Chenodeoxycholic Acid from Bile Inhibits Influenza A Virus Replication via Blocking Nuclear Export of Viral Ribonucleoprotein Complexes

Abstract

Influenza A virus (IAV) infection is still a major global threat for humans, especially for the risk groups: young children and the elderly. The currently licensed antiviral drugs target viral factors and are prone to viral resistance. In recent years, a few endogenous small molecules from host, such as estradiol and omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protection D1 (PD1), were demonstrated to be capable of inhibiting IAV infection. Chenodeoxycholic acid (CDCA), one of the main primary bile acids, is synthesized from cholesterol in the liver and classically functions in emulsification and absorption of dietary fats. Clinically, CDCA has been used in the treatment of patients with cholesterol gallstones for more than five decades. In this study, we showed that CDCA attenuated the replication of three subtypes of influenza A virus, including a highly pathogenic H5N1 strain, in A549 and MDCK cell cultures with IC50 ranging from 5.5 to 11.5 μM. Mechanistically, CDCA effectively restrained the nuclear export of viral ribonucleoprotein (vRNP) complexes. In conclusion, as an endogenous physiological small molecule, CDCA can inhibit IAV replication in vitro, at least in part, by blocking vRNP nuclear export, and affords further studies for development as a potential antiviral agent against IAV infections.

The Specific Bile Acid Profile of Shock: A Hypothesis Generating Appraisal of the Literature

“…Since this increase in bile acids is most likely an active process rather than a passive reaction to an extreme state of illness, further basic research will need to elate on the beneficial effects of these alterations; some of which have already been described [13,33]. With regard to raised bile acids in general, it has been shown already, that LPS (lipopolysaccharide, an endotoxin from the outer membrane of gram-negative bacteria) and SIRS (systemic inflammatory response syndrome) in general decrease expression of the nuclear farnesoid-X receptor (FXR) [6,32]. This reduction of FXR increases expression of CYP7A1 (cytochrome-P 7A1) that increases to the production of new bile acids [20], which in turn are excreted into the serum by the basolateral efflux-pumps MRP3 and MRP4 [21] and can thus be measured elevated.…”

Next-Generation Probiotics and Their Metabolites in COVID-19

“…CDCA was shown to inhibit some viruses, such as rotavirus [ 95 ]. Some in vitro studies also revealed that CDCA inhibits three different influenza A virus (IAV) strains, including the pathogenic H5N1 [ 78 ]. Treatment with CDCA resulted in a decrease in viruses both in infected A549 and MDCK cells.…”

“…Treatment with CDCA resulted in a decrease in viruses both in infected A549 and MDCK cells. CDCA can block viral ribonucleoprotein (vRNP) nuclear export, impairing IAV replication in vitro [ 78 ].…”

Fecal Microbiota Transplantation during and Post-COVID-19 Pandemic

“…Previous studies have shown that stool samples from rCDI patients were enriched with taurocholic acid, a potent C. difficile germinant, and show decreases in LCA and DCA, secondary bile acids that inhibit C. difficile germination prior to FMT [ 63 , 64 ]. Interestingly, emerging evidence suggests that CDCA and secondary bile acid (tauroursodeoxycholic acid) may inhibit rotavirus, hepatitis B/D, and Influenza A, as well as Influenza A and hepatitis B virus infection, respectively [ 65 , 66 , 67 , 68 ]. Bile acids have been proposed to possess anti-inflammatory properties and can inhibit the NF-κB-dependent transcription of pro-inflammatory cytokines via farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor Gpbar-1 (also known as TGR5) [ 69 ].…”