Trained Immunity: An Overview and the Impact on COVID-19

Abstract

Effectively treating infectious diseases often requires a multi-step approach to target different components involved in disease pathogenesis. Similarly, the COVID-19 pandemic has become a global health crisis that requires a comprehensive understanding of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection to develop effective therapeutics. One potential strategy to instill greater immune protection against COVID-19 is boosting the innate immune system. This boosting, termed trained immunity, employs immune system modulators to train innate immune cells to produce an enhanced, non-specific immune response upon reactivation following exposure to pathogens, a process that has been studied in the context of in vitro and in vivo clinical studies prior to the COVID-19 pandemic. Evaluation of the underlying pathways that are essential to inducing protective trained immunity will provide insight into identifying potential therapeutic targets that may alleviate the COVID-19 crisis. Here we review multiple immune training agents, including Bacillus Calmette-Guérin (BCG), β-glucan, and lipopolysaccharide (LPS), and the two most popular cell types involved in trained immunity, monocytes and natural killer (NK) cells, and compare the signaling pathways involved in innate immunity. Additionally, we discuss COVID-19 trained immunity clinical trials, emphasizing the potential of trained immunity to fight SARS-CoV-2 infection. Understanding the mechanisms by which training agents activate innate immune cells to reprogram immune responses may prove beneficial in developing preventive and therapeutic targets against COVID-19.

Immunosenescence and COVID-19

“…The mechanism of such dual action of the N protein includes dual effect on phosphorylation of IRF3, STAT1, and STAT2 and on their nuclear translocation ( Zhao et al, 2021 ). It was also demonstrated, that training of innate immunity using the BCG, beta-glucan or LPS, acting respectively via AKT/mTOR and MAPK/p38 pathways increases the production of IL-1, IL-6, IL-32 and TNF, thus possibly adding to the state of inflammaging ( Brueggeman et al, 2022 , Franceschi et al, 2017b ).…”

Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease

“…GSH is essential for immunomodulation of both innate and adaptive immune system functions, including T-lymphocyte proliferation, polymorphonuclear neutrophil phagocytosis, and dendritic cell functions, and is also important for fine-tuning the innate immune response to infection and for the first step of adaptive immunity involving antigen-presenting cell (macrophages, dendritic cells)-related antigen presentation ( Morris et al, 2013 ; Diotallevi et al, 2017 ). GSH works to modulate the behavior of many immune cells, augmenting both, innate immunity (and trained innate immunity or innate immune memory; Netea et al, 2020 ; Chumakov et al, 2021 ; Ferreira et al, 2021 ; Gong et al, 2021 ; Brueggeman et al, 2022 ), severely affected by SARS-CoV-2 viral infection ( Polonikov, 2020 ; Rodrigues et al, 2020 ; Forcados et al, 2021 ; Kozlov et al, 2021 ; Bellanti et al, 2022 ; Paludan and Mogensen, 2022 ), and adaptive immunity ( Dröge et al, 1991 ; Dröge and Breitkreutz, 2000 ; Dröge, 2002c ; Ghezzi, 2011 ; Morris et al, 2013 ; Fraternale et al, 2017 ), as well as conferring protection against oxidative stress caused by microbial, parasitic and viral infections such as SARS-CoV-2 that causes COVID-19 disease ( Morris et al, 2013 ; Diotallevi et al, 2017 ; Derouiche, 2020 ; Polonikov, 2020 ; Silvagno et al, 2020 ; Suhail et al, 2020 ; Forcados et al, 2021 ; Pérez de la Lastra et al, 2021 ; Bellanti et al, 2022 ; Kumar P. et al, 2022 ). Persistent and uncontrolled oxidative stress and exacerbating NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome activation during severe COVID-19 disease ( Lage et al, 2022 ), induce production of pro-inflammatory cytokines, such as IL-1β and IL-18, that can be explained because of sharply decreased macrophage GSH intracellular levels associated with increased GSH efflux ( Zhang T. et al, 2021 ).…”

The Natural Effect of BCG Vaccination on COVID-19: The Debate Continues

“…The primary immunization of BCG can activate innate immune cells to produce IL-1β, TNF-α, and IL-6, generating trained monocytes/macrophages with an “infection memory.” These trained monocytes/macrophages will respond rapidly by releasing higher levels of cytokines to combat the second unrelated pathogens’ invasion ( 8 ). The trained immunity induced by BCG has been demonstrated in both animal experiments and human clinical trials, and it may be beneficial for the prevention and treatment of SARS-CoV-2 infection ( 2 , 4 – 7 , 9 – 11 ).…”