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