Distinct profiles and kinetics of soluble infammatory markers in patients with acute and chronic HCV-infections and SARS-CoV-2-infections: Implications for the long-term consequences of viral infections?

Background and Aims Viral infections occur acutely but can also progress chronically, with the immune system having a central role in immunopathoge-nesis. The question arises whether all alterations in immune responses are reversible after viral elimination (spontaneously or by therapy). Therefore, the aim of this study is to compare soluble infammatory markers (SIM) during and after infection with SARS-CoV-2 and acute and chronic HCV-infections. Patients and Method Patients with acute HCV (n = 29), chronic HCV (n = 54), SARS-CoV-2 (n = 39) and 31 healthy-controls were included. Blood samples were tested at baseline, end of treatment/infection, and follow-up ( >= 9 months after baseline). IL-12p70, IL-1b, IL-4, IL-5, IL-6, IL-8, TNF, IFN-g, IL-10, IL-22, CXCL-10, MCP-1, MIP-1b, ITAC were quantified using the HD-SP-X Imaging and Analysis SystemTM. Results SIM profiles in patients with acute HCV were substantially elevated at baseline and the decrease during follow-up was considerably less compared to the SARS-CoV-2 cohort. In chronic HCV-patients, viral elimination by therapy resulted in a decrease in SIM, although not always to those of controls. Cirrhotic HCV patients had higher SIM levels after HCV elimination than non-cirrhotic chronic HCV-patients. In the SARS-CoV-2 cohort, most SIM returned to levels of controls 3 months after baseline. Conclusions SIM profiles and kinetics after viral elimination difer between blood-borne acute and chronic HCV- and respiratory SARS-CoV-2-infections. The immunologic imprint 9 months after cured HCV-infection (both acute and chronic) appears to be more pronounced than after SARS-CoV-2-infection. Further analysis is needed to correlate the SIM profle with the clinical pheno-type (long-HepC vs. long-COVID-19).

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

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.