Absence of macrophage inflammatory protein-1alpha prevents the development of blinding herpes stromal keratitis.
Prior studies in our laboratory have suggested that the CC chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) may be an important mediator in the blinding ocular inflammation which develops following herpes simplex virus type 1 (HSV-1) infection of the murine cornea. To directly test this hypothesis, MIP-1alpha-deficient (-/-) mice and their wild-type (+/+) counterparts were infected topically on the scarified cornea with 2.5 x 10(5) PFU of HSV-1 strain RE and subsequently graded for corneal opacity. Four weeks postinfection (p.i.), the mean corneal opacity score of -/- mice was 1.1 +/- 0.3 while that of the +/+ mice was 3.7 +/- 0.5. No detectable infiltrating CD4+ T cells were seen histologically at 14 or 21 days p.i. in -/- animals, whereas the mean CD4+ T-cell count per field (36 fields counted) in +/+ hosts was 26 +/- 2 (P < 0.001). In addition, neutrophil counts in the -/- mouse corneas were reduced by >80% in comparison to the wild-type controls. At 2 weeks p.i., no interleukin-2 or gamma interferon could be detected in six of seven -/- mice, whereas both T-cell cytokines were readily demonstrable in +/+ mouse corneas. Also, MIP-2 and monocyte chemoattractant protein-1 protein levels were significantly lower in MIP-1alpha -/- mouse corneas than in +/+ host corneas, suggesting that MIP-1alpha directly, or more likely indirectly, influences the expression of other chemokines. Interestingly, despite the paucity of infiltrating cells, HSV-1 clearance from the eyes of -/- mice was not significantly different from that observed in +/+ hosts. We conclude that MIP-1alpha is not needed to control virus growth in the cornea but is essential for the development of severe stromal keratitis.
Tumpey
T M
TM
Department of Microbiology and Immunology, University of South Alabama, Mobile 36688, USA.
Cheng
H
H
Cook
D N
DN
Smithies
O
O
Oakes
J E
JE
Lausch
R N
RN
D000818:Animals; D001766:Blindness / Q000276:immunology / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D002522:Chlorocebus aethiops; D003315:Cornea / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006561:Herpes Simplex / Q000276:immunology / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D016849:Keratitis, Herpetic / Q000276:immunology / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D015846:Monokines / Q000378:metabolism; D014709:Vero Cells
D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D007376:Interleukin-2; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D007371:Interferon-gamma