Absence of CCR5 increases neutrophil recruitment in severe herpetic encephalitis

Vilela, Márcia Carvalho; Lima, Graciela Kunrath; Rodrigues, David Henrique; Lacerda-Queiroz, Norinne; Pedroso, Vinicius Sousa Pietra; Miranda, Aline Silva de; Kroon, Erna Geessien; Campos, Marco Antônio; Teixeira, Antônio Lúcio; Sellner, Johann

doi:10.1186/1471-2202-14-19

Cited by 19 publications

(12 citation statements)

References 39 publications

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“…Among herpes viruses, herpes simplex viruses (HSV-1, -2) are neurotropic viruses that cause encephalitis in newborns and immunocompromised humans. CCL5 was shown to be produced during herpetic encephalitis in mice and mediate T cell recruitment to the CNS [82]. Other reports demonstrate that CCL5 is upregulated in latently infected trigeminal ganglia, a major feature of HSV-1 infection, which results in the retention of T lymphocytes in neurons of both mice and humans and prevents viral reactivation [83].…”

Section: Neurotropic Infectionsmentioning

confidence: 99%

Targeting CCL5 in inflammation

Marques

Guabiraba²,

Russo

et al. 2013

Expert Opinion on Therapeutic Targets

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260

196

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Although clinical trials are strongly biased toward HIV treatment and prevention with blockers of CCR5, the therapeutic potential for CCL5 and its receptors in other diseases is relevant. Overall, it is not likely that specific targeting of CCL5 will result in new adjunct strategies for the treatment of infectious diseases with a major inflammatory component. However, targeting CCL5 could result in novel therapies for chronic inflammatory diseases, where it may decrease inflammatory responses and fibrosis, and certain solid tumors, where it may have a role in angiogenesis.

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Section: Neurotropic Infectionsmentioning

confidence: 99%

Targeting CCL5 in inflammation

Marques

Guabiraba²,

Russo

et al. 2013

Expert Opinion on Therapeutic Targets

Self Cite

260

196

View full text Add to dashboard Cite

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“…We have also demonstrated that chemokine-driven leukocyte recruitment into the brain of HSV-1 infected mice was associated with infectious outcome (Vilela et al 2008;Vilela et al 2009, Vilela et al 2010Vilela et al 2013).…”

Section: Discussionmentioning

confidence: 91%

Platelet Activating Factor (PAF) Receptor Deletion or Antagonism Attenuates Severe HSV-1 Meningoencephalitis

Vilela

Lima

Rodrigues

et al. 2016

J Neuroimmune Pharmacol

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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.

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“…Mice were treated with 0.2 mg trimethoprim and 1 mg sulfamethoxazole (SEPTRA, GlaxoSmithKline, Mississauga, Ontario, Canada) per mL of sterile water ad libitum started 1 week before and maintained for 2 weeks after transplantation. WT and CCR2 -/recipient mice were exposed to 10 Gy total body irradiation using a 60 Co source (Theratron-780; MDS Analytical Technologies, Concord, Ontario, Canada). Bone marrow cells from age-and sex-matched WT and CCR2 -/donor mice were aseptically harvested by flushing the femurs and tibias with Dulbecco's phosphate-buffered saline (DPBS) containing 1 g/L glucose and 36 mg/L sodium pyruvate and supplemented with 2% fetal bovine serum (FBS; Wisent, St-Bruno, Quebec, Canada).…”

Section: Irradiation and Bone Marrow Transplantationmentioning

confidence: 99%

“…In this respect, the increased mortality rates observed in CCR2-deficient mice and when deficiency affects hematopoietic cells, were associated with elevated inflammatory cytokines (IL-1β and IL-6) and chemokines (CCL2, CCL3 and CCL5) production in the brain compared to WT. Indeed, it has been already reported that chemokine receptors deficiency may result in increased inflammatory cytokines and chemokines production during CNS insults, which could increase brain damages as well as lethality [16,17,44,60]. Furthermore, the excessive production of chemokines, such as CCL2, CCL3 and CCL5, observed in the more susceptible groups could induce the recruitment of peripheral immune cells such as natural killer (NK) cells and T cells that in turn may contribute to amplify the global inflammation triggered by the virally-infected cells [11].…”

Section: Fig 6 Effects Of Ccr2 Deficiency In Resident Cells Of the Cmentioning

confidence: 99%

Both Cerebral and Hematopoietic Deficiencies in CCR2 Result in Uncontrolled Herpes Simplex Virus Infection of the Central Nervous System in Mice

et al. 2016

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CCR2 is a chemokine receptor expressed on the surface of blood leukocytes, particularly «Ly6Chi» inflammatory monocytes and microglia. Signaling through this receptor is thought to influence the immune activity of microglia as well as monocytes egress from the bone marrow (BM) and their trafficking into the central nervous system (CNS) in several neurological diseases. During experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE), CCR2 deficiency has been reported to exacerbate the outcome of the disease. However, the precise contribution of CCR2 expressed in cells of the CNS or peripheral monocytes in the protection against HSE remains unclear. To dissect the differential role of CCR2 during HSE, chimeric mice with receptor deficiency in the brain or blood cells were generated by transplanting wild-type (WT) C57BL/6 or CCR2-/- BM-derived cells in CCR2-/- (WT→CCR2-/-) and WT (CCR2-/-→WT) mice, respectively. Our results indicate that following intranasal infection with 1.2x106 plaque forming units of HSV-1, CCR2 deficiency in hematopoietic cells and, to a lesser extent, in CNS exacerbates the outcome of HSE. Mortality rates of CCR2-/- (71.4%) and CCR2-/-→WT (57.1%) mice were significantly higher than that of WT (15.3%; P<0.01 and P<0.05, respectively) but the difference did not reach statistical significance for WT→CCR2-/- animals (42.8%; P = 0.16). Both peripheral and CNS deficiencies in CCR2 resulted in increased infectious viral titers and wider dissemination of HSV antigens in the brain as well as an overproduction of inflammatory cytokines and chemokines including IL-1β, IL-6, CCL2, CCL3 and CCL5. Furthermore, CCR2 deficiency in the hematopoietic system altered monocytes egress from the BM and their recruitment to the CNS, which may contribute to the failure in HSV-1 containment. Collectively, these data suggest that CCR2 expressed on cells of CNS and especially on peripheral monocytes is important for the control of HSV-1 replication and inflammatory environment during experimental HSE.

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Absence of CCR5 increases neutrophil recruitment in severe herpetic encephalitis

Cited by 19 publications

References 39 publications

Targeting CCL5 in inflammation

Targeting CCL5 in inflammation

Platelet Activating Factor (PAF) Receptor Deletion or Antagonism Attenuates Severe HSV-1 Meningoencephalitis

Both Cerebral and Hematopoietic Deficiencies in CCR2 Result in Uncontrolled Herpes Simplex Virus Infection of the Central Nervous System in Mice

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