Investigation of innate immune response in HSV-1 zosteriform infection of ENU-mutagenized mice that express IL-15 alternative splice variant
Date Issued
2012
Date
2012
Author(s)
Chuang, Che-Ming
Abstract
Interleukin-IL-15 (IL-15) is a pleiotropic cytokine expressed by a broad range of cell types. Not only it functions as a proinflammatory cytokine during innate immune response but also supports the development of natural killer cells and homeostasis of memory CD8 T cells. Therefore, it has been recognized as an important cytokine against viral infection. An ENU-mutagenized pedigree 191 (P191) generated at the Mouse Mutagenesis Program Core Facility (MMPCF) predominantly expresses an alternative splice IL-15 mRNA isoform called IL-15_ASE7. Studies from in vitro experiments demonstrated IL-15 splice variant protein inhibited IL-15 dependent cell proliferation; however, its function in vivo remains unclear. Using HSV-1 zosteriform mouse model, immunological consequences from HSV-1 infection were compared between B6 and P191 mice to clarify the role for IL-15 alternatively spliced variant in regulating innate immune response in skin.
Results from these experiments showed that HSV-1 created larger and severe skin lesions and delayed kinetics of skin lesion repair in P191 mice compared with B6 mouse skin. Furthermore, viral titers recovered from P191 lesional skin determined by plaque assay were higher than those from B6 lesional skin on days 3 and 5 post infection. Characteristics of HSV-1 resulted skin pathology including cell ballooning, reticular degeneration, chromosome condensation and vesicle formation in the epidermis were similar between B6 and P191 mice. However, levels of immune cell infiltration in the dermal layer were much reduced in P191 lesional skin. In addition, immunohistochemical analysis also confirmed that the influx of Gr1+ neutrophils on day 1 to day 2 and substantial infiltrations of lymphocytes and monocytes at day 3 to day 7 in B6 mice after infection were overall reduced in P191 skin (p<0.01). Importantly, real-time q-PCR analysis showed that the expression levels of MCP-1, IL-1b and TNF-a mRNA were comparable between B6 and P191 skin; however, the transcripts for neutrophil-attracting chemokine CXCL1 (KC) and IL-6 were marginally induced at 12 hr but dramatically down-regulated at 24 hr in HSV-1 infected P191 skin as opposed to elevated levels in B6 skin. The differential expression patterns of inflammatory cytokine and chemokine genes in skin between wild type and P191 mice after HSV-1 infection have implicated a yet defined role for IL-15 mediated signaling. The molecular mechanism by which IL-15 signaling controls innate immune response in skin against viral infection will be further explored.
Subjects
IL-15
HSV-1
skin
Type
thesis
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