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

Date Published: August 2, 2018

Publisher: Public Library of Science

Author(s): Deepak Tripathi, Elwyn Welch, Satyanarayana Swamy Cheekatla, Rajesh Kumar Radhakrishnan, Sambasivan Venkatasubramanian, Padmaja Paidipally, Abhinav Van, Buka Samten, Kamakshi P. Devalraju, Venkata Sanjeev Kumar Neela, Vijaya Lakshmi Valluri, Carol Mason, Steve Nelson, Ramakrishna Vankayalapati, David M. Lewinsohn.


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.

Partial Text

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]. It is difficult to diagnose and treat tuberculosis in aged individuals [3,4]. Approximately 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 [6–9]. In addition, individuals with alcoholism show higher relapse rates and a higher probability of having multidrug-resistant TB [10].

Chronic alcohol consumption modulates host immune defense mechanism(s) and makes the host susceptible to various fungal, viral and bacterial infections, including Mtb [13,15,19]. However, limited information is available regarding the mechanisms involved in alcohol-mediated host susceptibility to Mtb and other intracellular bacterial infections. In the current study, we fed young and old mice control and alcohol diets and determined the mortality rates and the immune mechanisms involved in host susceptibility to Mtb infection. Approximately 80% of the Mtb-infected alcohol-fed young mice died within 5 months; however, only 25% of Mtb-infected alcohol-fed old mice and 25% of alcohol-fed uninfected young mice died during the same period. There were no significant differences in the bacterial lung burdens of control and alcohol diet-fed young mice and alcohol diet-fed old and young mice. IFN-α levels were significantly higher in the lungs of Mtb-infected alcohol-fed young mice, and treatment with an anti-IFNAR-1 antibody increased their survival. In the lungs of Mtb-infected alcohol-fed young mice, IFN-α enhanced the expression of RIP-1 and RIP-3, which are known to be involved in necroptosis. Mtb-infected alcohol-fed old mice and Mtb-infected control diet-fed old and young mice did not express IFN-α, RIP-1 or RIP-3 in their lungs. In response to Mtb, PBMCs from alcoholic LTBI+ healthy individuals produced significantly higher amounts of IFN-α than PBMCs from non-alcoholic young LTBI+ individuals and alcoholic and non-alcoholic aged LTBI+ individuals. Our findings demonstrate that alcohol enhances Ly6G+ cell infiltration and IFN-α production and increases necroptosis in the lung macrophages of young mice infected with Mtb, which leads to enhanced mortality.