Absence of CXCL10 Aggravates Herpes Stromal Keratitis with Reduced Primary Neutrophil Influx in Mice

Shen, Fang; Wang, Shainn Wei; Yeh, Trai Ming; Tung, Yuk Ying; Hsu, Sheng Min; Chen, Shun Hua

doi:10.1128/jvi.01198-13

Cited by 30 publications

(36 citation statements)

References 47 publications

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“…Mouse eyes, TG, and brain stems were processed and assayed as described in our previous reports (40,41), using antibodies against mouse CD4 (clone GK1.5; eBioscience) or CD8a (clone 53-6.7; eBioscience).…”

Section: Methodsmentioning

confidence: 99%

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Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

Huang

Yao

Wang

et al. 2017

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484 -490, 1994, https://doi.org/10.1006/viro .1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30-to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1.IMPORTANCE Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drugresistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised patients with persistent infection. However, answers to the questions as to whether TKnegative (TK Ϫ ) HSV-1 can establish persistent infection in brains of immunocompromised hosts and whether neurons in vivo are permissive for TK Ϫ HSV-1 remain elusive. Using three genetically engineered HSV-1 TK Ϫ mutants and two strains of nude mice deficient in T cells, we found that all three HSV-1 TK Ϫ mutants can efficiently establish persistent infection in the brain stem and trigeminal ganglion and detected glycoprotein C, a true late viral antigen, in brainstem neurons. Our study provides evidence that TK Ϫ HSV-1 can persist in neural tissues and replicate in brain neurons of immunocompromised hosts.

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Section: Methodsmentioning

confidence: 99%

“…Mouse brain stems were processed and stained as described in our previous reports (40,42), using Hoechst dye for DNA and antibodies against HSV-1 (Dako), HSV-1 glycoprotein C (clone 3G9; Abcam), or mouse NeuN (clone A60; Millipore).…”

Section: Methodsmentioning

confidence: 99%

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

Huang

Yao

Wang

et al. 2017

J Virol

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“…Male ICR mice were infected with 1 ϫ 10 5 PFU/eye of 294.1, treated with TCP on the cornea immediately before infection and by intraperitoneal injection 1 day before infection to day 10 p.i., and monitored for body weight and survival. Female C57BL/6N mice were infected with 5 ϫ 10 5 PFU/eye of RE, treated with TCP on the cornea immediately before infection and by intraperitoneal injection 1 day before infection to day 9 p.i., and monitored for corneal opacity and angiogenesis as described in our previous reports (37,40). The corneal opacity was graded on a scale of 0 to 5 as follows: 0, normal cornea; 1, mild corneal haze; 2, moderate corneal opacity or scarring; 3, severe corneal opacity, iris visible; 4, opaque cornea, iris invisible; and 5, necrotizing cornea with vascularization.…”

Section: Cells and Virusesmentioning

confidence: 99%

“…We tested the effect of TCP treatment on reducing the severity of HSV-1-induced stromal keratitis. C57BL/6N mice were corneally infected with wild-type HSV-1 strain RE, which can induce stromal keratitis to result in corneal blindness in mice (37,40). Infected mice were treated with saline or TCP on the cornea immediately before infection and by intraperitoneal injection from 1 day before infection to day 9 p.i.…”

Section: Tcp Treatment Reduces the Titers Of Wild-type And Thymidine mentioning

confidence: 99%

Tranylcypromine Reduces Herpes Simplex Virus 1 Infection in Mice

Yao

Lin

Shen

et al. 2014

Antimicrob Agents Chemother

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Herpes simplex virus 1 (HSV-1) infects the majority of the human population and establishes latency by maintaining viral genomes in neurons of sensory ganglia. Latent virus can undergo reactivation to cause recurrent infection. Both primary and recurrent infections can cause devastating diseases, including encephalitis and corneal blindness. Acyclovir is used to treat patients, but virus resistance to acyclovir is frequently reported. Recent in vitro findings reveal that pretreatment of cells with tranylcypromine (TCP), a drug widely used in the clinic to treat neurological disorders, restrains HSV-1 gene transcription by inhibiting the histone-modifying enzyme lysine-specific demethylase 1. The present study was designed to examine the anti-HSV-1 efficacy of TCP in vivo because of the paucity of reports on this issue. Using the murine model, we found that TCP decreased the severity of wild-type-virus-induced encephalitis and corneal blindness, infection with the acyclovir-resistant (thymidine kinase-negative) HSV-1 mutant, and tissue viral loads. Additionally, TCP blocked in vivo viral reactivation in trigeminal ganglia. These results support the therapeutic potential of TCP for controlling HSV-1 infection.

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“…Furthermore, CXCL10 has been found to be expressed by human limbal epithelial progenitor cells 78 , while its absence decreased the level of IL-6 in mice corneas 79 . During wound healing, TGFB1 is highly expressed and it can induce VEGF expression which was also up-regulated in the LESCs, capable of provoking angiogenesis in a damaged tissue 80,81 .…”

Section: Discussionmentioning

confidence: 99%

Genomic and proteomic characterization of physiological and pathological angiogenesis in the human eye

Zoltán¹

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Absence of CXCL10 Aggravates Herpes Stromal Keratitis with Reduced Primary Neutrophil Influx in Mice

Cited by 30 publications

References 47 publications

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

Tranylcypromine Reduces Herpes Simplex Virus 1 Infection in Mice

Genomic and proteomic characterization of physiological and pathological angiogenesis in the human eye

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