Abstract
Respiratory syncytial virus (RSV) is a major respiratory pathogen of infants and young children. Multiple strains of both subgroup A and B viruses circulate during each seasonal epidemic. Genetic heterogeneity among RSV genomes, in large part due to the error prone RNA-dependent, RNA polymerase, could mediate variations in pathogenicity. We evaluated clinical strains of RSV for their ability to induce the innate immune response. Subgroup B viruses were used to infect human pulmonary epithelial cells (A549) and primary monocyte-derived human macrophages (MDM) from a variety of donors. Secretions of IL-6 and CCL5 (RANTES) from infected cells were measured following infection. Host and viral transcriptome expression were assessed using RNA-SEQ technology and the genomic sequences of several clinical isolates were determined. There were dramatic differences in the induction of IL-6 and CCL5 in both A549 cells and MDM infected with a variety of clinical isolates of RSV. Transcriptome analyses revealed that the pattern of innate immune activation in MDM was virus-specific and host-specific. Specifically, viruses that induced high levels of secreted IL-6 and CCL5 tended to induce cellular innate immune pathways whereas viruses that induced relatively low level of IL-6 or CCL5 did not induce or suppressed innate immune gene expression. Activation of the host innate immune response mapped to variations in the RSV G gene and the M2-1 gene. Viral transcriptome data indicated that there was a gradient of transcription across the RSV genome though in some strains, RSV G was the expressed in the highest amounts at late times post-infection. Clinical strains of RSV differ in cytokine/chemokine induction and in induction and suppression of host genes expression suggesting that these viruses may have inherent differences in virulence potential. Identification of the genetic elements responsible for these differences may lead to novel approaches to antiviral agents and vaccines.
Highlights
Respiratory syncytial virus (RSV) is a major respiratory pathogen of infants and children worldwide
We have previously demonstrated that clinical isolates of RSV differ in their capacity to induce cytokines and chemokines in a standard human respiratory epithelial cell line, A549 [14]
IL-6 and CCL5 induction was greater during infection with NH1125B than NH1067B (Fig 1C and 1D, respectively) indicating that there are likely viral-specific factors involved in the degree of cytokine and chemokine induction during infection
Summary
Respiratory syncytial virus (RSV) is a major respiratory pathogen of infants and children worldwide. RSV is the most common cause of acute lower respiratory tract infection responsible for significant mortality in children less than 5 years of age (up to 199,000 deaths per year), mostly in developing countries [2]. RSV strains can be classified, based on serological [5] or genetic methods [6], into 2 subgroups, A or B. Both subgroup A and B viruses circulate during seasonal epidemics (typically the late fall, winter and early spring in temperate climates) and unlike influenza virus pandemics, RSV strains may vary from location to location in any given RSV season [6]. Strains identified in one location may be similar to strains from vastly different geographic locations identified in different years [7]
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