Modulation of immune responses by human paraininfluenza virus
Noone, Cariosa (2007) Modulation of immune responses by human paraininfluenza virus. PhD thesis, Dublin City University.
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Human Parainfluenza virus type 3 (HPIV3) is a key respiratory pathogen responsible for bronchiolitis, pneumonia and croup. The persistent nature of this virus and its ability to reinfect within a short space of time has led to successive failures in the design of a vaccine against this virus. To understand the lack of protective immunity observed after HPIV3 infections, a comprehensive study investigating immune responses to this respiratory pathogen was undertaken. A human ex vivo model of viral infection was developed. Priming by HPIV3 was compared to immune responses induced by influenza A virus, which unlike HPIV3 primes immunity to reinfectionwith the same strain. HPIV3 infection generated potent and mature dendritic cells (DCs). However, unlike influenza A generated DCs, allogeneic human mixed leukocytes (MLR) failed to proliferate to HPIV3 generated DCs. Conversely pur3ed CD3+T cells were capable of expanding to these DCs. Further investigation revealed that autologous CD14-CD3- cells in the MLR were responsible for this control of T cell proliferation. Inhibition was contact dependent and reliant on the absence of IL-2. Follow on studies demonstrated that T cell proliferation control was due to CD56+ natural killer (NK) cells. Of interest, the regulation was not exerted by NK cytotoxicity but by partial arrest of cell cycle progression via regulation of p27 cyclin dependent kinase (cdk) inhibitor. Moreover, there was an overall control of T cell expansion by NK cells. The human ex vivo model was then used to assess the immunogenicity of a novel HPIV3 vaccine. Parallel studies involving murine immune models were also investigated. Studies revealed that the vaccine did not elicit the suppressive effects associated with HPIV3 whole virus infections. In conclusion, these studies identified a novel mechanism of immune regulation by NK cells in HPIV3 infections and demonstrated the potential of a novel vaccine against HPIV3.
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