Mutation S139N on Zika virus prM protein shifts immune response from Asian to contemporary strain

Abstract

Zika virus (ZIKV) has been associated with neurological diseases like microcephaly and Guillain-Barré syndrome. The S139N single mutation on the prM protein of the FSS13025 Asian strain increases the mortality rate in mice. Therefore, it is a valuable tool for studying the impact of immune responses on neural damage. Here, we used single-cell sequencing technology to systematically assess the immune response induced by three ZIKV strains: Asian ancestral strain FSS13025/2010, FSS13025 strain with S139N mutation (FSS13025-S139N), and contemporary strain GZ01/2016. By infecting 1-day-old mice, we observed that the immune spectrum elicited by FSS13025-S139N mutant resembled that induced by the contemporary strain. The FSS13025-S139N strain induces the proliferation of inflammatory microglial cells earlier than the FSS13025 strain, similar to GZ01. A specific cell cluster, Microglia_Ccr7, was induced by the S139N mutant strain and GZ01 strain, which suppresses T cell activation through the PDCD1LG2-PDCD1 signaling pathway. Furthermore, the proliferation of CD8⁺ T cells was weakened and prolonged in S139N strain-infected samples. Finally, we found that the S139N mutant strain causes more apoptosis of neurons compared to the FSS13025 strain. These results indicate that the S139N mutation plays an important role in the immune response pattern of ZIKV and prolongs the duration of neuroinflammation.