Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection

Abstract

SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.

Figure 1

Description of Host-Pathogen Interactions between SARS-CoVs and the Host Immune System The first event after inhalation of SARS-CoV is invasion of epithelial cells and type II pneumocytes through binding of the virus to angiotensin-converting enzyme 2 (ACE-2) receptors through the spike protein expressed on the surface of the virus. The complex formed is processed by TMPRSS2 leading to cleavage of ACE-2 and activation of the spike protein, facilitating viral entry into the target cell. Viral entry and cell infection trigger the immune response. Two possible mechanisms of initiation of the inflammatory cascade can be considered. One is release of danger signal molecules, such as certain cytokines (such as IL-1α or IL-8) or ATP. The second involves different recognition pathways mediated by immune cells that initiate the inflammatory response.

Figure 2

Innate Immune Dysregulation in the Pathophysiology of COVID-19 Genetic and non-genetic risk factors as well as the presence of co-morbidities determine the efficacy of host defense mechanisms. In the early phase of infection, a potent host defense leads to suppression of viral replication, which subsequently leads to low levels of inflammation, less severe symptoms, and a good prognosis. If host defense mechanisms are defective, then they can lead to massive viral replication, systemic hyperinflammation, high severity of disease, and, ultimately, death.

Figure 3

Trained Immunity Mechanisms and Improvement of Anti-viral Host Defense Trained immunity is defined as an enhanced innate immune response to different pathogens after an initial challenge, such as vaccination or infection. Certain microbial ligands capable of binding specific pattern recognition receptors are able to induce durable metabolic and epigenetic changes in innate immune cells. This reprogramming of the metabolic and epigenetic landscape of the cell allows quick accessibility of transcription factors to the promoter and enhancer regions of pro-inflammatory genes upon restimulation, facilitating gene expression. The increased metabolic activity of the cell affords fast supply of the energy and metabolites necessary to mount a robust immune response upon restimulation. Combination of these epigenetic and metabolic effects affords increased responsiveness upon secondary stimulation with the same or a different ligand and can even protect against a subsequent infection.

Figure 4

Trained Immunity Can Be Used to Prevent the Spread of New Infections Boosting the host defense by induction of trained immunity induces a durable state of activation in the cells of the innate immune system. In this scenario, these cells would offer faster and increased responsiveness upon contact with a new pathogen, decreasing the severity of the infection and limiting its transmission.