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Characterization of the novel type I Interferon-- Ifn-epsilon

thesis
posted on 22.03.2017 by Fung, Ka Yee
Interferon-epsilon (Ifn-ε) is a recently identified type I IFN whose function is unknown. In contrast to other type I IFNs, Ifn-ε is expressed constitutively in reproductive organs, whereas other type I IFNs are not constitutively expressed. However, Ifn-ε is not induced by synthetic TLR ligands, virus and is not transcriptionally activated by interferon regulatory factors (IRFs). Furthermore, Ifn-ε gene expression is changed during estrous cycle and is suppressed during implantation of normal and psuedopregnancy, suggesting that Ifn-ε is regulated by ovarian hormones. Furthermore, the promoter of Ifn-ε is distinct from other type I IFNs due to the lack of viral response elements. Besides, the promoter of Ifn-ε possesses a conserved Ets factor binding site across different species. Experimental validation identified that Elf3, one of the epithelial specific Ets family members, is crucial for Ifn-ε expression in the uterus. Therefore, Ifn-ε is unique amongst Type I IFNs and is hypothesized to play a role in reproductive health. In order to examine the in vivo function of Ifn-ε, mice with a null mutation in the Ifn-ε gene (Ifn-ε -/- mice) were generated. These mice are fertile and healthy with no developmental differences compared to wild type (Ifn-ε +/+) mice. Interestingly, Ifn-ε regulates the basal levels of anti-bacterial/viral Interferon regulated genes which prime essential immune responses. To determine the role of Ifn-ε in reproductive tract infection, we examined the course and outcome of Chlamydia muridarum and Herpes Simplex Virus-2 reproductive tract infection in Ifn-ε -/- mice. Importantly, Ifn-ε -/- mice are more susceptible to infection. Besides, Ifn-ε -/- mice presented with higher clinical scores, more bacterial/viral load and more pro-inflammatory gene expression following the infections. Therefore, I demonstrate the importance of Ifn-ε in both initial infection and clearance of bacteria and viruses. This unique cytokine Ifn-ε has evolved special mechanisms of regulation in order to perform an essential protective function in the unique environment of the female reproductive tract where the immune response is unique and must be able to provide an effective protection against pathogens and allow the foreign sperm entry and embryo implantation. Hence, this work has important implications for protection against sexually transmitted diseases which represent a global health problem and for the development of successful vaccines in this unusual mucosal site.

History

Principal supervisor

Paul Hertzog

Year of Award

2011

Department, School or Centre

Monash Institute of Medical Research. Centre for Innate Immunity and Infectious Diseases

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences

Exports