NK cell-derived extracellular granzyme B drives epithelial ulceration during HSV-2 genital infection
Ying Shiang Lim,
Aisha G. Lee,
Xiaoping Jiang,
Jason M. Scott,
Adjoa Cofie,
Sandeep Kumar,
Dania Kennedy,
David J. Granville,
Haina Shin
Affiliations
Ying Shiang Lim
Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Aisha G. Lee
Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Xiaoping Jiang
Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Jason M. Scott
Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Adjoa Cofie
Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Sandeep Kumar
Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Dania Kennedy
Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
David J. Granville
International Collaboration on Repair Discoveries Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V5Z 1M9, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada; BC Professional Firefighters’ Burn and Wound Healing Research Laboratory, Vancouver, BC V5V 3P1, Canada
Haina Shin
Division of Infectious Disease, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author
Summary: Genital herpes is characterized by recurrent episodes of epithelial blistering. The mechanisms causing this pathology are ill defined. Using a mouse model of vaginal herpes simplex virus 2 (HSV-2) infection, we show that interleukin-18 (IL-18) acts upon natural killer (NK) cells to promote accumulation of the serine protease granzyme B in the vagina, coinciding with vaginal epithelial ulceration. Genetic loss of granzyme B or therapeutic inhibition by a specific protease inhibitor reduces disease and restores epithelial integrity without altering viral control. Distinct effects of granzyme B and perforin deficiency on pathology indicates that granzyme B acts independent of its classic cytotoxic role. IL-18 and granzyme B are markedly elevated in human herpetic ulcers compared with non-herpetic ulcers, suggesting engagement of these pathways in HSV-infected patients. Our study reveals a role for granzyme B in destructing mucosal epithelium during HSV-2 infection, identifying a therapeutic target to augment treatment of genital herpes.
