Innate and Adaptive Immunity Alterations in Metabolic Associated Fatty Liver Disease and Its Implication in COVID-19 Severity

Abstract

The coronavirus infectious disease 2019 (COVID-19) pandemic has hit the world, affecting health, medical care, economies and our society as a whole. Furthermore, COVID-19 pandemic joins the increasing prevalence of metabolic syndrome in western countries. Patients suffering from obesity, type II diabetes mellitus, cardiac involvement and metabolic associated fatty liver disease (MAFLD) have enhanced risk of suffering severe COVID-19 and mortality. Importantly, up to 25% of the population in western countries is susceptible of suffering from both MAFLD and COVID-19, while none approved treatment is currently available for any of them. Moreover, it is well known that exacerbated innate immune responses are key in the development of the most severe stages of MAFLD and COVID-19. In this review, we focus on the role of the immune system in the establishment and progression of MAFLD and discuss its potential implication in the development of severe COVID-19 in MAFLD patients. As a result, we hope to clarify their common pathology, but also uncover new potential therapeutic targets and prognostic biomarkers for further research.

Keywords: COVID-19; MAFLD; NASH; SARS-CoV-2; adaptive immunity; innate immunity.

Figure 1

Alterations in immunity that amplify responses to SARS-CoV-2 in MAFLD, obese and DM2 patients. Obesity, diabetes mellitus type 2 (DM2) and metabolic associated fatty liver disease (MAFLD) are very common comorbidities. Each of them has broad effects on the immune system resulting in impairments in normal homeostasis that can lead to more severe COVID-19. Created with BioRender.com.

Figure 2

Involvement of innate immune system in MAFLD and SARS-CoV-2 infection. In metabolic associated fatty liver disease (MAFLD), intestinal barrier dysfunction caused by intrinsic endotoxemia due to alterations in gut microbiota, adipose tissue low grade inflammation and the excess of fat in hepatocytes, lead to a series of events triggering the innate immune response in order to restore the perturbed environment. SARS-CoV-2 infection also contributes to intestinal mucosal inflammation, in addition to main lung inflammation caused by the virus entry through angiotensin-converting enzyme 2 (ACE2) in alveoli, which can also lead to thrombosis through a “bradykinin storm”. All these triggers lead to a massive “cytokine storm” with multiorgan effect. Created with BioRender.com.

Figure 3

Involvement of adaptive immune system in MAFLD and SARS-CoV-2 infection. Lipid accumulation in metabolic associated fatty liver disease (MAFLD) causes oxidative stress and lipid peroxidation, generating oxidative stress derived epitopes (OSEs). These products lead to adaptive immune stimulating T cells toward Th1 proinflammatory phenotype and activating T CD8 cells which express interleukin 2 (IL-2) receptor to develop a cytotoxic response. These events, together with SARS-CoV-2 infection lead to an impaired adaptive immune response. Regulatory T cells (Tregs) infiltrate to the liver as a compensatory mechanism for the enhanced local immune response. Created with BioRender.com.