The Hao-Fountain syndrome gene USP7 restricts neurotropic orthoflavivirus entry through cell intrinsic control of endosomal dynamics

Neurodevelopmental disorders are linked to immune system abnormalities, such as autoinflammation, weakened immune response, and heightened infection risk. To investigate if genes tied to neurodevelopmental disorders have immune functions, researchers conducted a siRNA screen on 28 genes, each with distinct cellular roles. The screen revealed certain genes that impede Zika virus (ZIKV) infection and influence inflammatory responses upon infection.

Among these, the Hao-Fountain syndrome gene USP7 stood out for its strong ability to limit selected neurotropic orthoflaviviruses. USP7 works by preventing ZIKV entry into cells before the virus fuses with the cell membrane and releases its genetic material into the cytoplasm. Given USP7's role in managing endosomal tubulation and recycling, researchers examined whether these processes could restrict ZIKV infection.

They discovered that USP7 interacts with an E3 ubiquitin ligase called TRIM27, as well as recycling-associated Rab GTPases RAB11 and RAB35, which also play significant roles in blocking ZIKV infection. To confirm their findings, they tested cell lines with disease-causing USP7 variants and fibroblasts from individuals with Hao-Fountain syndrome.

They found that mutations in the USP7 gene associated with the syndrome reduce its antiviral capabilities and make cells more susceptible to ZIKV infection. These results align with recent cases of severe viral infections in early life among individuals with Hao-Fountain syndrome. Overall, the study highlights endosomal recycling pathways as crucial innate defense mechanisms against neurotropic orthoflaviviruses and suggests that pathogenic USP7 variations could be a candidate for an inherited condition affecting the immune system.