PARP1 inhibition protects mice against Japanese encephalitis virus infection

Area of Science:

• Virology
• Neuroscience
• Immunology

Background:

• Japanese encephalitis (JE) is a severe vector-borne viral disease causing acute encephalitis, particularly in children.
• Current treatments for JE lack effective antiviral therapies, highlighting an unmet medical need.
• Japanese encephalitis virus (JEV) infection poses a significant global health challenge.

Purpose of the Study:

• To investigate the role of poly(ADP-ribose) polymerase 1 (PARP1) in JEV pathogenesis.
• To evaluate the therapeutic potential of PARP1 inhibition against JEV infection.
• To elucidate the molecular mechanisms underlying PARP1's involvement in JEV-induced encephalitis.

Main Methods:

• Utilized Neuro-2a cells and a mouse model of JEV infection.
• Administered small molecular PARP1 inhibitors (olaparib, 3-aminobenzamide) to infected mice.
• Assessed viral load, clinical signs, survival rates, and molecular pathways including autophagy, AKT, PTEN, and FoxO activity.

Main Results:

• PARP1 inhibition significantly reduced clinical symptoms, viral load in serum and brain, and improved survival in mice.
• PARP1 was identified as critical for JEV pathogenesis in both cellular and animal models.
• PARP1 inhibition conferred protection by suppressing autophagy, downregulating AKT phosphorylation, and reducing FoxO activity.

Conclusions:

• PARP1 plays a crucial role in the pathogenesis of Japanese encephalitis.
• Targeting PARP1 with inhibitors like olaparib or 3-AB demonstrates therapeutic promise for JE.
• Inhibition of PARP1 offers a novel strategy to combat JEV infection by modulating key cellular pathways.