Abstract
Human parainfluenza virus type 1 (hPIV1) and 3 (hPIV3) cause seasonal epidemics, but little is known about their interaction with human airway cells. In this study, we determined cytopathology, replication, and progeny virion release from human airway cells during long-term infection in vitro. Both viruses readily established persistent infection without causing significant cytopathic effects. However, assembly and release of hPIV1 rapidly declined in sharp contrast to hPIV3 due to impaired viral ribonucleocapsid (vRNP) trafficking and virus assembly. Transcriptomic analysis revealed that both viruses induced similar levels of type I and III IFNs. However, hPIV1 induced specific ISGs stronger than hPIV3, such as MX2, which bound to hPIV1 vRNPs in infected cells. In addition, hPIV1 but not hPIV3 suppressed genes involved in lipid biogenesis and hPIV1 infection resulted in ubiquitination and degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate limiting enzyme in cholesterol biosynthesis. Consequently, formation of cholesterol-rich lipid rafts was impaired in hPIV1 infected cells. These results indicate that hPIV1 is capable of regulating cholesterol biogenesis, which likely together with ISGs contributes to establishment of a quiescent infection.
Highlights
Parainfluenza viruses are one of the major causes of acute respiratory illnesses in infants, elderly and immunocompromised patients [1]
We found that Human parainfluenza virus type 1 (hPIV1) infection induced ubiquitination and degradation of 3-hydroxy-3methylglutaryl-coenzyme A reductase, a rate limiting enzyme in cholesterol biosynthesis
Humans are the only known host for both hPIV1 and 3, but how these viruses are maintained within the population and emerge during specific seasons is not known
Summary
Parainfluenza viruses are one of the major causes of acute respiratory illnesses in infants, elderly and immunocompromised patients [1]. Population based studies over the past several decades show an occurrence of hPIV3 infections annually during spring while hPIV1 causes unique biennial outbreaks during fall in odd numbered years [1,3]. Persistent infection can be a reason why these viruses are maintained during inter-epidemic periods. Evidence showing an outbreak of parainfluenza virus infection at the South Pole after 10 and 29 weeks of complete social isolation suggests persistent, asymptomatic infections [6,7]. Studies show viral persistent infection can cause chronic diseases, such as subacute sclerosing panencephalitis and postviral olfactory dysfunction in the case of measles virus and hPIV3, respectively [8,9]. Persistent infection has a significant impact on viral epidemics and pathogenesis, few studies have been performed regarding understanding the mechanism by which hPIVs establish persistent infection
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