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Elucidating the Role of Cholesterol in Respiratory RNA Virus Infection and Transmission
Başlık:
Elucidating the Role of Cholesterol in Respiratory RNA Virus Infection and Transmission
Yazar:
Bajimaya, Shringkhala, author.
ISBN:
9780355974898
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (217 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Toru Takimoto Committee members: Cheeptip Benyajati; Joshua Munger; Brian Ward.
Özet:
Acute respiratory infection (ARI) is one of the leading causes of mortality among infants and young children, globally. Influenza (IAV), respiratory syncytial (RSV) and parainfluenza (PIV) viruses are the major causes of ARI, but vaccines or effective antivirals are available only for limited viruses. These respiratory RNA viruses primarily target lung epithelial cells for infection. After genome replication and protein synthesis, viral components are transported to the plasma membrane assembly sites to be incorporated into budding virions. These respiratory viruses are known to utilize cholesterol-rich microdomains called lipid rafts for viral assembly and formation of progeny virions. However, the precise mechanism and functional role of cholesterol in assembly, infectivity and stability of respiratory RNA viruses are not fully elucidated.
In this study, we analyzed the role of cholesterol in infectious IAV, RSV and PIV1 production using cholesterol-reducing agents. Depletion of cellular cholesterol significantly decreased production of all respiratory viruses tested. Interestingly, cholesterol-reducing agents did not inhibit virion assembly or release of IAV and RSV. However, the released virions were less stable and diverse in virion density. The viruses contained less cholesterol in their membranes and rapidly lost infectivity rendering them non-infectious. In contrast, depletion of cholesterol inhibited PIV assembly and limited formation and release of progeny virions. The cholesterol reducing agents prevented cell surface accumulation of PIV glycoproteins and association of nucleocapsids with the raft membranes. These results suggest requirement of cholesterol in virus assembly differs among respiratory viruses.
In addition, we found that human parainfluenza virus type 1 (hPIV1) regulates cholesterol biosynthesis in infected cells. HPIV1 infection induced specific degradation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis pathway. This effect was detected as early as 12 h post infection and lasted for at least 8 days post infection. Importantly, hPIV1 did not cause cytopathic effects in respiratory epithelial cells unlike other acute respiratory viruses. Infected cells continued producing viral proteins, while cellular cholesterol level and progeny virion production gradually decreased. These results suggest that hPIV1 may regulate cholesterol homeostasis to establish quiescent status for a prolonged infection in the cells.
Taken together, our study indicates that cholesterol is a key component for the process of respiratory virus assembly, progeny virion formation, and maintaining infectivity for transmission. These data suggest that cholesterol could be an attractive target for the development of broadly reactive antivirals against respiratory viruses. Furthermore, we provide evidence for the first time that hPIV1 alters cellular cholesterol biosynthesis to establish quiescent infection in respiratory epithelial cells. These novel findings will be fundamental for future analysis on how hPIV1 survives in human population and causes seasonal infection.
Notlar:
School code: 0188
Tüzel Kişi Ek Girişi:
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(680022.1) | 680022-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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