Host Proteome Correlates of Vaccine-Mediated Enhanced Disease in a Mouse Model of Respiratory Syncytial Virus Infection

Abstract

Respiratory syncytial virus (RSV) is Respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in children, being responsible for up to 80% of the cases of acute bronchiolitis and frequent subsequent hospital admission in industrialized countries (1, 2). It has been estimated that RSV causes 33.8 million acute lower respiratory tract infections globally each year, resulting in 66,000 to 199,000 deaths among children under 5 years of age, 99% of which occur in developing countries (3). In addition to young children, immunocompromised individuals and the elderly are at increased risk for severe RSV disease and hospitalization. A licensed RSV vaccine is currently not available, and the development of a vaccine against RSV infection has proven to be very difficult. Formalin-inactivated RSV (FI-RSV) vaccine trials in the 1960s failed to induce protection upon natural RSV infection and even predisposed patients for enhanced disease, resulting in two deaths and hospitalization of 80% of the vaccinated subjects (4-7). Experimental inactivated and subunit vaccines tend to prime for the induction of unbalanced, type 2 T-helper (Th2) host responses that result in enhanced disease accompanied by an influx of inflammatory cells (8). On the other hand, development of live attenuated RSV vaccines that are more likely to induce balanced host responses appears difficult to tune and these live vaccines tend either to be over-or underattenuated (9, 10). Several RSV infection animal models have been developed, and these are exploited for vaccine research and studies on virus-induced (immuno)pathology. Multiple virological and immunological parame-

Transcriptome assists prognosis of disease severity in respiratory syncytial virus infected infants

“…Individual DE genes in severe RSV disease revealed overexpression of the neutrophil associated genes MMP8 and MMP9, which have previously been related to severe RSV disease44. ARG1 and CHI3L1 that have been linked to alternatively activated macrophages in a mouse model for vaccine enhanced RSV disease16 were also found to be strongly up-regulated. This suggests that the collected blood transcriptome profiles indeed reflect local lung host response.…”

“…Genomic technologies have contributed to study the virus-host interaction, including virus discovery, pathogenesis studies, the design of antiviral strategies and identification of biomarkers to support clinical management of infectious diseases11121314. For RSV infections, this has supported the characterization of vaccine-induced skewed host responses upon infection1516. Meijas et al 17.…”

Novel insights into human respiratory syncytial virus-host factor interactions through integrated proteomics and transcriptomics analysis

“…These host factors required for viral replication may provide potential drug targets for RSV treatment. Several studies used microarray and proteomic methods to identify host factors required for RSV replication [ 8 – 23 ]. Excellent reviews on these host factors and their role in RSV disease and pathogenesis had been published [ 24 , 25 ].…”

Identification of differentially expressed peptides in high-throughput proteomics data

“…Whereas proteomics has until now been a separate discipline, it is now increasingly being combined with other -omics technologies. Previously, we have seen that proteome and messenger RNA profiling provides valuable but distinct information on disease induced by a vaccination-challenge experiment on respiratory syncytial virus [16] (our unpublished observations). By investigating samples with multiple technologies, more accurate predictions on protein isoforms and location can be made, which greatly enhances the understanding of a biological system more than any single technology could.…”