The Innate and Adaptive Immune Response to Measles Virus

measles;vitamin A;Th17;not listed

Putnam, NicoleGriffin, Diane E. ;

Johns Hopkins University

关键词: measles;    vitamin A;    Th17;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37214/PUTNAM-THESIS-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Measles is one of the most important causes of childhood morbidity and mortality worldwide. Although a vaccine is available, the high transmission rate of measles virus requires population of 95% to interrupt its transmission. The World Health Organization and the United Nations Children’s Fund recommend that children that develop measles receive vitamin A supplementation, as a safe, cheap, and efficacious way to reduce the burden of disease. Due to differences between strains and confounding data of measles stocks contaminated with defective interfering RNA particles, the immune response to measles virus infection has not been well defined. Furthermore, the mechanism by which vitamin A protects against severe measles-induced disease is unknown. In this thesis, I investigate the innate and adaptive immune response to measles virus infection. Measles virus strains were purified of defective interfering RNA particles and used for in vitro infections of monocyte derived dendritic cells. Gene expression changes of interferon-stimulated genes and viral stress-induced genes, IFIT1 and Mx1, were upregulated in response to infection with the Edmonston measles virus vaccine strain, as well as the wild-type strains of Bilthoven, IC-B, and C- and V-protein knockout strains, as compared to mock infected cells. Unexpectedly, there were no differences between transcript levels of these genes between C and V protein knockout strains and the respective wild-type infection. Additionally, the absence of type I interferon production supports the theory that measles virus induces the transcription of these genes through the viral stress-induced pathway, and not the interferon-stimulated pathway. While a previous study had detected measles virus-specific IL-17-producing T cells in measles virus-infected rhesus macaques, the Th17 response to measles virus has not been characterized. Th17 cell differentiation was inhibited early after measles virus infection in vitro. There was a significant decrease in IL-23A transcripts and a significant increase in IL-27 transcripts, both of which affect Th17 cell differentiation negatively. However, in a rhesus macaque model of infection, a biphasic Th17 response was observed with peaks at days 18 and 56. The effects of vitamin A supplementation following measles virus infection on the immune response was explored in a rhesus macaque model using supplemented and non-supplemented groups. While some data has yet to be explored, major differences were not observed between the two groups up to three months following infection, in regards to clearance of infectious virus, immune cell composition, or immune cell function. Archived data will elucidate the role of vitamin A in measles virus RNA persistence, and Th1 and T follicular helper cell responses. Data will continue to be analyzed out to six months post infection. A larger cohort will be necessary to elucidate the role of vitamin A in protection against severe disease and death due to measles.