MLKL‒OPTN axis regulates herpesvirus-induced neurological sequelae.

Area of Science:

• Neurovirology
• Molecular and Cellular Biology
• Immunology

Background:

• Herpes simplex virus-1 (HSV-1) infections are lifelong and implicated in neurological diseases like multiple sclerosis (MS).
• The precise mechanisms linking HSV-1 to neurological damage remain unclear.
• Understanding host-pathogen interactions is crucial for developing therapeutic strategies.

Purpose of the Study:

• To elucidate the molecular dynamics of HSV-1 infection and its impact on the host.
• To investigate the role of mixed lineage kinase domain-like (MLKL) protein beyond its known function in necroptosis.
• To explore the therapeutic potential of targeting the MLKL-Optineurin (OPTN) axis in HSV-1-induced neurological damage.

Main Methods:

• Investigated molecular dynamics following HSV-1 infection.
• Examined the interaction between MLKL and OPTN in regulating MLKL activity.
• Utilized Optn knockout mice to study the in vivo role of the MLKL-OPTN axis.
• Assessed the therapeutic effects of the MLKL inhibitor Necrosulfonamide (NSA).

Main Results:

• Identified MLKL as a key regulator of HSV-1 nuclear transport, independent of its necroptotic function.
• Demonstrated a critical regulatory interaction between MLKL and OPTN, influencing MLKL activity in both necroptosis-dependent and independent pathways.
• Showcased that the MLKL-OPTN axis is vital for preventing oligodendrocyte death and demyelination in HSV-1 infected Optn knockout mice, mimicking MS.
• Necrosulfonamide (NSA) treatment preserved myelin integrity and reduced neurological deficits in HSV-1 infected models.

Conclusions:

• MLKL plays a significant role in HSV-1 pathogenesis, with its dysregulation contributing to severe neurological damage.
• The MLKL-OPTN axis is a critical factor in controlling HSV-1 infection, oligodendrocyte survival, and preventing demyelination.
• Targeting MLKL, particularly with inhibitors like NSA, offers a promising therapeutic strategy for managing HSV-1-induced neurodegeneration and demyelinating diseases.