The Innate Immune Response to Herpes Simplex Virus 1 Infection Is Dampened in the Newborn Brain and Can Be Modulated by Exogenous Interferon Beta To Improve Survival

Abstract

Newborns are particularly susceptible to severe forms of herpes simplex virus 1 (HSV-1) infection, including encephalitis and multisystemic disseminated disease. The underlying age-dependent differences in the immune response that explain this increased susceptibility relative to the adult population remain largely understudied. Using a murine model of HSV-1 infection, we found that newborn mice are largely susceptible to intracranial and intraperitoneal challenge while adult mice are highly resistant. This age-dependent difference correlated with differential basal-level expression of components of innate immune signaling pathways, which resulted in dampened interferon (IFN) signaling in the newborn brain. To explore the possibility of modulating the IFN response in the newborn brain to recapitulate the adult phenotype, we administered exogenous IFN-β in the context of disseminated HSV-1 infection. IFN-β treatment resulted in significantly increased survival and delayed viral neuroinvasion in the newborn. These effects were associated with changes in the type I IFN response in the brain, reduced viral replication in the periphery, and the stabilization of the blood-brain barrier (BBB). Our study reveals important age-dependent differences in the innate immune response to HSV-1 infection and suggests a contribution of the BBB and the brain parenchyma in mediating the increased susceptibility to HSV-1 infection observed in the newborn. These results could provide the basis for potential new therapeutic strategies for life-threatening HSV-1 infection in newborns. IMPORTANCE Herpes simplex virus (HSV) is a ubiquitous human pathogen affecting 50 to 80% of the population in North America and Europe. HSV infection is commonly asymptomatic in the adult population but can result in fatal encephalitis in the newborn. Current treatment with acyclovir has improved mortality in the newborn; however, severe neurologic sequelae are still a major concern following HSV encephalitis. For this reason, there is a critical need to better understand the underlying differences in the immune response between the two age groups that could be used to develop more effective treatments. In this study, we investigated differences in the innate immune response to viral infection in the brains of newborn and adult mice. We found that, similar to humans, newborn mice are more susceptible to HSV infection than the adult. Increased susceptibility was associated with dampened innate immune responses in the newborn brain that could be rescued by administering interferon beta.

Inhibition of Herpes Simplex Virus Type 1 Attachment and Infection by Sulfated Polyglycerols with Different Architectures

“…The acetal protection of glycidol (1) was performed according to a previously reported protocol, 36 and two other monomers (6 and 10) were synthesized from the modification of solketal ( 5) and firstgeneration of dendritic PG (9) based on a slightly modified protocol for similar compounds, respectively (Figures S1− S3). 37 After polymerization, the acetal groups were deprotected to hydroxy groups in a slightly acidic environment (2,5,8). 36 The removal of acetal-protecting groups was monitored via 1 H NMR where the corresponding δ shift values at around 1.30 and 1.14 ppm disappeared.…”

“…The virus is known to establish a lifelong infection in the sensory neurons of the host, out of which it can periodically recrudesce by different stimuli such as stress, local trauma, or specific bacterial infections. − HSV-1 often causes oral and pharyngeal infection, while its close relative, HSV-2, primarily targets the genital tract . Although HSV-1 infection is usually mild and locally confined, HSV-1 is the main cause of encephalitis in newborns and immunocompromised patients, and recent studies suggest a role of HSV-1 infection in dementia and neurodegenerative diseases like Alzheimer’s disease . At the late stages of infection, it can lead to keratitis or permanent infectious blindness. , …”

Organoid modeling of Zika and herpes simplex virus 1 infections reveals virus-specific responses leading to microcephaly

“…More intriguing is the poor antiviral activity of IFNb against HSV-1 because this effect could be specific to the brain. In fact, IFNb potently inhibits HSV-1 replication in other cells and in mice (Arao et al, 1997;Carr et al, 2003;Giraldo et al, 2020;H€ arle et al, 2001). Our pre-and post-treatment IFNb experiments with WT and ICP34.5-null HSV-1 viruses indicate that HSV-1 selectively neutralizes IFNb action, in line with the well-described ability of HSV-1 to evade IFN-I signaling (Danastas et al, 2020).…”

Is Short-Term Acyclovir Treatment Related With More Unfavourable Outcomes in Patients With HSV-1 Encephalitis?

“…Additionally, Acyclovir doesn’t have an inhibitor effect on the replication of the HSV-1 in human neural cell lines without human interferon-alpha (IFN-alpha) 14 . IFN-β treatment in baby mice with HSV encephalitis model decreased neuro-invasion and increase the survival rate 15 . We may conclude that the combined effect of Acyclovir implementation and host interferon response can be achieved only at the early days of the HSE.…”