Only the PySRA‐F2 fragment conferred strong protection: mice immunised with F2 showed low parasitemia, 66.7% survival, and intact spleen structure, while others reached ~80% parasitemia and died by day 13. PySRA‐F2 bound to CD68 on macrophages, activated NF‐κB and MAPK pathways, induced pro‐inflammatory cytokines (IL‐1β, TNF‐α, IL‐6) and macrophage apoptosis, but also regulated inflammation to aid survival. Attempts to knock out PySRA or PySRA‐F2 failed, indicating essentiality. Here, IL1B is linked to parasitic infectious disease.