Molecular Signatures of Inflammatory Profile and B-Cell Function in Patients with Severe Fever with Thrombocytopenia Syndrome

Abstract

Dabie bandavirus (severe fever with thrombocytopenia syndrome virus [SFTSV]) induces an immunopathogenic disease with a high fatality rate; however, the mechanisms underlying its clinical manifestations are largely unknown. In this study, we applied targeted proteomics and single-cell transcriptomics to examine the differential immune landscape in SFTS patient blood. Serum immunoprofiling identified low-risk and high-risk clusters of SFTS patients based on inflammatory cytokine levels, which corresponded to disease severity. Single-cell transcriptomic analysis of SFTS patient peripheral blood mononuclear cells (PBMCs) at different infection stages showed pronounced expansion of B cells with alterations in B-cell subsets in fatal cases. Furthermore, plasma cells in which the interferon (IFN) pathway is downregulated were identified as the primary reservoir of SFTSV replication. This study identified not only the molecular signatures of serum inflammatory cytokines and B-cell lineage populations in SFTSV-induced fatalities but also plasma cells as the viral reservoir. Thus, this suggests that altered B-cell function is linked to lethality in SFTSV infections. IMPORTANCE SFTSV is an emerging virus discovered in China in 2009; it has since spread to other countries in East Asia. Although the fatality rates of SFTSV infection range from 5.3% to as high as 27%, the mechanisms underlying clinical manifestations are largely unknown. In this study, we demonstrated that SFTSV infection in fatal cases caused an excessive inflammatory response through high induction of proinflammatory cytokines and chemokines and the aberrant inactivation of adaptive immune responses. Furthermore, single-cell transcriptome sequencing (RNA-seq) analysis of SFTS patient PBMCs revealed that SFTSV targets the B-cell lineage population, especially plasma cells, as the potential viral reservoir in patients for whom the infection is fatal. Thus, SFTSV infection may inhibit high-affinity antibody maturation and secretion of plasma B cells, suppressing neutralizing antibody production and thereby allowing significant virus replication and subsequent fatality.

Single-cell landscape of peripheral immune responses to fatal SFTS

“…B cells were also suspected for main targets of SFTSV infection (Mendoza et al, 2019). However, two studies reported controversial data on the susceptibility of peripheral blood plasmablasts to SFTSV based on ex vivo infection of PBMCs (Suzuki et al, 2020;Park et al, 2021). Here, through flow cytometry analysis of peripheral blood samples from patients with SFTS, we demonstrated that plasmablasts were susceptible to SFTSV infection, with a significantly higher infection rate in deceased patients than in surviving patients.…”

“…Disruption of B cell immunity, such as an impaired humoral response and overproliferating plasmablasts, was previously disclosed in severe patients with SFTS (Song et al, 2018;Park et al, 2021). B cells were also suspected for main targets of SFTSV infection (Mendoza et al, 2019).…”

“…Here, through flow cytometry analysis of peripheral blood samples from patients with SFTS, we demonstrated that plasmablasts were susceptible to SFTSV infection, with a significantly higher infection rate in deceased patients than in surviving patients. A study by Park et al (2021) found plasma cells as the main cell type harboring SFTSV RNAs and suggested that SFTSV-infected B cells had reduced IFN signaling relative to uninfected B cells, while only 23 cells harbored one or more viral transcripts. In contrast, our scRNA-seq data from 10x Genomics did not identify any SFTSV sequences, due to the lack of polyadenylated ends either in the SFTSV genome or during expression (Guu et al, 2012).…”

Single-Cell Transcriptomic Analysis of Peripheral Blood Reveals a Novel B-Cell Subset in Renal Allograft Recipients With Accommodation

“…At present, studies have shown the important roles of B-cell subpopulations in inflammatory bowel disease and noted that B cells significantly remodel the phenotype in the course of disease development ( Castro-Dopico et al, 2020 ). In addition, Park et al (2021) found that in Dabie bandavirus –infected individuals, B cells are greatly expanded and that SFTSV infection can suppress the maturation of high-affinity antibodies and inhibit neutralizing antibodies secreted by plasma B cells, leading to a large amount of viral replication and subsequent death. In addition, through the single-cell sequencing technology, Sutton et al (2021) found that SARS-CoV exists in malaria-infected patients.…”

Kinetics of Glycoprotein-Specific Antibody Response in Patients with Severe Fever with Thrombocytopenia Syndrome

“…Failure in B-cell class switching with the absence of virus-specific antibody are suggested to be key factors for determining the disease severity and clinical outcomes of SFTS [7,11,19]. Song et al revealed that anti-NP-specific IgM and IgG and anti-Gn-specific IgG were negative in deceased patients with SFTS, and that the intracellular staining of IgG and IgM in plasmablasts were negative in fatal SFTS patients [7].…”