Papel da fosfatidilinositol 3-quinase γ na patogênese da infecção pelo Zika virus

Abstract

Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family and Orthoflavivirus genus, with tropism for the central nervous system (CNS), where it triggers a series of cellular damages to the nervous system (NS) including neuroinflammation and neurodegeneration. Due to its confirmed association with microcephaly and other neurological complications, ZIKV is considered a virus of global public health importance. ZIKV is known to utilize cellular mechanisms to multiply in host cells and inhibit apoptosis, including the stimulation of survival pathways such as the PI3K/AKT pathway. This study aimed to evaluate the impact of the phosphatidylinositol 3-kinase γ (PI3Kγ) pathway during ZIKV infection. PI3Kγ is a kinase widely distributed in the brain and leukocytes and plays a vital role in several cellular processes, such as differentiation, recruitment, and cell survival. For this purpose, primary cultures of neurons derived from PI3Kγ-deficient mice (PI3Kγkd/kd) or immortalized cultures of human neuroblastoma SH-SY5Y were treated with the PI3Kγ pathway inhibitor AS605240 and infected with ZIKV. To investigate the involvement of the PI3Kγ pathway in the neuroinflammatory process triggered by ZIKV, mice deficient for the type I interferon receptor α/β (A129) were treated with the selective inhibitor AS605240 before or after ZIKV infection. The results demonstrated that both pharmacological blockade and PI3Kγ deficiency inhibit ZIKV replication and neuronal death in vitro. Similarly, mice treated with the PI3Kγ inhibitor showed greater protection against ZIKV infection in vivo, resulting in reduced viral replication and milder brain lesions. This neuroprotective phenotype was associated with differential modulation of astrocyte and microglia activation, with reduced TNF production in activated microglia. Furthermore, inhibition of the PI3Kγ pathway prevented the influx and activation of CD8+ T cells, as well as the production of pro-inflammatory mediators such as IFN-γ and IL-17 in the brain tissue of ZIKV-infected mice. Our findings suggest that activation of the PI3Kγ pathway contributes to ZIKV replication and induction of neuroinflammation, highlighting a therapeutic potential of this pathway in mitigating damage associated with ZIKV infection in the SN.