Herpesvirus hominis Infection in Newborn Mice. I. An Experimental Model and Therapy with Iododeoxyuridine

Kern, Earl R.; Overall, James C.; Glasgow, Lowell A.

doi:10.1093/infdis/128.3.290

Cited by 97 publications

(55 citation statements)

References 32 publications

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“…Systemic dissemination, which we and others have observed in mouse models after i.n. inoculation (35,36), is likely secondary to hematogenous spread of virus. Although our model of systemic infection demonstrated that nectin-1 is not required for disease and viral spread, the delay in mortality in newborn nectin-1 KO mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis of Neonatal Herpes Simplex 2 Disease in a Mouse Model Is Dependent on Entry Receptor Expression and Route of Inoculation

Kopp

Karaba

Cohen

et al. 2013

J Virol

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cHerpes simplex virus (HSV) pathogenesis in mice differs based on availability of the principal entry receptors herpesvirus entry mediator (HVEM) and nectin-1 in a manner dependent upon route of inoculation. After intravaginal or intracranial inoculation of adult mice, nectin-1 is a major mediator of neurologic disease, while the absence of either receptor attenuates disease after ocular infection. We tested the importance of receptor availability and route of infection on disease in mouse models of neonatal HSV. We infected 7-day-old mice lacking neither or one principal HSV receptor or both principal HSV receptors with HSV-2 via a peripheral route (intranasal), via a systemic route (intraperitoneal), or by inoculation directly into the central nervous system (intracranial). Mortality, neurologic disease, and visceral dissemination of virus were significantly attenuated in nectin-1 knockout mice compared with HVEM knockout or wild-type mice after intranasal inoculation. Mice lacking both entry receptors (double-knockout mice) showed no evidence of disease after inoculation by any route. Nectin-1 knockout mice had delayed mortality after intraperitoneal inoculation relative to wild-type and HVEM knockout mice, but virus was able to spread to the brain and viscera in all genotypes except double-knockout mice. Unlike in adult mice, HVEM was sufficient to mediate disease in neonatal mice after direct intracranial inoculation, and the absence of HVEM delayed time to mortality relative to that of wild-type mice. Additionally, in wild-type neonatal mice inoculated intracranially, HSV antigen did not primarily colocalize with NeuNpositive neurons. Our results suggest that differences in receptor expression between adults and newborns may partially explain differences in susceptibility to HSV-2. H erpes simplex virus (HSV) causes neonatal infection in about 1 in 3,200 live births in the United States (1). More than half of infants with neonatal HSV disease have disseminated disease or encephalitis (2), which, despite effective antiviral treatment, results in the deaths of more than 25% of those with disseminated disease and in neurologic morbidity in more than two-thirds of survivors of encephalitis (3). Relative to other populations infected with HSV, newborns have the highest rates of dissemination and central nervous system (CNS) disease (4). Although differences in immune responses from those of adults have been implicated, precise reasons for the increased severity of disease in infants remain unknown (5).Infection of susceptible human and mouse cells by HSV requires binding of the viral glycoprotein gD with one of its cell surface receptors (6, 7). HSV gD binds to three general classes of surface receptors, including herpesvirus entry mediator (HVEM), nectin-1 and Ϫ2, and specific sites in heparan sulfate (7). Of these, HVEM and nectin-1 appear to mediate viral entry most efficiently in both humans and mice (8, 9). The mouse receptors are orthologous to the human receptors, and HSV disease in mice resembles that i...

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Section: Discussionmentioning

confidence: 99%

Pathogenesis of Neonatal Herpes Simplex 2 Disease in a Mouse Model Is Dependent on Entry Receptor Expression and Route of Inoculation

Kopp

Karaba

Cohen

et al. 2013

J Virol

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“…Previous studies of neonatal HSV infection by ourselves and others have used oral, nasal or i.p. routes of inoculation [18,21,22]. In this study, we infected mice s.c. because oral and intranasal infection result in antigen being distributed to multiple LN groups [23] (Evans and Jones, unpublished observations).…”

Section: Introductionmentioning

confidence: 99%

HSV induces an early primary Th1 CD4 T cell response in neonatal mice, but reduced CTL activity at the time of the peak adult response

Evans

Jones

2005

Eur J Immunol

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Neonates are highly susceptible to HSV. In this study, we analyzed the primary neonatal cell-mediated response to HSV at the site of T cell activation, the draining lymph nodes (LN), and examined the effects of dose and the ability of HSV to replicate on the strength and character of this response. Neonatal mice mounted a predominantly Th1 cytokine (IFN-c) response at all doses of a replication-competent thymidine kinase-negative HSV-2 strain (186DKpn) and at high doses of a replication-defective HSV-2 virus (dl5-29, UL5-/UL29 -). Both neonates and adults showed increased production of Th2 cytokines (IL-4 and/or IL-5) at high doses of the replication-defective or inactivated HSV strains. An age-dependent difference in the strength of the Th1 response was noted, with neonates mounting adult-like responses at low but not high doses of HSV. Neonatal mice also showed impaired CD8 + T cell activation and reduced HSV-specific CTL effector function at the time of the peak adult response. These studies are the first to highlight the impaired primary neonatal T cell response to HSV in the LN.

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“…Although haematogenous spread of virus has been reported, particularly in young animals (Johnson, 1964;Kern et al, 1973;Lascano & Berria, 1980) this route does not appear to be of major importance in experimental or natural infection with HSV. Nevertheless, intravenous inoculation of inactivated or thymidine kinase (TK)-deficient virus has been used experimentally to induce 'split tolerance" [suppression of delayed-type hypersensitivity to HSV (Nash et al, 1981;Altmann & Blyth, 1985)].…”

Section: Introductionmentioning

confidence: 99%

Infection of the Adrenal Gland as a Route to the Central Nervous System after Viraemia with Herpes Simplex Virus in the Mouse

Hill¹,

Yirrell²,

Blyth³

1986

Journal of General Virology

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SUMMARYIntravenous inoculation of 4-week-old female NIH (inbred) mice with herpes simplex virus type 1 (HSV-1) strain P2C6 (defective in thymidine kinase) produced bilateral hind limb paralysis in nearly all animals by the 5th day after inoculation; very few mice died. In male mice the incidence and severity of paralysis was considerably lower than in females. The parental strain, CL(101), produced similar paralysis but all mice died by day 7. Observations on paralysis and death after intravenous inoculation are given for other strains of HSV-1 and HSV-2. By day 1 after inoculation of P2C6 significant virus replication had occurred in the adrenal glands but in none of the other organs tested. Titres of virus were similar in the adrenal glands of male and female mice. Histology of the adrenals showed most extensive replication in the cortex with some involvement of the medulla, particularly at the corticomedullary junction. By the 2nd and 3rd days, virus was detected in the lower thoracic spinal cord of both male and female animals but clearance was possibly quicker from males. Adrenalectomy proved that virus reached the cord via the adrenals. In the cord the infection was associated with bilateral demyelination in the ventral white matter as early as day 3.

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Herpesvirus hominis Infection in Newborn Mice. I. An Experimental Model and Therapy with Iododeoxyuridine

Cited by 97 publications

References 32 publications

Pathogenesis of Neonatal Herpes Simplex 2 Disease in a Mouse Model Is Dependent on Entry Receptor Expression and Route of Inoculation

Pathogenesis of Neonatal Herpes Simplex 2 Disease in a Mouse Model Is Dependent on Entry Receptor Expression and Route of Inoculation

HSV induces an early primary Th1 CD4 T cell response in neonatal mice, but reduced CTL activity at the time of the peak adult response

Infection of the Adrenal Gland as a Route to the Central Nervous System after Viraemia with Herpes Simplex Virus in the Mouse

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