Respiratory syncytial virus (RSV) is the major cause of viral respiratory infections in children. Our previous study showed that the RSV infection induced lung epithelial cell cycle arrest, which enhanced virus replication. To address the mechanism of RSV-induced cell cycle arrest, we examined the contribution of RSV-matrix (RSV-M) protein. In this report, we show that in both the A549 cell line and primary human bronchial epithelial (PHBE) cells, transfection with RSV-M protein caused the cells to proliferate at a slower rate than in control cells. The cell cycle analysis showed that RSV-M protein induced G1 phase arrest in A549 cells, and G1 and G2/M phase arrest in PHBE cells. Interestingly, RSV-M expression induced p53 and p21 accumulation and decreased phosphorylation of retinoblastoma protein (Rb). Further, induction of cell cycle arrest by RSV-M was not observed in a p53-deficient epithelial cell line (H1299). However, cell cycle arrest was restored after transfection of p53 cDNA into H1299 cells. Taken together, these results indicate that RSV-M protein regulates lung epithelial cell cycle through a p53-dependent pathway, which enhances RSV replication.
bThe conventional hemagglutinin (HA)-and neuraminidase (NA)-based influenza vaccines need to be updated most years and are ineffective if the glycoprotein HA of the vaccine strains is a mismatch with that of the epidemic strain. Universal vaccines targeting conserved viral components might provide cross-protection and thus complement and improve conventional vaccines. In this study, we generated DNA plasmids and recombinant vaccinia viruses expressing the conserved proteins nucleoprotein (NP), polymerase basic 1 (PB1), and matrix 1 (M1) from influenza virus strain A/Beijing/30/95 (H3N2). BALB/c mice were immunized intramuscularly with a single vaccine based on NP, PB1, or M1 alone or a combination vaccine based on all three antigens and were then challenged with lethal doses of the heterologous influenza virus strain A/PR/8/34 (H1N1). Vaccines based on NP, PB1, and M1 provided complete or partial protection against challenge with 1.7 50% lethal dose (LD 50 ) of PR8 in mice. Of the three antigens, NP-based vaccines induced protection against 5 LD 50 and 10 LD 50 and thus exhibited the greatest protective effect. Universal influenza vaccines based on the combination of NP, PB1, and M1 induced a strong immune response and thus might be an alternative approach to addressing future influenza virus pandemics.T he conventional influenza vaccines that are available currently to prevent seasonal flu outbreaks depend mainly on the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) (1, 2). However, HA-and NA-based conventional influenza vaccines sometimes fail to prevent flu epidemics because the HA and/or NA in the vaccine strains is a mismatch with that in circulating virus strains (3-7). Universal influenza vaccines (UIVs) that induce effective and long-term cross-protection and address the risk of mismatch may overcome the shortcomings of conventional influenza vaccines. Therefore, the development of a UIV capable of inducing long-term immunity and cross-protection remains a priority in influenza vaccine research (8).Influenza viruses are classified as type A, B, or C based on their nucleoprotein (NP) and matrix protein (M). Among the three subtypes, influenza A virus has been the target of UIVs, because the diverse influenza A strains frequently trigger influenza epidemics and pandemics. A previous study indicated that humans mount a good response to the highly conserved internal proteins NP, M1, and polymerase basic 1 (PB1) of influenza A virus (9); therefore, these highly conserved influenza A virus antigens are the basis of UIVs. Multiple studies have investigated the potential of NP (10-13), matrix protein 1 (M1) (14-17), and ion channel (M2, mainly M2e) (18-27) as alternative vaccine antigens for the prevention of seasonal and pandemic flu outbreaks. PB1 has also shown protective potential but requires further investigation for inclusion in UIVs. Košík et al. (28) constructed a DNA vaccine based on PB1, which provided some protective immunity in a mouse model. We previously constructed DNA vaccines ...
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