Tumor Necrosis Factor Alpha and Interleukin-6 Facilitate Corneal Lymphangiogenesis in Response to Herpes Simplex Virus 1 Infection

Bryant-Hudson, Katie M.; Gurung, Hem R.; Zheng, Min; Carr, Daniel J.J.

doi:10.1128/jvi.01841-14

Cited by 44 publications

(36 citation statements)

References 30 publications

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“…As the major pro-inflammatory cytokines in virus infection 33, 34 , serum TNF-α and IL-6 are good indicators of cytokine storm. Additionally, IL-1β, a pleiotropic cytokine 35 involved in both inflammation and innate immune response, was also determined.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Interferon-β and Inhibition of TLR3 Expression are associated with Fatal Outcome of Severe Fever with Thrombocytopenia Syndrome

Song

Zheng

Zhang

et al. 2017

Sci Rep

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Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease with high mortality and increasing prevalence in the East Asia. Though the etiological agent has been identified as a novel Bunyavirus, cellular mechanisms of viral pathogenesis and host immune response to SFTS virus infection remain unknown. A comprehensive study was conducted on a cohort of 70 patients on clinical manifestations, viral loads, modulation of cytokines, serum interferon level, immune related gene expression in peripheral blood cells, and dynamic changes of circulating dendritic cells during the acute phase of SFTSV infection. We found that high level viremia, reduced platelets, coagulation dysfunction, multi-organ injuries, elevated IL-6 and TNF-α were closely associated with the aggravation of SFTS. In addition, we demonstrated strong correlations between disease severity and the decline of serum IFN-β and IL-1β level, reduction of myeloid dendritic cells (mDCs) and suppressed Toll like receptor 3 expression in monocytes and mDCs. In general, dysfunction of innate immune response and cytokine storm are both involved in the pathogenesis of SFTS. Reduction of myeloid DCs contributes to the fatal outcome of SFTS virus infection, and the regulation of TLR3 could probably be the mechanism.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Interferon-β and Inhibition of TLR3 Expression are associated with Fatal Outcome of Severe Fever with Thrombocytopenia Syndrome

Song

Zheng

Zhang

et al. 2017

Sci Rep

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“…In addition to VEGF-A, VEGF-C released from CD8 + T cells infiltrating the infected corneas have also been shown to promote the invasion of lymphatic vessels into central cornea [98]. Lastly, pro-inflammatory cytokines like TNF-α and IL-6 potentiate the action of VEGF to promote virus induced lymphangiogenesis in infected corneas [109]. Additional studies are warranted to define the clinical significance of lymphangiogenesis in regulating HSK pathogenesis.…”

Section: Recent Developments In Understanding Viral Clearance Andmentioning

confidence: 99%

Challenges of corneal infections

Hazlett

Suvas

McClellan

et al. 2016

Expert Review of Ophthalmology

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Introduction Ocular infections remain an important cause of blindness worldwide and represent a challenging public health concern. In this regard, microbial keratitis due to fungal, bacterial, or viral infection can result in significant vision loss secondary to corneal scarring or surface irregularity. Left untreated corneal perforation and endophthalmitis can result, leading to loss of the eye. Rigorously studied animal models of disease pathogenesis have provided novel information that suggests new modes of treatment that may be efficacious clinically and emerging clinical data is supportive of some of these discoveries. Areas covered This review focuses on advances in our understanding of disease pathogenesis in animal models and clinical studies and how these relate to improved clinical treatment. We also discuss a novel approach to treatment of microbial keratitis due to infection with these bacterial pathogens using PACK-CXL and recommend increased basic and clinical studies to address and refine the efficacy of this procedure. Expert commentary Because resistance to antibiotics has developed over time to these bacterial pathogens, caution must be exercised in treatment. Attractive novel modes of treatment that hold new promise for further investigation include lipid based therapy, as well as use of small molecules that bind deleterious specific host responsive molecules and use of microRNA based therapies.

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“…Given that the different survival phenotypes arising in STING Ϫ/Ϫ and control mice following central or peripheral HSV-1 infection appeared to be independent of IFN synthesis, we hypothesized that a dysregulated immune response may be causing the pathology observed. A key early regulator that mediates corneal damage during HSV-1 infection is tumor necrosis factor alpha (TNF-␣) (48,49). Using real-time PCR, we measured TNF-␣ expression in corneas dissected from STING Ϫ/Ϫ and control mice infected with HSV-1 KOS on day 3 postinfection (Fig.…”

Section: Larly Infected Stingmentioning

confidence: 99%

Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1

Parker

Murphy

Leib

2015

J Virol

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STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING ؊/؊ ) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING ؊/؊ mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely lethal to STING ؊/؊ mice by the i.v. route. Corneally infected STING ؊/؊ mice also showed increased periocular disease and increased corneal and trigeminal ganglia titers, although there was no difference in brain titers. They also showed elevated expression of tumor necrosis factor alpha (TNF-␣) and CXCL9 relative to control mice but surprisingly modest changes in type I interferon expression. Finally, we also showed that HSV strains lacking the ability to counter autophagy and the PKR-driven antiviral state had near-wild-type virulence following intracerebral infection of STING ؊/؊ mice. Together, these data show that while STING is an important component of host resistance to HSV in the cornea, its previously shown immutable role in mediating host survival by the i.v. route was not recapitulated following a mucosal infection route. Furthermore, our data are consistent with the idea that HSV counters STING-mediated induction of the antiviral state and autophagy response, both of which are critical factors for survival following direct infection of the nervous system. Herpes simplex virus 1 (HSV-1) is a member of the Alphaherpesvirus subfamily with high seroprevalence in the human population (1). Infection at mucosal surfaces such as the mouth, eyes, and genitalia leads initially to lytic replication in mucosal epithelial cells, followed by infection of the innervating sensory neurons. HSV-1 then travels in a retrograde direction to the neuronal cell body, where it establishes latency. It is this ability to establish latency that renders HSV-1 refractory to clearance by the immune system, allowing persistence for the lifetime of the host. During periods of reactivation from latency, HSV-1 can travel in the anterograde direction to mucosal tissues, causing diseases ranging in severity from the common cold sore to herpetic stromal keratitis (HSK), the most common cause of infectious blindness in the developed world (2). HSV-1 can also gain entry into the central nervous system (CNS) to cause herpes simplex encephalitis (HSE) (3). HSE is a leading cause of viral encephalitis, further underscoring the significant morbidity and mortality associated with HSV-1.In order to effectively respond to infection, host cells have evolved a broad spectrum of sensors of evolutionarily conserved pathogen-associated molecular patterns (PAMPS) (for reviews, see refer...

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Tumor Necrosis Factor Alpha and Interleukin-6 Facilitate Corneal Lymphangiogenesis in Response to Herpes Simplex Virus 1 Infection

Cited by 44 publications

References 30 publications

Downregulation of Interferon-β and Inhibition of TLR3 Expression are associated with Fatal Outcome of Severe Fever with Thrombocytopenia Syndrome

Downregulation of Interferon-β and Inhibition of TLR3 Expression are associated with Fatal Outcome of Severe Fever with Thrombocytopenia Syndrome

Challenges of corneal infections

Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1

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