Statins significantly repress rotavirus replication through downregulation of cholesterol synthesis

Abstract

Rotavirus is the most common cause of severe diarrhea among infants and young children and is responsible for more than 200,000 pediatric deaths per year. There is currently no pharmacological treatment for rotavirus infection in clinical activity. Although cholesterol synthesis has been proven to play a key role in the infections of multiple viruses, little is known about the relationship between cholesterol biosynthesis and rotavirus replication. The models of rotavirus infected two cell lines and a human small intestinal organoid were used. We investigated the effects of cholesterol biosynthesis, including inhibition, enhancement, and their combinations on rotavirus replication on these models. The knockdown of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was built by small hairpin RNAs in Caco2 cells. In all these models, inhibition of cholesterol synthesis by statins or HMGCR knockdown had a significant inhibitory effect on rotavirus replication. The result was further confirmed by the other inhibitors: 6-fluoromevalonate, Zaragozic acid A and U18666A, in the cholesterol biosynthesis pathway. Conversely, enhancement of cholesterol production increased rotavirus replication, suggesting that cholesterol homeostasis is relevant for rotavirus replication. The effects of all these compounds toward rotavirus were further confirmed with a clinical rotavirus isolate. We concluded that rotavirus replication is dependent on cholesterol biosynthesis. To be specific, inhibition of cholesterol synthesis can downregulate rotavirus replication; on the contrary, rotavirus replication is upregulated. Statin treatment is potentially an effective novel clinical anti-rotavirus strategy.

Atorvastatin Effectively Inhibits Ancestral and Two Emerging Variants of SARS-CoV-2 in vitro

“…On the other hand, a previous study revealed that the antiviral activity of statins against rotavirus was independent of the cell line used (Ding et al, 2021). Consistent with this report, our data showed that ATV also inhibited D614G strain in Caco-2 (EC50 = 7.4 μM), a colorectal epithelial cell line highly permissive for SARS-CoV-2 infection (Uemura et al, 2021;Wurtz et al, 2021).…”

Advances in the development of antivirals for rotavirus infection

“…Statins may also have beneficial effects for the treatment of rotavirus infections. Rotavirus replication is significantly inhibited after statin treatment (99) or HMGCR knockdown (100). Notably, viral titres in the drugtreated group of cells decrease by 2 log values while viral mRNA remains relatively unchanged, suggesting that statins affect viral assembly.…”

Aspects of Antiviral Strategies Based on Different Phototherapy Approaches: Hit by the Light

“…The GE therapy research is limited, as there are some difficulties with growing certain viruses and/or specific strains [ 85 ]. There are not so many new antivirals and treatments found, as more attention has been on repurposing drugs [ 86 ], such as nitazoxanide [ 87 , 88 , 89 , 90 , 91 ], rupintrivir, and citrate among others [ 76 , 85 , 92 , 93 , 94 ]. However, none of the potential treatments has been introduced as accepted therapy [ 76 ].…”

“…Phototherapy approach Norovirus (NoV) Gastroenteritis UVB photoactivated curcumin showed an effect on NoV surrogates; it also altered the morphology and inactivated NoV in oysters [94,95]. There was an inactivation effect of high-intensity ultrasound on NoV surrogates noted [96].…”