The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis

Abstract

Newborns are significantly more susceptible to severe viral encephalitis than adults, with differences in the host response to infection implicated as a major factor. However, the specific host signaling pathways responsible for differences in susceptibility and neurologic morbidity have remained unknown. In a murine model of HSV encephalitis, we demonstrated that the choroid plexus (CP) is susceptible to herpes simplex virus 1 (HSV-1) early in infection of the newborn but not the adult brain. We confirmed susceptibility of the CP to HSV infection in a human case of newborn HSV encephalitis. We investigated components of the type I interferon (IFN) response in the murine brain that might account for differences in cell susceptibility and found that newborns have a dampened interferon response and significantly lower basal levels of the alpha/beta interferon (IFN-α/β) receptor (IFNAR) than do adults. To test the contribution of IFNAR to restricting infection from the CP, we infected IFNAR knockout (KO) adult mice, which showed restored CP susceptibility to HSV-1 infection in the adult. Furthermore, reduced IFNAR levels did not account for differences we found in the basal levels of several other innate signaling proteins in the wild-type newborn and the adult, including protein kinase R (PKR), that suggested specific regulation of innate immunity in the developing brain. Viral targeting of the CP, a region of the brain that plays a critical role in neurodevelopment, provides a link between newborn susceptibility to HSV and long-term neurologic morbidity among survivors of newborn HSV encephalitis.

Spontaneous activation of a MAVS-dependent antiviral signaling pathway determines high basal interferon-β expression in cardiac myocytes

“…High basal IFN in this cell type correlates with changes in abundance of components of the IFN signaling pathway during neuronal development and a concomitant increase in neuronal antiviral protection (28, 77, 100). The specific type I IFN subtypes expressed at higher basal levels in these neurons are, however, different from the ones expressed in cardiac myocytes (13, 54, 87).…”

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

“…The choroid plexus sits at the interface between the blood and the cerebral spinal fluid (CSF) and is perfectly situated to play a role in delivering virus to the CNS in extracellular vesicles PLOS PATHOGENS [31]. The choroid plexus is also known to play an important role in modulating immune responses in the CNS so it is reasonable to suspect that it could play a similar role in restricting viral growth under normal circumstances [25,31]. These functions may be partially disrupted in patients who are profoundly immunosuppressed or who are treated with immunomodulatory drugs.…”

“…The BCSFB separates the cerebrospinal fluid (CSF) from the peripheral blood and restricts the migration of both cells and microbes between the periphery, CSF, and brain [21]. The choroid plexus is also known to respond to inflammatory signals by relaying information between the blood and the brain using extracellular vesicles [22][23][24][25]. Extracellular vesicles derived from choroid plexus epithelial cells are capable of delivering specific cargo to distant sites within the CNS [26].…”

STING controls Herpes Simplex Virusin vivoindependent of type I interferon induction

“…S3a). Given that type I IFNs are essential for resistance to HSV-1 [46, 47], and that STING is required for type I IFN induction to HSV-1 [40-42, 48], we were surprised that S365A mice were not as susceptible to infection as Gt and ΔCTT mice. One possibility to explain this result is that S365A is not required for STING-dependent type I IFN induction in vivo .…”