Harnessing Innate Immune Memory and Trained Innate Immunity Against Bacterial and Viral Infections

Abstract

In recent years, the ability to harness innate immune memory as a strategy to provide broad nonspecific protection against various pathogens has gained significant attention. Recent evidence indicates that systemic and more recently local immunological exposure to immune stimuli leads to alterations in the innate immune cell compartment, specifically tissue-resident macrophages at mucosal sites. Such alterations within the innate immune cell compartment can result in a strengthened immune response leading to enhanced innate immune protection or trained innate immunity (TII), against either a homologous or heterologous pathogen. We have shown that systemic Bacillus Calmette- Guerin (BCG) vaccination-induced TII enhances host defence against pulmonary pneumococcal infection via increased neutrophil responses in the lung, independent of centrally trained circulating monocytes. In addition, we demonstrate that acute exposure to a microbial component, lipopolysaccharide (LPS), induces long lasting changes in airway macrophages, which leads to TII capable of protecting against pneumococcal infection but extends minimal protection against SARS-CoV-2. Lastly, we demonstrate respiratory mucosal vaccination with an unrelated Ad-vectored TB vaccine provides robust protection against SARS-CoV-2 via enhanced disease tolerance. Collectively, these studies provide valuable insight into the mechanisms of innate immune memory and associated TII and its potential as a vaccination strategy for protecting against a wide range of respiratory pathogens.