Abstract
Enterovirus D68 (EV-D68) is an emerging pathogen that recently caused a large outbreak of severe respiratory disease in the United States and other countries. Little is known about the relationship between EV-D68 virus and host cells. In this study, we assessed the effect of the host cell cycle on EV-D68 viral production, as well as the ability of EV-D68 to manipulate host cell cycle progression. The results suggest that synchronization in G0/G1 phase, but not S phase, promotes viral production, while synchronization in G2/M inhibits viral production. Both an early EV-D68 isolate and currently circulating strains of EV-D68 can manipulate the host cell cycle to arrest cells in the G0/G1 phase, thus providing favorable conditions for virus production. Cell cycle regulation by EV-D68 was associated with corresponding effects on the expression of cyclins and CDKs, which were observed at the level of the protein and/or mRNA. Furthermore, the viral non-structural protein 3D of EV-D68 prevents progression from G0/G1 to S. Interestingly, another member of the Picornaviridae family, EV-A71, differs from EV-D68 in that G0/G1 synchronization inhibits, rather than promotes, EV-A71 viral replication. However, these viruses are similar in that G2/M synchronization inhibits the production and activity of both viruses, which is suggestive of a common therapeutic target for both types of enterovirus. These results further clarify the pathogenic mechanisms of enteroviruses and provide a potential strategy for the treatment and prevention of EV-D68-related disease.
Highlights
Human enterovirus 68 (EV-D68) is an emerging pathogen that can cause severe respiratory disease and is associated with cases of paralysis, especially among children
Enterovirus D68 (EV-D68) was first identified in California in 1962, the number of people in one breakout in 2014 with confirmed EV-D68 infection was much greater than the number reported in previous years
We investigated the pathogenic mechanism of EV-D68 to reveal the relationship between virus infection and the host cell cycle
Summary
Human enterovirus 68 (EV-D68) is an emerging pathogen that can cause severe respiratory disease and is associated with cases of paralysis, especially among children. It was first isolated from samples obtained in California in 1962 from four children with pneumonia and bronchiolitis (Schieble et al, 1967). The representative of HEV-A serotype is human enterovirus 71 (EV-A71), which is a primary causative agent for Hand, foot, and mouth disease (HFMD) that is associated with the recent outbreaks in Asia (Liu et al, 2011; Wang et al, 2012). EV-D68 is assigned to HEV-D serotype, but EV-D68 is unlike other enteroviruses in that it is acid labile and biologically more similar to human rhinoviruses that are associated with respiratory diseases (Smura et al, 2010)
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