Role of STAT1 in modulating the host immune response to <i>Plasmodium yoelii</i> 17XL-infected murine blood-stage malaria

The spleen is critically involved in the immune response to malaria parasite infections. However, the precise molecular mechanisms underlying splenic immune regulation and anemia during malaria remain elusive. This study aimed to identify the key regulatory proteins in <i>Plasmodium yoelii</i> (Py)-infected host spleen and investigate its role in malaria pathogenesis. Notably, significantly upregulated proteins in <i>Py</i>17XL-infected mice spleens were enriched in interferon (IFN) signaling, with signal transducer and activator of transcription (STAT)1, a critical component of the IFN pathway, emerging as the core molecule in the interaction network. Subsequent validation confirmed marked STAT1 upregulation in the spleens of infected hosts. Genetic ablation of STAT1 enhanced mouse survival rates and substantially reduced peripheral parasitemia post-infection and splenic parasite burden. Furthermore, STAT1 deficiency markedly reduced proportions of IFN-γ-producing CD8⁺ T cells and interleukin-10-producing CD4⁺ T cells at day 7 post-infection. Interestingly, hemoglobin concentrations and the proportion of peripheral blood reticulocytes significantly increased in STAT1-knockout mice compared with those in wild-type mice, indicating that STAT1 deficiency may alleviate malarial anemia. Altogether, the findings of this study elucidate the impact of dynamic protein changes, particularly STAT1, in the host spleen during malaria and provide a research basis for developing therapeutic interventions for malaria.IMPORTANCEThe cumulative findings demonstrate the pathogenic role of STAT1 in host spleen during <i>Py</i>17XL parasite infection, highlighting its role in promoting IFN-γ production and exacerbating malarial anemia. This study offers novel insights into the key pathogenic mechanisms observed in the host spleen during malaria, providing potential therapeutic targets for malaria.