In summary, our results revealed that in the acute phase of macrophage activation after infection by E. coli, PrPC actively participates in the regulation of the process by protecting against excess inflammation through negative regulation of phagocytosis, phagosome maturation, cytokine expression, and microbicidal activity, which provides new insights into the physiological functions of PrPC in macrophages. The gene discussed is PRNP; the disease is infection.