title: Platelet Activating Factor (PAF) Receptor Deletion or Antagonism Attenuates Severe HSV-1 Meningoencephalitis.
abstract: 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 104plaque-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.
authors.affiliation: Laboratório Interdisciplinar de Investigação Médica, Sala 281, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), 30130-100 Av. Alfredo Balena, 190. Santa Efigênia, Belo Horizonte, MG, Brazil. marciacvilela@gmail.com.|Departamento de Ciências Básicas da Vida, Universidade Federal de Juiz de Fora, Governador Valadares, MG, Brazil. marciacvilela@gmail.com.
authors.forename: Márcia Carvalho
authors.initials: MC
authors.lastname: Vilela
authors.affiliation: Departamento de Microbiologia, ICB/UFMG, Belo Horizonte, Brazil.
authors.forename: Graciela Kunrath
authors.initials: GK
authors.lastname: Lima
authors.affiliation: Laboratório Interdisciplinar de Investigação Médica, Sala 281, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), 30130-100 Av. Alfredo Balena, 190. Santa Efigênia, Belo Horizonte, MG, Brazil.|Departamento de Ciências Básicas da Vida, Universidade Federal de Juiz de Fora, Governador Valadares, MG, Brazil.
authors.forename: David Henrique
authors.initials: DH
authors.lastname: Rodrigues
authors.affiliation: Laboratório Interdisciplinar de Investigação Médica, Sala 281, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), 30130-100 Av. Alfredo Balena, 190. Santa Efigênia, Belo Horizonte, MG, Brazil.
authors.forename: Norinne
authors.initials: N
authors.lastname: Lacerda-Queiroz
authors.affiliation: Laboratório Interdisciplinar de Investigação Médica, Sala 281, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), 30130-100 Av. Alfredo Balena, 190. Santa Efigênia, Belo Horizonte, MG, Brazil.
authors.forename: Vinicius Sousa Pietra
authors.initials: VS
authors.lastname: Pedroso
authors.affiliation: Laboratório Interdisciplinar de Investigação Médica, Sala 281, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), 30130-100 Av. Alfredo Balena, 190. Santa Efigênia, Belo Horizonte, MG, Brazil.|Departamento de Morfologia, ICB/UFMG, Belo Horizonte, Brazil.
authors.forename: Aline Silva
authors.initials: AS
authors.lastname: de Miranda
authors.affiliation: Laboratório Interdisciplinar de Investigação Médica, Sala 281, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), 30130-100 Av. Alfredo Balena, 190. Santa Efigênia, Belo Horizonte, MG, Brazil.|Departamento de Patologia Geral, ICB/UFMG, Belo Horizonte, Brazil.
authors.forename: Milene Alvarenga
authors.initials: MA
authors.lastname: Rachid
authors.affiliation: Departamento de Microbiologia, ICB/UFMG, Belo Horizonte, Brazil.
authors.forename: Erna Geessien
authors.initials: EG
authors.lastname: Kroon
authors.affiliation: Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil.
authors.forename: Marco Antônio
authors.initials: MA
authors.lastname: Campos
authors.affiliation: Laboratório Interdisciplinar de Investigação Médica, Sala 281, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), 30130-100 Av. Alfredo Balena, 190. Santa Efigênia, Belo Horizonte, MG, Brazil.
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: Laboratório Interdisciplinar de Investigação Médica, Sala 281, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), 30130-100 Av. Alfredo Balena, 190. Santa Efigênia, Belo Horizonte, MG, Brazil. altexjr@hotmail.com.
authors.forename: Antonio Lucio
authors.initials: AL
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use; D006561:Herpes Simplex / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018259:Herpesvirus 1, Human; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008590:Meningoencephalitis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000172:deficiency*; D012720:Severity of Illness Index
chemical_list: D004095:Dihydropyridines; D007093:Imidazoles; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C073027:modipafant
keywords: Chemokines; Encephalitis; Herpes simplex virus-1; PAFR; PAFR antagonist ‘UK-74,505’