ABSTRACT
The current SARS-CoV-2/COVID-19 pandemic wreaks medical and socioeconomic havoc. Despite the availability of vaccines, cost-effective acute treatment options preventing morbidity and mortality are urgently needed. To identify affordable, ubiquitously available, and effective treatments, we tested herbs consumed worldwide as herbal teas regarding their antiviral activity against SARS-CoV-2. Aqueous infusions prepared by boiling leaves of the Lamiaceae perilla and sage elicit potent and sustained antiviral activity against SARS-CoV-2 in therapeutic as well as prophylactic regimens. The herbal infusions exerted antiviral effects comparable to interferon-{beta} and remdesivir but outperformed convalescent sera and interferon-2 upon short-term treatment early after infection. Based on protein fractionation analyses, we identified caffeic acid, perilla aldehyde, and perillyl alcohol as antiviral compounds. Global mass spectrometry (MS) analyses performed comparatively in two different cell culture infection models revealed changes of the proteome upon treatment with herbal infusions and provided insights into the mode of action. As inferred by the MS data, induction of heme oxygenase 1 (HMOX-1) was confirmed as effector mechanism by the antiviral activity of the HMOX-1-inducing compounds sulforaphane and fraxetin. In conclusion, herbal teas based on perilla and sage exhibit antiviral activity against SARS-CoV-2 including variants of concern such as Alpha, Beta, Delta, and Omicron.
ABSTRACT
BackgroundThe newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated. MethodsMice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1{beta} were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry. ResultsStrikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1{beta} in the lungs. Higher gene expression of cytokines IL-6 and IL-1{beta} was found in ischemic brain hemispheres and a reduced number of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression. ConclusionsWe demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions. HighlightsBrain tissue injury increases ACE2 levels in the lungs Brain injury induces pro-inflammatory cytokine expression in the lungs Brain injury causes parenchymal inflammation and systemic lymphopenia
