TY - JOUR
T1 - Platelet Activating Factor (PAF) Receptor Deletion or Antagonism Attenuates Severe HSV-1 Meningoencephalitis
AU - Vilela, Márcia Carvalho
AU - Lima, Graciela Kunrath
AU - Rodrigues, David Henrique
AU - Lacerda-Queiroz, Norinne
AU - Pedroso, Vinicius Sousa Pietra
AU - de Miranda, Aline Silva
AU - Rachid, Milene Alvarenga
AU - Kroon, Erna Geessien
AU - Campos, Marco Antônio
AU - Teixeira, Mauro Martins
AU - Teixeira, Antonio Lucio
N1 - Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Herpes simplex virus type 1 (HSV-1) is a human pathogen that may cause severe encephalitis. The exacerbated immune response against the virus contributes to the disease severity and death. Platelet activating factor (PAF) is a mediator capable of inducing increase in vascular permeability, production of cytokines on endothelial cells and leukocytes. We aimed to investigate the activation of PAF receptor (PAFR) and its contribution to the severity of the inflammatory response in the brain following HSV-1 infection. C57BL/6 wild-type (WT) and PAFR deficient (PAFR−/−) mice were inoculated intracranially with 104 plaque-forming units (PFU) of HSV-1. Visualization of leukocyte recruitment was performed using intravital microscopy. Cells infiltration in the brain tissue were analyzed by flow cytometry. Brain was removed for chemokine assessment by ELISA and for histopathological analysis. The pharmacological inhibition by the PAFR antagonist UK-74,505 was also analyzed. In PAFR−/− mice, there was delayed lethality but no difference in viral load. Histopathological analysis of infected PAFR−/− mice showed that brain lesions were less severe when compared to their WT counterparts. Moreover, PAFR−/− mice showed less TCD4+, TCD8+ and macrophages in brain tissue. This reduction of the presence of leukocytes in parenchyma may be mechanistically explained by a decrease in leukocytes rolling and adhesion. PAFR−/− mice also presented a reduction of the chemokine CXCL9 in the brain. In addition, by antagonizing PAFR, survival of C57BL/6 infected mice increased. Altogether, our data suggest that PAFR plays a role in the pathogenesis of experimental HSV-1 meningoencephalitis, and its blockade prevents severe disease manifestation.
AB - Herpes simplex virus type 1 (HSV-1) is a human pathogen that may cause severe encephalitis. The exacerbated immune response against the virus contributes to the disease severity and death. Platelet activating factor (PAF) is a mediator capable of inducing increase in vascular permeability, production of cytokines on endothelial cells and leukocytes. We aimed to investigate the activation of PAF receptor (PAFR) and its contribution to the severity of the inflammatory response in the brain following HSV-1 infection. C57BL/6 wild-type (WT) and PAFR deficient (PAFR−/−) mice were inoculated intracranially with 104 plaque-forming units (PFU) of HSV-1. Visualization of leukocyte recruitment was performed using intravital microscopy. Cells infiltration in the brain tissue were analyzed by flow cytometry. Brain was removed for chemokine assessment by ELISA and for histopathological analysis. The pharmacological inhibition by the PAFR antagonist UK-74,505 was also analyzed. In PAFR−/− mice, there was delayed lethality but no difference in viral load. Histopathological analysis of infected PAFR−/− mice showed that brain lesions were less severe when compared to their WT counterparts. Moreover, PAFR−/− mice showed less TCD4+, TCD8+ and macrophages in brain tissue. This reduction of the presence of leukocytes in parenchyma may be mechanistically explained by a decrease in leukocytes rolling and adhesion. PAFR−/− mice also presented a reduction of the chemokine CXCL9 in the brain. In addition, by antagonizing PAFR, survival of C57BL/6 infected mice increased. Altogether, our data suggest that PAFR plays a role in the pathogenesis of experimental HSV-1 meningoencephalitis, and its blockade prevents severe disease manifestation.
KW - Chemokines
KW - Encephalitis
KW - Herpes simplex virus-1
KW - PAFR
KW - PAFR antagonist ‘UK-74,505’
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U2 - 10.1007/s11481-016-9684-7
DO - 10.1007/s11481-016-9684-7
M3 - Article
C2 - 27193134
AN - SCOPUS:84969856066
SN - 1557-1890
VL - 11
SP - 613
EP - 621
JO - Journal of Neuroimmune Pharmacology
JF - Journal of Neuroimmune Pharmacology
IS - 4
ER -