Delayed but Not Early Glucocorticoid Treatment Protects the Host during Experimental Herpes Simplex Virus Encephalitis in Mice

Sergerie, Yan; Boivin, Guy; Gosselin, David; Rivest, Serge

doi:10.1086/511987

Cited by 70 publications

(54 citation statements)

References 30 publications

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“…Taken together, these data suggest that HSV infection detected by TLR2 resulted in an immoderate cytokine response that had lethal consequences for the host, although this is usually a protective mechanism. These studies support the concept advanced by several investigators that the inflammatory response may exacerbate pathology in HSV encephalitis (Sergerie et al, 2007;Fitch and van de Beek, 2008;Lundberg et al, 2008). Perhaps the ancient sentinels of the body have not received the benefits of evolutionary refinement from the 'double-edged sword' of TLR2 activation in response to virus infection.…”

Section: Hsv and Tlr2supporting

confidence: 83%

Herpesviral infection and Toll-like receptor 2

Cai

Zheng

2012

Protein Cell

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In the last decade, substantial progress has been made in understanding the molecular mechanisms involved in the initial host responses to viral infections. Herpesviral infections can provoke an inflammatory cytokine response, however, the innate pathogen-sensing mechanisms that transduce the signal for this response are poorly understood. In recent years, it has become increasingly evident that the Toll-like receptors (TLRs), which are germline-encoded pattern recognition receptors (PRRs), function as potent sensors for infection. TLRs can induce the activation of the innate immunity by recruiting specific intracellular adaptor proteins to initiate signaling pathways, which then culminating in activation of the nuclear factor kappa B (NF-κB) and interferon-regulatory factors (IRFs) that control the transcription of genes encoding type I interferon (IFN I) and other inflammatory cytokines. Furthermore, activation of innate immunity is critical for mounting adaptive immune responses. In parallel, common mechanisms used by viruses to counteract TLR-mediated responses or to actively subvert these pathways that block recognition and signaling through TLRs for their own benefit are emerging. Recent findings have demonstrated that TLR2 plays a crucial role in initiating the inflammatory process, and surprisingly that the response TLR2 triggers might be overzealous in its attempt to counter the attack by the virus. In this review, we summarize and discuss the recent advances about the specific role of TLR2 in triggering inflammatory responses in herpesvirus infection and the consequences of the alarms raised in the host that they are assigned to protect.

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Section: Hsv and Tlr2supporting

confidence: 83%

Herpesviral infection and Toll-like receptor 2

Cai

Zheng

2012

Protein Cell

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“…A previous report demonstrated that dexamethasone completely inhibits cytokine production after a peripheral challenge with lipopolysaccharide (Teeling et al 2010). Delayed but not early glucocorticoid treatment has also been shown to protects the host, increase survival and decrease cerebral damage during experimental herpes simplex virus encephalitis in mice (Sergerie et al 2007). Because delayed administration of glucocorticoids reduced death and disease severity after serial AED it is reasonable to suggest that the cytokine storm previously observed in secondary DENV infection (Rothman 2009, Guabiraba et al 2010, Tan et al 2010 and AED (Balsitis et al 2010) may be inhibited by corticoids (Sergerie et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Environmental influences on antibody-enhanced dengue disease outcomes

Diniz

Fôro

Turiel³

et al. 2012

Mem. Inst. Oswaldo Cruz

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Because an enriched environment (EE) enhances T-cell activity and T-lymphocytes contribute to immunopathogenesis during heterologous dengue virus (DENV) infections, we hypothesised that an EE increases dengue severity. To compare single serotype (SS) and antibody-enhanced disease (AED) infections regimens, serial intraperitoneal were performed with DENV3 (genotype III) infected brain homogenate or anti-DENV2 hyperimmune serum followed 24 h later by DENV3 (genotype III) infected brain homogenate. Compared AED for which significant differences were detected between the EE and impoverished environmental (IE) groups (Kaplan-Meyer log-rank test, p = 0.0025), no significant differences were detected between the SS experimental groups (Kaplan-Meyer log-rank test, p = 0.089). Survival curves from EE and IE animals infected with the AED regimen were extended after corticoid injection and this effect was greater in the EE than in the IE group (Kaplan-Meyer log-rank test, p = 0.0162). Under the AED regimen the EE group showed more intense clinical signs than the IE group. Dyspnoea, tremor, hunched posture, ruffled fur, immobility, pre-terminal paralysis, shock and death were associated with dominant T-lymphocytic hyperplasia and presence of viral antigens in the liver and lungs. We propose that the increased expansion of these memory T-cells and serotype cross-reactive antibodies facilitates the infection of these cells by DENV and that these events correlate with disease severity in an EE

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“…Additionally, it has been reported that corticosteroid treatment does not increase HSV-1 replication and dissemination in a rat model of focal encephalitis (47). However, it was recently reported that the timing of treatment with immunosuppressive steroids is critical (42), consistent with a balanced immune response being required for survival. These results, demonstrating a beneficial effect of combined ACV and corticosteroid therapy over ACV therapy alone, are consistent with host immune responses to HSV-1 being a significant cause of longterm MRI abnormalities in the brain (29,35,47).…”

Section: Discussionmentioning

confidence: 99%

The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis

Lundberg¹,

Ramakrishna²,

Brown

et al. 2008

J Virol

116

114

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Herpes simplex virus type 1 (HSV-1) infections are widespread in developed countries, with estimates of seropositivity exceeding 50% (54). Primary infections in immunocompetent individuals are usually mild or even asymptomatic and result in lifelong latent infections in sensory ganglia and the central nervous system (CNS) (5). Reactivated HSV-1 can result in recurrent diseases of mucous membranes (e.g., gingivostomatitis and herpes labialis) and herpes keratitis, an immunopathological disease that is a leading cause of blindness (39). Also, HSV-1 is the most common cause of fatal, sporadic encephalitis in immunocompetent individuals (40, 56). Improvements in diagnosis and antiviral drug treatment have dramatically reduced the morbidity and mortality of HSV-1 encephalitis (HSE) (55), although some patients fail to respond or subsequently suffer neurological relapses after completing a standard treatment course (18,55).Clinical and animal model studies have clearly demonstrated the importance of genetic makeup in resistance to a broad range of infectious agents (15,41). In regard to HSV-1, C57BL/6 (B6) and related B10 mouse strains are resistant, while other strains, such A/J, BALB/c, 129S6 (129), and DBA/ 2J, are susceptible to fatal infections (21,23,25). In these animal models, mortality results from CNS infection. In prior studies, we defined the herpes resistance locus (Hrl) on mouse chromosome 6 as a major determinant of resistance (22, 25); however, ongoing studies indicate that resistance to HSE is genetically very complex, involving multiple interacting loci, with tumor necrosis factor playing a critical role (26) (unpublished results). The mechanism by which HSV-1 CNS infection causes death has not been defined. Counterintuitively, necropsy virus titers of nervous system tissues do not correlate with mouse resistance or susceptibility genotype (25,26). These and other observations have led to the suggestion that variation of the host inflammatory response may play a major role in determining HSV fatality. Intense inflammatory responses in CNS tissues in a mouse model of HSE have been reported, with tumor necrosis factor and macrophage chemoattractant protein 1 being expressed prominently (43). Also, in vitro and in vivo studies have shown that human and mouse microglia nonproductively infected with HSV-1 express a variety of proinflammatory cytokines and chemokines, consistent with their involvement in

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Delayed but Not Early Glucocorticoid Treatment Protects the Host during Experimental Herpes Simplex Virus Encephalitis in Mice

Abstract: Administration of GCs at a critical time during viral infection is associated with neuroprotection and survival in experimental HSV-1 encephalitis.

Cited by 70 publications

References 30 publications

Herpesviral infection and Toll-like receptor 2

Herpesviral infection and Toll-like receptor 2

Environmental influences on antibody-enhanced dengue disease outcomes

The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis

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