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. 2020 Dec;9(1):2303-2314.
doi: 10.1080/22221751.2020.1830717.

Rapid humoral immune responses are required for recovery from haemorrhagic fever with renal syndrome patients

Yaoni Li  1 , Chuansong Quan  2 , Weijia Xing  3 , Peihan Wang  2 , Jiming Gao  4 , Zhenjie Zhang  2 , Xiaolin Jiang  5 , Chuanmin Ma  2 , Michael J Carr  6   7 , Qian He  3 , Lei Gao  8 , Yuhai Bi  9 , Hua Tang  4 , Weifeng Shi  2
Affiliations

Rapid humoral immune responses are required for recovery from haemorrhagic fever with renal syndrome patients

Yaoni Li et al. Emerg Microbes Infect. 2020 Dec.

Abstract

ABSTRACT Haemorrhagic fever with renal syndrome (HFRS) following Hantaan virus (HTNV) infection displays variable clinical signs. Humoral responses elicited during HTNV infections are considered important, however, this process remains poorly understood. Herein, we have investigated the phenotype, temporal dynamics, and characteristics of B-cell receptor (BCR) repertoire in an HFRS cohort. The serological profiles were characterized by a lowered expression level of nucleoprotein (NP)-specific antibody in severe cases. Importantly, B-cell subsets were activated and proliferated within the first two weeks of symptom onset and moderate cases reacted more rapidly. BCR analysis in the recovery phase revealed a dramatic increase in the immunoglobulin gene diversity which was more significantly progressed in moderate infections. In severe cases, B-cell-related transcription was lower with inflammatory sets overactivated. Taken together, these data suggest the clinical signs and disease recovery in HFRS patients were positively impacted by rapid and efficacious humoral responses.

Keywords: B cell; Haemorrhagic fever with renal syndrome; Hantaan virus; humoral response; virus infection.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s). The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of manuscript, and in the decision to publish results.

Figures

Figure 1.
Figure 1.
The flow chart of HFRS patient recruitment in Baoji Central Hospital in Shaanxi province from November 2018 to January 2019.
Figure 2.
Figure 2.
The antibody responses to the nucleocapsid protein among moderate and severe HTNV cases. (A) The IgM and IgG antibody titres against NP were examined by twofold dilutions and OD450 measurements in 1:10,240 and 1:40 diluted serum determined by a commercial ELISA kit in HTNV patients after symptom onset. Comparison of moderate and severe cases during acute phase was assessed by Kruskal–Wallis or Fisher's exact test. (B) Plasma viral load of patients at time different points was determined by real-time quantitative RT-PCR, and then compared to the first and second weeks by Kruskal–Wallis test. (C) Spearman's correlation coefficient was calculated between plasma viral load and NP-IgG titre using viremic samples. X-axis denotes the 1:40 diluted serum and reads the number at OD450 nm. r and P indicate the correlation coefficient and significance, respectively. (D) The dynamic changes of IgM and IgG to NP, and viral loads of moderate and severe cases at different time points. Data for P25 were not available. The blue, red, and green squares represent IgG, IgM, and virus copies/0.1 mL, respectively. In panels A–C and the first column of panel D, the blue and red colours represent the moderate and severe cases, respectively.
Figure 3.
Figure 3.
Dynamic analysis of B-cell subsets in HFRS patients. (A) FACS gating strategy for the measurement of functional B-cell subsets. Activated B cells (AB), marginal zone-like (marginal B), memory B cells (MB), and plasmablasts (PB), represented by CD21+CD80+, CD27+IgD+, CD27+IgD−, and CD27+CD38+ markers, respectively. (B–D) The changes of different B-cell subsets in both moderate and severe cases from first to third weeks after symptom onset in typical cases: the moderate case P30 and severe case P37. Paired t-test was used to assess the significance. The red line represents the severe group and the blue line represents moderate cases. (E) A heat map showing fold increase (red) or decrease (blue) in gene expression that is related to different B-cell subtypes. M2 and S2 represent the moderate and severe cases in week 2, respectively. Similarly, M1 and S1 represent the moderate and severe cases in week 1, respectively.
Figure 4.
Figure 4.
The increased BCR repertoire diversity in HFRS cases. (A) BCR diversity, assessed by chaoE and chao1, was rapidly expanded in cases with antibody titres producing fourfold increase in either IgM or IgG subtype. Ac represents the acute phase and Re represents the recovery phase before and after fourfold rises in antibody titres. (B) V and J gene rearrangement characteristics from two typical cases, moderate P9 and severe P18, were depicted based on the read number of genes. The top 15V genes and all of the J genes were labelled in the circos plots. Genes from the same major class were assigned the same color. For example, IGHV4-34 and IGHV4-39 are shown in pink, and IGHV2-5 and IGHV2-70 are shown in orange. (C) IGHV segment usage ratio in HTNV patients. Packaged bars indicate the respective percentages of top 20 V genotypes. (D) Dominant antibody sequence characteristics identified following a fourfold rise in titre. The proportion of IGHV1-18 and IGHV 5-51 were calculated for the total and corresponding IGHV genotype. The region of VH, DH, and JH was confirmed by IgBlast in NCBI.
Figure 5.
Figure 5.
Gene expression array analysis and related serum cytokine in HTNV patients. (A) The gene set analysis shows the identifiers and names of the top 20 BTM gene sets of each comparison sorted by the significance score. Red indicates positive enrichment of a gene set and blue indicates negative enrichment. Circle size is proportional to the significance score that assigns high scores to the gene sets with strong fold-changes and high statistical significance. The blue, brown and green stars represent gene sets enriched in B cells, monocytes and neutrophils, and cell cycle, respectively. S-Ac: severe cases in the acute phase; M-Ac: moderate cases in the acute phase; S-Re: severe cases in the recovery phase; M-Re: moderate cases in the recovery phase. (B) Dynamic comparison of serum cytokine concentrations in both moderate and severe groups during the 3-week period post symptom onset. Blue squares, red dots and blue dashed lines represent means of moderate, severe and health group, respectively. The mean +/- standard error is shown for each group and the P-value is determined by t-test or Kruskal–Wallis test. Statistical significance was represented by asterisk, * P < 0.05, ** P < 0.01.
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Grants and funding

This study was funded by the Academic Promotion Programme of Shandong First Medical University (2019PT008 and 2019QL006) and the Key Research and Development Project of Shandong Province (2017GSF19106). Weifeng Shi was supported by the Taishan Scholars Programme of Shandong Province (ts201511056). Weijia Xing was supported by the Young Taishan Scholars Program of Shandong Province (No. tsqn20161046).