{"doi":"10.1016/j.jare.2024.08.027","title":"Dual nature of type I interferon responses and feedback regulations by SOCS1 dictate malaria mortality","abstract":"A working model to illustrate the dual nature of type I IFN responses and feedback regulations by SOCS1 dictate malaria mortality. Differential dynamics of TFs (NF-κB, MAPK, and type I IFN signaling pathways) and SOCS1 synergistically determine the distinct production of type I IFN during 17XL and PbANKA infections. 17XL infection induces an early spike of TFs and weak SOCS1 response that does not trigger I1-FFL, leading to early IFN-α/β production. SOCS1 production in late infection shuts down type I IFN response by a strong negative feedback loop. The early IFN-α/β responses induced by TLR7-IRF7 signaling enhance anti-malarial immunity through expanding CD11a hi CD49d hi CD4 + T cells. In contrary, PbANKA infection triggers early strong SOCS1 expression to activate I1-FFL on type I IFN production and delays TFs response, leading to a late IFN-α/β production. Late IFN-α/β responses induced by both TLR9-IRF7 and STING-IRF3 mediated signaling impede host immunity through inhibiting malaria antigen-specific CD4 + T cells and inducing PD-1 + CD8 + cells during PbANKA infection. • The timing of IFN-α/β are species-specific, determining the nature of host immunity. • 17XL triggered early TLR7-IRF7-dependent IFN-α/β response and expanded CD4 + T cell. • PbANKA induced late TLR9-IRF7/STING-IRF3-IFN-α/β and expanded PD-1 + CD8 + T cells. • SOCS1 mediated diverse IFN-α/β responses via negative feedback and I1-FFL. Type I interferon (IFN-I, IFN-α/β), precisely controlled by multiple regulators, including suppressor of cytokine signaling 1 (SOCS1), is critical for host defense against pathogens. However, the impact of IFN-α/β on malaria parasite infections, beneficial or detrimental, remains controversial. The contradictory results are suspected to arise from differences in parasite species and host genetic backgrounds. To date, no prior study has employed a comparative approach utilizing two parasite models to investigate the underlying mechanisms of IFN-I response. Moreover, whether and how SOCS1 involves in the distinct IFN-α/β dynamics is still unclear. Here we perform single-cell RNA sequencing analyses (scRNA-seq) to dissect the dynamics of IFN-α/β responses against P. yoelii 17XL (17XL) and P. berghei ANKA (PbANKA) infections; conduct flow cytometry analysis and functional depletion to identify key cellular players induced by IFN-I; and establish mathematical models to explore the mechanisms underlying the differential IFN-I dynamics regulated by SOCS1. 17XL stimulates an early protective but insufficient toll-like receptor 7 (TLR7)-interferon regulatory factor 7 (IRF7)-dependent IFN-α/β response, resulting in CD11a hi CD49d hi CD4 + T cell activation to enhance anti-malarial immunity. On the contrary, a late IFN-α/β induction through toll-like receptor 9 (TLR9)-IRF7/ stimulator of interferon genes (STING)- interferon regulatory factor 3 (IRF3) dependent pathways expands programmed cell death protein 1 (PD-1) + CD8 + T cells and impairs host immunity during PbANKA infection. Furthermore, functional assay and mathematical modeling show that SOCS1 significantly suppresses IFN-α/β production via negative feedback and incoherent feed-forward loops (I1-FFL). Additionally, differential activation patterns of various transcriptional factors (TFs) synergistically regulate the distinct IFN-I responses. This study reveals the dual functions of IFN-I in anti-malarial immunity: Early IFN-α/β enhances immune responses against Plasmodium infection by promoting CD11a hi CD49d hi CD4 + T cell, while late IFN-α/β suppresses these response by expanding PD-1 + CD8 + T cells. Moreover, both the SOCS1-related network motifs and TFs activation patterns contribute to determine distinct dynamics of IFN-I responses. Hence, our findings suggest therapies targeting SOCS1- or TFs-regulated IFN-I dynamics could be an efficacious approach for preventing malaria and enhancing vaccine efficacy.","journal":"Journal of Advanced Research","year":2024,"id":466228,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9445,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":557434,"name":"Zhiqiang Hu","orcid":"0000-0001-8854-3410","position":1,"is_corresponding":false},{"id":1130937,"name":"Huaji Jiang","orcid":"0000-0003-0197-239X","position":2,"is_corresponding":false},{"id":1298008,"name":"Zebin Wen","orcid":"0009-0007-1903-5034","position":3,"is_corresponding":false},{"id":1130933,"name":"Hongyu Li","orcid":"0000-0003-1784-4595","position":4,"is_corresponding":false},{"id":258971,"name":"Jian Li","orcid":"0000-0002-7076-3332","position":5,"is_corresponding":false},{"id":1130935,"name":"Ke Zeng","orcid":"0000-0001-8876-6665","position":6,"is_corresponding":false},{"id":1130938,"name":"Yingchao Xie","orcid":"0009-0003-2163-7430","position":7,"is_corresponding":false},{"id":1298433,"name":"Huadan Chen","orcid":null,"position":8,"is_corresponding":false},{"id":290725,"name":"Xin‐zhuan Su","orcid":"0000-0003-3246-3248","position":9,"is_corresponding":false},{"id":1298009,"name":"Chunmei Cai","orcid":"0000-0002-6984-4637","position":10,"is_corresponding":false},{"id":456729,"name":"Xiao Yu","orcid":"0000-0003-2491-9110","position":11,"is_corresponding":false},{"id":908034,"name":"Jiansen Lu","orcid":"0000-0003-3875-5583","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T02:04:54.606394Z","pmid":"39181199","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}