AUTHOR=Jaggi Ujjaldeep , Wang Shaohui , Tormanen Kati , Matundan Harry , Ljubimov Alexander V. , Ghiasi Homayon 

TITLE=Role of Herpes Simplex Virus Type 1 (HSV-1) Glycoprotein K (gK) Pathogenic CD8+ T Cells in Exacerbation of Eye Disease

JOURNAL=Frontiers in Immunology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02895

DOI=10.3389/fimmu.2018.02895

ISSN=1664-3224

ABSTRACT=HSV-1-induced corneal scarring (CS), also broadly referred to as Herpes Stromal Keratitis (HSK), is the leading cause of infectious blindness in developed countries. It is well established that HSK is in fact an immunopathological disease. The contribution of the potentially harmful T cell effectors that lead to CS remains an area of intense study. Although the HSV-1 gene(s) involved in eye disease is not yet known, we have demonstrated that gK, which is one of the 12 known HSV-1 glycoproteins, has a crucial role in CS. Immunization of HSV-1 infected mice with gK, but not with any other known HSV 1 glycoprotein, significantly exacerbates CS and dermatitis. The gK-induced eye disease occurs independently of the strain of the virus or mouse. HSV-1 mutants that lack gK are unable to efficiently infect and establish latency in neurons. HSV-1 recombinant viruses expressing two additional copies of the gK (total of three gK genes) exacerbated CS as compared with wild type HSV-1 strain McKrae that contains one copy of gK. Furthermore, we have shown that an 8mer (ITAYGLVL) within the signal sequence of gK enhanced CS in ocularly infected BALB/c mice, C57BL/6 mice, and NZW rabbits. In HSV-infected “humanized” HLA-A*0201 transgenic mice, this gK 8mer induced strong IFN-g-producing cytotoxic CD8+ T cell responses. gK induced CS is dependent on gK binding to signal peptide peptidase (SPP).  gK also binds to HSV-1 UL20, while UL20 binds GODZ (DHHC3) and these quadruple interactions are required for gK induced pathology. Thus, potential therapies might include blocking of gK-SPP, gK-UL20, UL20-GODZ interactions, or a combination of these strategies.