Alcohol enhances type 1 interferon-α production and mortality in young mice infected with Mycobacterium tuberculosis.

Deepak Tripathi,Buka Samten,Rajesh Kumar Radhakrishnan,Ramakrishna Vankayalapati,Satyanarayana Swamy Cheekatla,Elwyn Welch,Vijaya Lakshmi Valluri,Kamakshi P Devalraju,Sambasivan Venkatasubramanian,Abhinav Van,Padmaja Paidipally,Venkata Sanjeev Kumar Neela,Steve Nelson,Carol Mason

doi:10.1371/journal.ppat.1007174

Abstract

In the current study, we used a mouse model and human blood samples to determine the effects of chronic alcohol consumption on immune responses during Mycobacterium tuberculosis (Mtb) infection. Alcohol increased the mortality of young mice but not old mice with Mtb infection. CD11b+Ly6G+ cells are the major source of IFN-α in the lungs of Mtb-infected alcohol-fed young mice, and IFN-α enhances macrophage necroptosis in the lungs. Treatment with an anti-IFNAR-1 antibody enhanced the survival of Mtb-infected alcohol-fed young mice. In response to Mtb, peripheral blood mononuclear cells (PBMCs) from alcoholic young healthy individuals with latent tuberculosis infection (LTBI) produced significantly higher amounts of IFN-α than those from non-alcoholic young healthy LTBI+ individuals and alcoholic and non-alcoholic old healthy LTBI+ individuals. Our study demonstrates that alcohol enhances IFN-α production by CD11b+Ly6G+ cells in the lungs of young Mtb-infected mice, which leads to macrophage necroptosis and increased mortality. Our findings also suggest that young alcoholic LTBI+ individuals have a higher risk of developing active TB infection.

Highlights

It is estimated that more than two billion people worldwide are infected with Mycobacterium tuberculosis (Mtb), but only 5–10% of these individuals develop TB during their lifetime [1,2]
Limited information is available about the mechanisms involved in alcohol-mediated host susceptibility to Mtb and other intracellular bacterial infections
We found that peripheral blood mononuclear cells (PBMCs) from young alcoholic individuals with latent tuberculosis infection (LTBI) produced significantly higher amounts of IFN-α than those from young non-alcoholic, old alcoholic and old non-alcoholic LTBI+ individuals

Summary

Introduction

It is estimated that more than two billion people worldwide are infected with Mycobacterium tuberculosis (Mtb), but only 5–10% of these individuals develop TB during their lifetime [1,2]. The geriatric population represents a large reservoir of latent tuberculosis infection (LTBI) [3]. 57% of tuberculosis deaths occur in the aged population (above 50), and this burden is high in developed countries [5]. Immunosuppressive conditions, such as HIV infection, diabetes mellitus and drug and alcohol abuse, are risk factors that increase the chances of tuberculosis (TB) reactivation in people with LTBI [6,7,8,9]. Individuals with alcoholism show higher relapse rates and a higher probability of having multidrug-resistant TB [10]

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Discussion

Conclusion