Effects of CXCR3 signaling on development of fatal encephalitis and corneal and periocular skin disease in HSV-infected mice are mouse-strain dependent.
OBJECTIVE
The host inflammatory response to ocular infection with herpes simplex virus (HSV) can be either protective, with disease-free survival, or it can promote diseases such as HSV corneal disease (or herpes stromal keratitis [HSK] in humans) and encephalitis (HSE), depending on mouse strain. The role of CXCR3 chemokine signaling in HSV-induced central nervous system (CNS) inflammation and corneal disease was evaluated, and responses in genetically susceptible and resistant strains of mice were contrasted.


METHODS
Resistant C57BL/6J (B6) and susceptible 129S6 (129) mice were given monoclonal antibodies (mAbs) to neutralize the CXCR3 ligands monokine induced by interferon-gamma (MIG, CXCL9) and interferon inducible protein-10 (IP-10, CXCL10) during HSV infection. In addition, the development of HSV disease was monitored in CXCR3-null mutant mice derived from resistant (B6) and susceptible (BALB/c) strains. Inflammatory cells infiltrating the cornea and brain stem were isolated and stained for flow cytometric analysis.


RESULTS
MIG and IP-10 were induced in nervous system tissue after HSV inoculation by the corneal route. HSV-infected 129 mice treated with MIG- or IP-10-neutralizing mAbs showed significantly enhanced survival compared with mice treated with control isotype antibody, whereas survival of the B6 mice was unaltered. Similarly, greater survival was observed for BALB.CXCR3(-/-) mice compared with control BALB/c mice. Reduced CNS inflammation was documented that extended to the cornea, such that HSV corneal disease severity was reduced in susceptible BALB.CXCR3(-/-). In contrast, although survival of B6 and B6.CXCR3(-/-) mice was indistinguishable, B6.CXCR3(-/-) mice developed more severe corneal and periocular skin disease.


CONCLUSIONS
The effects of CXCR3 signaling in HSV infection are strongly dependent on mouse strain.
Lundberg
Patric
P
Division of Virology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Openshaw
Harry
H
Wang
Mingwu
M
Yang
Hui-Jung
HJ
Cantin
Edouard
E
D000818:Animals; D001933:Brain Stem / Q000378:metabolism; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000502:physiology; D003315:Cornea / Q000821:virology; D004198:Disease Susceptibility; D020803:Encephalitis, Herpes Simplex / Q000235:genetics / Q000401:mortality* / Q000503:physiopathology; D005434:Flow Cytometry; D018259:Herpesvirus 1, Human / Q000502:physiology; D007113:Immunity, Innate; D016849:Keratitis, Herpetic / Q000235:genetics / Q000401:mortality* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D017193:Skin Diseases, Viral / Q000235:genetics / Q000401:mortality* / Q000503:physiopathology; D012668:Trigeminal Ganglion / Q000378:metabolism; D015854:Up-Regulation
C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine