Microglial cells initiate vigorous yet non-protective immune responses during HSV-1 brain infection.
Central nervous system (CNS) infection with herpes simplex virus (HSV)-1 triggers neuroinflammatory responses leading to peripheral immune cell infiltration into the brain. Previous in vitro studies from our laboratory, using primary human brain cells, implicated microglia as the cellular source of infection-induced chemokines, such as CXC ligand 10 (CXCL10) and CC ligand 2 (CCL2). Here, we evaluated the role of microglial cells in HSV-induced neuroimmune responses using an in vivo murine model of herpes encephalitis. Data obtained during this study demonstrated robust levels of CXCL10, CCL2 and CXCL9 detectable in the brains of infected BALB/c mice between 5 and 8 days post-infection (p.i.). Microglial cells were identified as a source of this HSV-induced chemokine production. Additional experiments established that induction of these immune mediators preceded the presence of CD3, CD4, CD8, and CD45 mRNA in the brain, and immunohistochemical analysis confirmed the presence of infiltrating CD3(+) cells. Further analysis suggested that microglia-derived chemokines drive peripheral immune cell chemotaxis, as antibodies to CXCL10 and CCL2 blocked the migration of murine splenocytes toward HSV-infected microglia by approximately 59.3+/-4.1% and 17.5+/-1.4%, respectively. Taken together, these results demonstrate that a vigorous microglia-driven cascade of pro-inflammatory immune responses is not sufficient to protect susceptible mice from HSV-1 brain infection.
Marques
Cristina P
CP
Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, USA.
Hu
Shuxian
S
Sheng
Wen
W
Lokensgard
James R
JR
D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000821:virology; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000378:metabolism; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D020803:Encephalitis, Herpes Simplex / Q000276:immunology*; D018259:Herpesvirus 1, Human; D007371:Interferon-gamma / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000276:immunology*; D009336:Necrosis / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; D012333:RNA, Messenger; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens