Iron Metabolism Upregulates Innate Immune Response in Sickle Cell Disease

BACKGROUND: Sickle cell disease (SCD) is a hereditary disorder characterized by hemolysis and changes in iron metabolism. We previously showed that increased expression of ferroportin (FPN), an iron export protein, leads to reduced intracellular iron and activation of antiviral response in SCD PBMCs. Here, we recruited a cohort of SCD patients with HIV infection and compared their antiviral innate and iron regulatory factors to SCD patients without HIV-1 infection. METHODS: PBMCs were isolated from whole blood of SCD patients without and with HIV-1 infection (SCD HIV+), HIV+ participants and healthy controls. Illumina NextSeq 500 was used for RNA Seq analysis. Normalized gene counts were used for gene set enrichment analysis (GSEA). Plasma cytokines were analyzed on Bio-Plex 200. RESULTS: GSEA of antiviral genes in SCD versus controls showed strong innate antiviral gene expression in SCD PBMCs (NES=0.91). The top 5 genes included IFITM3, MX2, IFI16, NFKBA and APOBEC3A. Iron regulatory genes were also highly expressed in SCD PBMCs comparing to controls (NES=1) and included BMP6, TFRC, TFR2, NCOA4, ERFE, FTH1 and HAMP. GSEA analysis showed strong upregulation of heme metabolism (NES = 1.21), IL-6 signaling (NES=1.12), hypoxia (NES=1.10), TNFα signaling (NES=1.28) and inflammatory response (NES=1.05). Innate antiviral factors (NES=0.68) and iron regulatory factors (NES=0.82) were upregulated in SCD compared to SCD patients with HIV-1 infection. SCD patients had statistically lower levels of hemoglobin and hematocrit compared to SCD HIV+ group and higher levels of IL-1β and IL-6. CONCLUSION: Our study shows that SCD patients have upregulated levels of innate antiviral response and also upregulated iron metabolism. The SCD patients with HIV-1 infection were hematologicaly closer to the non-infected individuals, demonstrating less pronounced expression of innate antiviral factors and less upregulated iron metabolism. Our findings indicate that HIV-1 infection might occur in SCD patients with less severe SCD manifestation. This work was supported by NIH grants 1R01HL125005, 5U54MD007597, 1P30AI117970-06 and 1SC1HL150685. George Washington University SPH Genomics Core conducted sequencing. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.