected, EtOH-consuming mice. Conclusions These findings highlight the previously unrecognized depth of the lesion in the IAV-specific CD8 T cell response during chronic EtOH consumption. Given the important role CD8 T cell immunity plays in control of IAV, these findings may aid in the development of vaccination and/or therapeutic strategies to reverse these defects in the CD8 T cell response and reduce serious disease outcomes associated with IAV infections in alcoholics.

Investigating the Impact of Delivery System Design on the Efficacy of Self-Amplifying RNA Vaccines

“…SAM-NPs induced a similar phenotype in CD8 + T-cells to Rabipur, however, the quality of released cytokines was different. This finding correlated with the observed cytotoxic profile and was in line with what has been already documented in the literature [ 19 , 39 , 54 , 92 ]. Overall, results reported here showed differences in quantity rather than quality of cytokines proliferation induced by the SAM-loaded candidates tested, with NPs eliciting higher CD4 + and CD8 + cytokines release compared to both liposomes.…”

Novel detection of post-translational modifications in human monocyte-derived dendritic cells after chronic alcohol exposure: Role of inflammation regulator H4K12ac

“…Although we did not measure reactive oxygen species (ROS), ROS signaling is crucial during innate and adaptive immunity and the effect of post-translational modifications on proteins related to ROS signaling may be playing a role on the immunomodulation observed after chronic alcohol exposure of MDDCs such as in the case of hypoxia inducible factor (HIF-1α) 56 or elevated mitochondrial superoxide (O 2 − ) levels, which has been shown to disrupt normal T-cell development impairing adaptive immune function under other stress conditions such as influenza challenge 57 . Furthermore, chronic ethanol exposure may be modulating the ability of DCs to activate co-stimulatory molecules and induce cytokine response as in the case of chronic ethanol feeding in mice, which limits the ability of DCs to stimulate T cell proliferation 58 , 59 .…”

Alcohol exposure differentially effects anti-tumor immunity in females by altering dendritic cell function

“…Many studies have implicated significant impacts of ethanol on host immune responses from inhibiting T and B cell development to (Barr et al, 2016; Hemann, McGill, & Legge, 2014; Pasala, Barr, & Messaoudi, 2015; Song et al, 2002) altering cytokine production and signaling in macrophages (Huang et al, 2015; Karavitis, Murdoch, Deburghgraeve, Ramirez, & Kovacs, 2012; Qin et al, 2014; Rendon, Janda, Bianco, & Choudhry, 2012). In each case, the effect of ethanol on the immune system is varied depending on whether it is a situation of acute or chronic exposure to ethanol and is focused on immune responses to injury or foreign antigen such as LPS, CPG or viral infection.…”