The role of TAM receptors and its ligand, Gas6, during Zika virus infection in SJL and C57BL/6 mice

Author(s)

Lilian Gomes de Oliveira

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2019-08-06

Examining board members

Jean Pierre Schatzmann Peron; Bruna Cunha de Alencar Bargieri; José Luiz Proença Modena; Paula Carolina de Souza

• Advisor: Jean Pierre Schatzmann Peron

Abstract

Introduction. Zika virus (ZIKV) has emerged as a global health problem and still demands efforts by scientific community to understand the molecular mechanisms involved in its infection in host cells. ZIKV belongs to Flavivirus genus, such as the Dengue virus, whose mechanism of cell invasion is elucidated in the literature. In this, it is clear the involvement of membrane receptors as TAM family, such as Tyro3, Axl, and Mer, as well as their soluble ligands, Gas6 and Protein S in a phenomenon called apoptotic mimicry. In this mechanism, phosphatidylserine exposed in the viral envelope interacts with TAM receptors and, thus, resulting in the internalization of viral particle. Studies conducted by our group demonstrated a possible relationship between increased TAM receptor expression and ZIKV infection, as well as the susceptibility of SJL mouse line to infection. Despite this, the molecular mechanisms related to TAM receptors in ZIKV infection are still not fully understood. Aim. Evaluate the relevance of TAM receptors in ZIKV infection in experimental models in vitro and in vivo Results and discussion. We observed that susceptible SJL animals present higher Tyro3, Axl and Gas6 expression levels compared to resistant C57BL/6. In this context, we demonstrated that the combination of ZIKV&#43rmGas6 in SJL and C57BL/6 mice leads to increased viral load in spleen and serum. Meanwhile, treatment of animals with Axl kinase blocker, R428, did not reduced the amount of viral particles. Interestingly, we found that C57BL/6 pregnancy infection with ZIKV&#43rmGas6 allowed the appearance of phenotypic changes in the fetuses, which was not observed in the ZIKV control. In vitro experiments using dendritic cells and macrophages showed no difference in viral replication or Gas6 release after infection, even with the use of Axl knockout cells. Conclusion. In short, our data corroborate with the literature in two distinct points. The first one in the dispensability of TAM for in vitro infection of immunocompetent cells. The second, evidences the role of TAM receptors in a dependent on the presence of Gas6. (AU)

• FAPESP's process: 16/21259-0 - The role of TAM receptors and their ligands, Gas6 and Pros 1 during infection by Zika virus in bone marrow-derived dendritic cells and macrophages of SJL and C57BL/6 mice
• Grantee: Lilian Gomes de Oliveira
• Support Opportunities: Scholarships in Brazil - Master