HFRS encompasses a spectrum of clinical manifestations ranging from subclinical to severe symptoms. Early diagnosis is challenging due to the transient and nonspecific nature of initial symptoms [4, 11, 12]. In this study, we conducted a systematic investigation into the transcriptomic dynamics across OP, DP and CP of HFRS. Our findings indicate a greater similarity in the transcriptomic profiles between CP and DP than between DP and OP, highlighting the pronounced alterations occurring during the transition from DP to OP. A cohort of 38 genes displayed varied expression patterns throughout the three phases analyzed, underscoring their potential significance. Notably, among the eight genes with a monotonically increasing expression pattern validated by qPCR, CD83 and NR4A1 are involved in immune checkpoint regulation, which attenuates the immune response post-infection and during inflammation [13–15]. Conversely, of the four genes with a monotonically decreasing expression pattern, IFI27 and RNASE2, also validated by qPCR, are implicated in antiviral and immunomodulatory functions through interactions with innate immune responses[16–19]. These findings suggest a stage-wise alleviation of the immune response, facilitated by the action of immune checkpoint genes.
OP is identified as a critical juncture, with approximately half of the total fatalities occurring during this stage, characterized by elevated levels of creatinine and urea [20]. Our study revealed an upregulation of genes associated with tissue morphogenesis, as well as urogenital and renal system development, indicating a recovery of the renal system during the transition from OP to DP. Expression of JUN and HSPA1B increased during the transition from the OP to DP, indicating their role in tissue repair and immune response regulation[21–24]. Conversely, the antiviral protein IFIT1 and the kidney injury marker LCN2 both showed decreased expression[25, 26]. The rapid humoral innate immune response is crucial for combating virus infections, including hantavirus [9, 27]. Our results revealed that myeloid leukocyte mediated immune response was attenuated during the transition from OP to DP. Meanwhile, deconvolution analysis revealed a decrease in T cells CD4 memory activated, T cells follicular helper, Mast cells resting, and Neutrophils, indicating a reduction in immune response during the recovery phases post-virus infection.
During the transition from DP to CP, an increase in Macrophages M2 suggested an anti-inflammatory response, while the rise in T cells CD4 memory resting indicated that the body had established a long-term immune memory of the virus. Additionally, translational initiation and protein transport processes were enhanced during the transition from DP to CP, suggesting tissue cell repair and regeneration. Concurrently, there was a downregulation of phagocytosis, immunoglobulin production, and complement activation, indicating a return of the immune response to baseline levels during this phase. This result was supported by the down-regulation of MZB1, which plays a role in immunoglobulin production and inflammation mitigation [28–30].
In conclusion, our investigation delineates the transcriptomic dynamics across the later three phases in patients recovering from hantavirus infection. We identified 38 dysregulated genes during these transitions, which may serve as biomarkers and therapeutic targets for clinical intervention. The immune response to hantavirus infection was attenuated by immune checkpoint genes, while genes related to tissue repair and regeneration were upregulated, facilitating the restoration of renal system function. Despite the limitations posed by the scarcity of available patient samples across all three recovery phases, our findings provide valuable insights into the molecular mechanisms underlying HFRS recovery, which will facilitate future investigations with larger cohorts and experimental validation.