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)
Summary
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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
