RIPK3 and caspase 8 collaborate to limit herpes simplex encephalitis

Area of Science:

• Neurovirology
• Immunology
• Cellular Biology

Background:

• Herpes simplex virus 1 (HSV1) infection of the brain can cause herpes simplex encephalitis (HSE), a severe condition with high morbidity and mortality.
• Programmed cell death pathways, including necroptosis, are crucial antiviral defenses against HSV1 in peripheral tissues.
• HSV1 protein ICP6 differentially affects necroptosis in human and murine cells, preventing it in human cells while inducing it in murine cells to restrict viral replication.

Purpose of the Study:

• To investigate the role of receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis in the neuropathogenesis of HSV1.
• To determine the impact of RIPK3 on HSE progression and viral replication in a mouse model.

Main Methods:

• Utilized a mouse model of herpes simplex encephalitis (HSE) following corneal inoculation with herpes simplex virus 1 (HSV1).
• Compared disease susceptibility and progression in RIPK3 knockout mice versus wildtype mice.
• Assessed the role of RIPK3's kinase domain and its signaling partner, caspase 8, in HSE pathogenesis.

Main Results:

• RIPK3 knockout mice exhibited increased susceptibility to HSE, indicating RIPK3 limits disease progression.
• RIPK3's protective function against HSE was independent of its kinase domain, suggesting a death-independent mechanism.
• RIPK3's kinase function, however, limited viral replication in corneal tissue, demonstrating tissue-specific roles.

Conclusions:

• RIPK3 plays a dual role in controlling HSV1 infection: restricting viral replication in the cornea via necroptosis and limiting brain pathology through a kinase-independent pathway.
• The kinase-independent RIPK3 function in the brain collaborates with caspase 8 to restrict HSE neuropathogenesis.
• Loss of RIPK3 or caspase 8 in mice correlated with reduced recruitment of antiviral lymphocytes and inflammatory mediators to the brain, impairing host defense.