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 10 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.

Of vascular defense, hemostasis, cancer, and platelet biology: an evolutionary perspective

“…Rolling platelet behavior is initiated by surface-level, multimeric GPIb-complex interactions with vWF that activate a key stabilization integrin α IIb β 3 [252][253][254][255] to bind a variety of RGD (arginine-glycine-aspartic acid)-containing ligands [252][253][254][255] including fibrin, fibrinogen, fibronectin, vitronectin, thrombospondin, or vWF complexes. Platelets also interact with hanta-and adenoviruses through α IIb β 3 receptors [94,98,[256][257][258][259][260]. Certain integrins bind to echo-and rotaviruses [261] while vitronectin is engaged by platelet α v β 3 integrin heterodimers that also bind to echovirus9; coxsackieviruses A9 and -A16; and hanta-, parecho-, and coronaviruses [98,256,257].…”

Insights into the pathogenesis of herpes simplex encephalitis from mouse models

“…The role of lymphangiogenesis is less clear in the brain of HSE-susceptible mice. However, both vascular permeability and lymphoid or myeloid cell CNS infiltration is reduced in platelet activating factor receptor-deficient ( Ptafr −/− ) mice, resulting in delayed mortality upon intracranial HSV-1 (Vilela et al 2016 ).…”