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      The cholesterol transport inhibitor U18666A inhibits type I feline coronavirus infection


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          Feline infectious peritonitis (FIP) is a feline coronavirus (FCoV)-induced fatal disease in wild and domestic cats. FCoV exists in two serotypes. Type I FCoV is the dominant serotype worldwide. Therefore, it is necessary to develop antiviral drugs against type I FCoV infection. We previously reported that type I FCoV is closely associated with cholesterol throughout the viral life cycle. In this study, we investigated whether U18666A, the cholesterol synthesis and transport inhibitor, shows antiviral effects against type I FCoV. U18666A induced cholesterol accumulation in cells and inhibited type I FCoV replication. Surprisingly, the antiviral activity of U18666A was suppressed by the histone deacetylase inhibitor (HDACi), Vorinostat. HDACi has been reported to revert U18666A-induced dysfunction of Niemann-Pick C1 (NPC1). In conclusion, these findings demonstrate that NPC1 plays an important role in type I FCoV infection. U18666A or other cholesterol transport inhibitor may be considered as the antiviral drug for the treatment of cats with FIP.


          • U18666A, cholesterol synthesis and transport inhibitor, shows antiviral effect against type I FCoV, but not type II FCoV.

          • U18666A induced cholesterol accumulation in cells and inhibited type I FCoV replication.

          • The antiviral activity of U18666A was suppressed by the histone deacetylase inhibitor.

          • Our study suggested that Niemann-Pick C1 plays an important role in type I FCoV infection.

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          Most cited references24

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          Immunopathogenesis of coronavirus infections: implications for SARS

          Key Points The severe acute respiratory syndrome (SARS), which was first identified in 2003, is caused by a novel coronavirus: the SARS coronavirus (SARS-CoV). Many features of the infection indicate that an excessive, but perhaps 'normal', immune response contributes to SARS. Several coronaviruses cause diseases that result in considerable morbidity and mortality in animals. Some of these diseases are also immune mediated and provide insights into the pathogenesis of SARS. Feline infectious peritonitis virus (FIPV) causes a fatal, immune-mediated disease of felines. Macrophage infection, lymphocyte depletion and antibody-dependent disease enhancement are hallmarks of this disease. Infection with the murine coronavirus murine hepatitis virus (MHV) strain JHM results in immune-mediated demyelination. Similar to SARS, macrophage activation is a key component in the pathogenic process. Another strain of MHV, MHV-3, causes a fatal, fulminant hepatitis. MHV-3 infection of macrophages, with subsequent activation and induction of expression of a novel procoagulant, fibrinogen-like protein 2 (FGL2), is required for severe disease. Chickens that are infected with avian infectious bronchitis virus (IBV) develop respiratory and renal disease. An excessive innate immune response contributes to the pathogenic process in these animals. To develop effective therapies for SARS will require understanding of the contributions of direct injury by virus and of the host immune response to pathogenesis. This requires further studies of the interactions of SARS-CoV with its target cells and necessitates the development of an animal model that reproduces the pulmonary infection that is observed in infected humans.
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            How cells handle cholesterol.

            Cholesterol plays an indispensable role in regulating the properties of cell membranes in mammalian cells. Recent advances suggest that cholesterol exerts many of its actions mainly by maintaining sphingolipid rafts in a functional state. How rafts contribute to cholesterol metabolism and transport in the cell is still an open issue. It has long been known that cellular cholesterol levels are precisely controlled by biosynthesis, efflux from cells, and influx of lipoprotein cholesterol into cells. The regulation of cholesterol homeostasis is now receiving a new focus, and this changed perspective may throw light on diseases caused by cholesterol excess, the prime example being atherosclerosis.
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              Human coronavirus 229E binds to CD13 in rafts and enters the cell through caveolae.

              CD13, a receptor for human coronavirus 229E (HCoV-229E), was identified as a major component of the Triton X-100-resistant membrane microdomain in human fibroblasts. The incubation of living fibroblasts with an anti-CD13 antibody on ice gave punctate labeling that was evenly distributed on the cell surface, but raising the temperature to 37 degrees C before fixation caused aggregation of the labeling. The aggregated labeling of CD13 colocalized with caveolin-1 in most cells. The HCoV-229E virus particle showed a binding and redistribution pattern that was similar to that caused by the anti-CD13 antibody: the virus bound to the cell evenly when incubated on ice but became colocalized with caveolin-1 at 37 degrees C; importantly, the virus also caused sequestration of CD13 to the caveolin-1-positive area. Electron microscopy confirmed that HCoV-229E was localized near or at the orifice of caveolae after incubation at 37 degrees C. The depletion of plasmalemmal cholesterol with methyl beta-cyclodextrin significantly reduced the HCoV-229E redistribution and subsequent infection. A caveolin-1 knockdown by RNA interference also reduced the HCoV-229E infection considerably. The results indicate that HCoV-229E first binds to CD13 in the Triton X-100-resistant microdomain, then clusters CD13 by cross-linking, and thereby reaches the caveolar region before entering cells.

                Author and article information

                Antiviral Res
                Antiviral Res
                Antiviral Research
                Elsevier B.V.
                3 August 2017
                September 2017
                3 August 2017
                : 145
                : 96-102
                [1]Laboratory of Veterinary Infectious Disease, School of Veterinary Medicine, Kitasato University, Towada, Japan
                Author notes
                []Corresponding author. hohdatsu@ 123456vmas.kitasato-u.ac.jp
                © 2017 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                : 14 June 2017
                : 24 July 2017
                : 31 July 2017

                Infectious disease & Microbiology
                feline coronavirus,cholesterol,u18666a,histone deacetylase inhibitor,npc1


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