MicroRNAs modulate SARS-CoV-2 infection in primary human hepatocytes by regulating the entry factors ACE2 and TMPRSS2

ABSTRACT

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current coronavirus disease 2019 (COVID-19) pandemic. Despite a preferential respiratory tropism of SARS-CoV-2, multi-organ involvement has been described. SARS-CoV-2 entry into host cells is mediated by the entry factors angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Recent studies suggest that SARS-CoV-2 causes direct hepatic impairment in COVID-19 patients. Interestingly, ACE2 and TMPRSS2 are also expressed in primary human hepatocytes (PHH). Despite this evidence, data on infection and factors modulating functional regulation of SARS-CoV-2 infection in PHHs are scarce. MicroRNAs (miRNAs) are a class of small non-coding RNAs that have been described to modulate various cellular processes and have been implicated as potential therapeutic target. We aimed to study the infection of PHHs with SARS-CoV-2 and to evaluate the potential of miRNAs for modulating viral infection. We could demonstrate that PHHs can be readily infected with SARS-CoV-2. Bioinformatics analyses revealed miR- 200c-3p, miR-429, let-7c-5p and miR-141-3p as candidate miRNAs targeting ACE2 and TMPRSS2. All miRNAs were able to reduce SARS-CoV-2 burden in PHH by supressing ACE2 and TMPRSS2. Our findings provide the first evidence of the applicability of miRNA molecules in reducing SARS-CoV-2 viral loads.