This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cells of the innate and adaptive immune system are capable of exerting a range of potent anti-viral effects, both directly and in collaboration with other cell types. These responses are critical for protection against pathogenic respiratory viruses such as human respiratory syncytial virus (HRSV) and influenza A virus. Pathogenic viruses, in turn, have evolved mechanisms for escaping, exacerbating, or suppressing human cellular immune responses. The work completed over the previous year focused on the interaction between human immune cells of the monocyte/macrophage, natural killer (NK), and T cell lineages with virion components of HRSV and influenza A virus, with the goal of distinguishing between protective and pathological responses triggered by specific virion proteins. Immune cells were cultured with whole inactivated virions, fractionated virion components, or synthetic peptides corresponding to viral proteins to examine their effect on the immune cells. Expression of immunologically relevant inflammatory mediators, cytokines, and cell surface molecules by the human immune cells were characterized by real-time polymerase chain reaction (RT-PCR) following a two or four hour exposure. HRSV is known to promote an allergic-type inflammatory response by boosting interleukin (IL)-5 and IL-13 expression. The role of specific human immune cells in this inappropriate response is not well-defined. We have shown that HRSV exposure caused an upregulation of IL-5,IL -6, IL-10, and IL-13 gene expression in human NK cells. These cytokines are linked to either immune suppression or an aberrant inflammatory response, and the results indicate that NK cells, as one of the first immune cells to reach the site of viral infection, may be important mediators of a deleterious immune response. Additional results have linked regions of both the F and G virion proteins to these cytokine responses from NK cells. Exposure of NK cells to influenza A virus enhanced IL-17A expression. High expression levels of this cytokine are associated with pathological inflammation. Both HRSV and influenza A virus altered the expression of other immunologically relevant genes such as colony stimulating factor I and OX40 ligand. Altered expression of these immune response mediators in vivo would impact the course of infection and the effectiveness of innate and adaptive immune responses. Future work will continue to investigate the cause of these immune modulations, with virion fractionation and testing of isolated viral glycoproteins. Signaling molecules involved in generating the NK cell response will also be investigated. Understanding the immunomodulatory potential of virion components will yield insights into viral pathogenesis and allow the design of more effective subunit vaccines.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-4 (01))
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University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
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