Traditional use of Cissampelos pareira L. for hormone disorder and fever provides molecular links of ESR1 modulation to viral inhibition (preprint)

In traditional systems, a single herbal formulation is often used in the treatment of diverse diseases, including some that are newly emergent and prevalent today. We provide here a multi-omics framework to probe the molecular basis of a multicomponent example herb, Cissampelos pareira L. (Cipa) used in the treatment of hormonal disorders and fever in Ayurveda. Cipa treated MCF7 cells exhibit downregulation of signatures of estrogen response. 38 constituent molecules in Cipa potentially bind ({triangleup}G< -7.5) with ER at the same site as estrogen. Cipa transcriptome signatures in the connectivity map exhibit positive scores with protein translation inhibitors and knockdown signatures of genes linked to the antiviral response. This includes the knockdown signature of RPL7, a coactivator of ESRI with a connectivity score > 99.69. This axis was found to be upregulated in the COVID-19 patient transcriptome. The antiviral activity through ESR1 modulation was validated in the DENV-2 infection model. We further observed 98% inhibition of SARs-COV-2 replication in infected Vero cell cultures with the whole extract. A few of its prominent pure constituents e.g pareirarine, cissamine, magnoflorine exhibited 40-80% inhibition. This study provides a novel framework for querying the molecular links of multicomponent Ayurveda formulations and explains their use in the treatment of disparate diseases. The novel biological targets identified here can become potential that could be applicable to more than one viral infection, such as the use of Cipa in dengue and COVID-19.

Kinetics of viral load, immunological mediators and characterization 1 of a SARS-CoV-2 isolate in mild COVID-19 patients during acute phase of infection (preprint)

Over 95% of the COVID-19 cases are mild-to-asymptomatic who contribute to disease transmission whereas most of the severe manifestations of the disease are observed in elderly and in patients with comorbidities and dysregulation of immune response has been implicated in severe clinical outcomes. However, it is unclear whether asymptomatic or mild infections are due to low viral load or lack of inflammation. We have measured the kinetics of SARS-CoV-2 viral load in the respiratory samples and serum markers of inflammation in hospitalized COVID-19 patients with mild symptoms. We observed a bi-phasic pattern of virus load which was eventually cleared in most patients at the time of discharge. Viral load in saliva samples from a subset of patients showed good correlation with nasopharyngeal samples. Serum interferon levels were downregulated during early stages of infection but peaked at later stages correlating with elevated levels of T-cell cytokines and other inflammatory mediators such as IL-6 and TNF-alpha which showed a bi-phasic pattern. The clinical recovery of patients correlated with decrease in viral load and increase in interferons and other cytokines which indicates an effective innate and adaptive immune function in mild infections. We further characterized one of the SARS-CoV-2 isolate by plaque purification and show that infection of lung epithelial cells (Calu-3) with this isolate led to cytopathic effect disrupting epithelial barrier function and tight junctions. Finally we showed that zinc was capable of inhibiting SARS-CoV-2 infection in this model suggesting a beneficial effect of zinc supplementation in COVID-19 infection.