ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed essential for viral replication. We examined the master UPR sensor IRE1 kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1 as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1 through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1 was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1, perhaps as a strategy to eliminate detection by the host immune system. IMPORTANCESARS-CoV-2 is the third lethal respiratory coronavirus after MERS-CoV and SARS-CoV to emerge this century, causing millions of deaths world-wide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1 (IRE1) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1 kinase and RNase activities, SARS-CoV-2 only partially activates IRE1, promoting its kinase activity but not RNase activity. Based on IRE1-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1 RNase activation as a strategy to limit detection by the host immune system.
ABSTRACT
The rapid spread of COVID-19 underscores the need for new treatments. Here we report that cannabidiol (CBD), a compound produced by the cannabis plant, inhibits SARS-CoV-2 infection. CBD and its metabolite, 7-OH-CBD, but not congeneric cannabinoids, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after cellular infection, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcription. CBD induces interferon expression and up-regulates its antiviral signaling pathway. A cohort of human patients previously taking CBD had significantly lower SARS-CoV-2 infection incidence of up to an order of magnitude relative to matched pairs or the general population. This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection.
ABSTRACT
ObjectiveTo explore the correlation between butylphthalide and plasma brain-type creatine kinase isoenzyme (CK-BB),endothelin (ET),calcitonin gene related peptide (CGRP) in patients with acute cerebral infarction (ACI).MethodsSixty patients with ACI were divided into treatment group and control group with 30 cases each by random digits table method.Both groups received normal treatment continuously for 7 days,and butylphthalide of 200 mg was added to treatment group for 3 times per day.The levels of plasma CK-BB,ET and CGRP of two groups before and after treatment were measured and compared.ResultsThe levels of plasma CK-BB,ET of two groups both decreased significantly after treatment,but CGRP rose obviously.It showed significant differences before and after treatment of both groups (P ＜0.01 or ＜ 0.05).The levels of plasma CK-BB,ET of treatment group after treatment were lower than those of control group in the same period [(216.48±36.95) U/L vs.(333.07±54.03) U/L,(83.33±26.48)ng/L vs.(98.46±31.46) ng/L,P ＜ 0.05 ].The level of plasma CGRP of treatment group after treatment was significantly higher than that of control group in the same period [ (44.16±13.28 ) ng/L vs.(36.42±12.31 )ng/L,P ＜ 0.05 ].ConclusionButylphthalide can reduce the plasma enzyme activity,balance ET and CGRP,extend the cerebral arteries to antagonize ET,improve cerebral ischemia and cerebral hypoxia,which can protect brain cells and endothelial cells.
