Increased blood CD226^- inflammatory monocytes with low antigen presenting potential correlate positively with severity of hemorrhagic fever with renal syndrome

Abstract

Background

Hantaan virus (HTNV) infection can cause severe hemorrhagic fever with renal syndrome (HFRS). Inflammatory monocytes (iMOs) are involved in early antiviral responses. Previous studies have found that blood iMOs numbers increase in the acute phase of HFRS. Here, we further identified the phenotypic characteristics of iMOs in HFRS and explored whether phenotypic changes in iMOs were associated with HFRS severity.

Materials and Methods

Blood samples from 85 HFRS patients were used for phenotypic analysis of iMOs by flow cytometry. Plasma HTNV load was determined using RT-PCR. THP-1 cells overexpressing CD226 were used to investigate the effects of CD226 on HLA-DR/DP/DQ and CD80 expression. A mouse model was used to test macrophage phenotype following HTNV infection.

Results

The proportion of CD226^- iMOs in the acute phase of HFRS was 66.83 (35.05-81.72) %, which was significantly higher than that in the convalescent phase (5.32 (1.36-13.52) %) and normal controls (7.39 (1.15-18.11) %) (p < 0.0001). In the acute phase, the proportion of CD226^- iMOs increased more in patients with more severe HFRS and correlated positively with HTNV load and negatively with platelet count. Notably, CD226^- iMOs expressed lower levels of HLA-DR/DP/DQ and CD80 than CD226⁺ iMOs, and overexpression CD226 could enhance the expression of HLA-DR/DP/DQ and CD80. In a mouse model, HTNV also induced the expansion of CD226^- macrophages, with decreased expression of I-A/I-E and CD80.

Conclusions

CD226^- iMOs increased during HTNV infection and the decrease in CD226 hampered the expression of HLA-DR/DP/DQ and CD80, which may promote the immune escape of HTNV and exacerbate clinical symptoms.

Keywords:

• Hantaan virus
• hemorrhagic fever with renal syndrome
• inflammatory monocyte
• CD226
• antigen presentation

Ethical approval

This study was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants. The research involving human materials was also approved by the Ethical Review Board of the Fourth Military Medical University (KY20183312-1). Animal experiments were approved by the Institutional Animal Care and Use Committee of the Fourth Military Medical University (20200469).

Author contributions

Conceptualization: KT, BJ, LC (Lihua Chen), and YM.; Data curation, CZ, RZ, and YZ; Formal analysis, KT, YH, LC (Linfeng Cheng), and YZ (Yusi Zhang); Funding acquisition, KT, CZ, YZ (Yun Zhang) and YM; Investigation, KT, YH, LC (Linfeng Cheng), and YZ (Yusi Zhang); Methodology, KT, YH, LC (Linfeng Cheng), and YM; Resources, JL, QQ, XZ, and XJ; Software, KT and YH; Supervision, LC (Lihua Chen) and YM; Validation, YH and YZ; Visualization, KT and YH; Writing – original draft, KT; Writing – review & editing, LC (Lihua Chen) and YM. All the authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors report no conflict of interest.

Data availability statement

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (grant numbers 81901600, 81871239, and 82272331) and Natural Science Basic Research Program of Shaanxi (grant number 2022JZ-45).