Abstract

Herpes simplex virus type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE), a condition characterized by acute inflammation and viral replication in the brain. Host genetics contribute to HSE onset, including monogenic defects in type I interferon signaling in cases of childhood HSE. Mouse models suggest a further contribution of immune cell-mediated inflammation to HSE pathogenesis. We have previously described a truncating mutation in the c-Rel transcription factor (RelC307X) that drives lethal HSE in 60% of HSV-1-infected RelC307X mice. In this study, we combined dual host-virus RNA sequencing with flow cytometry to explore cell populations and mechanisms involved in RelC307X-driven HSE. At day 5 postinfection, prior to HSE clinical symptom onset, elevated HSV-1 transcription was detected together with augmented host interferon-stimulated and inflammatory gene expression in the brainstems of high-responding RelC307X mice, predictive of HSE development. This early induction of host gene expression preceded pathological infiltration of myeloid and T cells in RelC307X mice at HSE onset by day 7. Thus, we establish c-Rel as an early regulator of viral and host responses during mouse HSE. These data further highlight the importance of achieving a balanced immune response and avoiding excess interferon-driven inflammation to promote HSE resistance.

Highlights

  • Herpes simplex virus type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE), a condition characterized by acute inflammation and viral replication in the brain

  • We have previously demonstrated that RelC307X mutant mice are susceptible to HSE, where over half of RelC307X mice exhibit high viral titers and reach clinical endpoint between days 6 to 9 post-HSV-1 infection, compared to resistant Rel+/+ ­littermates[29]

  • We focused on the brainstem, which during experimental mouse HSE is a well-characterized site of viral replication and contains varied resident and infiltrating hematopoietic cell types at the height of the ­disease[29,30]; in our model, wild-type c-Rel protein expression was detected in resident microglia and neurons as well as infiltrating lymphocytes and myeloid cells, both at steady-state and at day 5 post-HSV-1 infection (Supplementary Fig. 1)

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Summary

Introduction

Herpes simplex virus type 1 (HSV-1) is the predominant cause of herpes simplex encephalitis (HSE), a condition characterized by acute inflammation and viral replication in the brain. At day 5 postinfection, prior to HSE clinical symptom onset, elevated HSV-1 transcription was detected together with augmented host interferonstimulated and inflammatory gene expression in the brainstems of high-responding RelC307X mice, predictive of HSE development. Genetic factors are known to contribute to HSE onset and severity in children, namely, single gene defects in the Toll-like receptor 3 (TLR3) cascade including TLR3, UNC93B1, TRIF, TRAF3, TBK1, IRF3 and IFNAR15–11 These mutations result in defective type I interferon (IFN) production, where for example TLR3 deficient patient-derived neurons and oligodendrocytes exhibit compromised cell-intrinsic control of HSV-1 i­nfection[12]. Excessive IFN-mediated responses can be detrimental in the brain and underlie various interferonopathies in mice and h­ umans[17,18] This tightly regulated balance between beneficial and damaging host responses has been further explored in the context of the immune cell-mediated response to mouse HSE. Defects in c-Rel-dependent regulation of infiltrating immune cells and of brain-resident cells, together, lead to increased viral load, neuroinflammation, and caspase-3-dependent cell death in moribund RelC307X mice

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