The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report ...the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.
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•We generated a single-cell atlas of PBMCs in both COVID-19 and influenza patients•Plasma cells increase significantly in both COVID-19 and influenza patients•COVID-19 is featured with XAF1-, TNF-, and FAS-induced T cell apoptosis•COVID-19 activates distinct pathway (STAT1/IRF3) versus influenza (STAT3/NFκB)
COVID-19 and influenza are both respiratory infections with cytokine release syndrome. Zhu et al. use single-cell RNA sequencing of longitudinally collected PBMCs in both patients to reveal distinct immune response landscapes of the two diseases and identify virus-specific cell composition and immune response pathways.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the pandemic of coronavirus disease 2019 (COVID-19). Great international efforts have been put into the development of ...prophylactic vaccines and neutralizing antibodies. However, the knowledge about the B cell immune response induced by the SARS-CoV-2 virus is still limited. Here, we report a comprehensive characterization of the dynamics of immunoglobin heavy chain (IGH) repertoire in COVID-19 patients. By using next-generation sequencing technology, we examined the temporal changes in the landscape of the patient’s immunological status and found dramatic changes in the IGH within the patient’s immune system after the onset of COVID-19 symptoms. Although different patients have distinct immune responses to SARS-CoV-2 infection, by employing clonotype overlap, lineage expansion, and clonotype network analyses, we observed a higher clonotype overlap and substantial lineage expansion of B cell clones 2–3 weeks after the onset of illness, which is of great importance to B-cell immune responses. Meanwhile, for preferences of V gene usage during SARS-CoV-2 infection, IGHV3-74 and IGHV4-34, and IGHV4-39 in COVID-19 patients were more abundant than those of healthy controls. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic development as well as mechanistic research.
Zika virus (ZIKV)-specific T cells are activated by different peptides derived from virus structural and nonstructural proteins, and contributed to the viral clearance or protective immunity. Herein, ...we have depicted the profile of CD8+ and CD4+ T cell immunogenicity of ZIKV proteins in C57BL/6 (H-2
) and BALB/c (H-2
) mice, and found that featured cellular immunity antigens were variant among different murine alleles. In H-2
mice, the proteins E, NS2, NS3 and NS5 are recognized as immunodominant antigens by CD8+ T cells, while NS4 is dominantly recognized by CD4+ T cells. In contrast, in H-2
mice, NS1 and NS4 are the dominant CD8+ T cell antigen and NS4 as the dominant CD4+ T cell antigen, respectively. Among the synthesized 364 overlapping polypeptides spanning the whole proteome of ZIKV, we mapped 91 and 39 polypeptides which can induce ZIKV-specific T cell responses in H-2
and H-2
mice, respectively. Through the identification of CD8+ T cell epitopes, we found that immunodominant regions E
and NS4
are hotspots epitopes with a distinct immunodominance hierarchy present in H-2
and H-2
mice, respectively. Our data characterized an overall landscape of the immunogenic spectrum of the ZIKV polyprotein, and provide useful insight into the vaccine development.
The BBIBP-CorV severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inactivated vaccine has been authorized for emergency use and widely distributed. We used single-cell transcriptome ...sequencing to characterize the dynamics of immune responses to the BBIBP-CorV inactivated vaccine. In addition to the expected induction of humoral immunity, we found that the inactivated vaccine induced multiple, comprehensive immune responses, including significantly increased proportions of CD16+ monocytes and activation of monocyte antigen presentation pathways; T cell activation pathway upregulation in CD8+ T cells, along with increased activation of CD4+ T cells; significant enhancement of cell-cell communications between innate and adaptive immunity; and the induction of regulatory CD4+ T cells and co-inhibitory interactions to maintain immune homeostasis after vaccination. Additionally, comparative analysis revealed higher neutralizing antibody levels, distinct expansion of naive T cells, a shared increased proportion of regulatory CD4+ T cells, and upregulated expression of functional genes in booster dose recipients with a longer interval after the second vaccination. Our research will support a comprehensive understanding of the systemic immune responses elicited by the BBIBP-CorV inactivated vaccine, which will facilitate the formulation of better vaccination strategies and the design of new vaccines.
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•A single-cell atlas of dynamic immune responses to the SARS-CoV-2 inactivated vaccine.•The proportion of CD16+ monocytes and the antigen presentation pathway are elevated.•Both CD4+ T cells and CD8+ T cells are activated by inactivated vaccine.•Cell-cell communications between innate and adaptive immunity are enhanced.•Tregs and co-inhibitory pathways are induced to maintain immune homeostasis.
Abstract
Background
The longitudinal antigen-specific immunity in COVID-19 convalescents is crucial for long-term protection upon individual re-exposure to SARS-CoV-2, and even more pivotal for ...ultimately achieving population-level immunity. We conducted this cohort study to better understand the features of immune memory in individuals with different disease severities at 1 year post–disease onset.
Methods
We conducted a systematic antigen-specific immune evaluation in 101 COVID-19 convalescents, who had asymptomatic, mild, moderate, or severe disease, through 2 visits at months 6 and 12 after disease onset. The SARS-CoV-2–specific antibodies, comprising neutralizing antibody (NAb), immunoglobulin (Ig) G, and IgM, were assessed by mutually corroborated assays (ie, neutralization, enzyme-linked immunosorbent assay ELISA, and microparticle chemiluminescence immunoassay MCLIA). Meanwhile, T-cell memory against SARS-CoV-2 spike, membrane, and nucleocapsid proteins was tested through enzyme-linked immunospot assay (ELISpot), intracellular cytokine staining, and tetramer staining-based flow cytometry, respectively.
Results
SARS-CoV-2–specific IgG antibodies, and NAb, can persist among >95% of COVID-19 convalescents from 6 to 12 months after disease onset. At least 19/71 (26%) of COVID-19 convalescents (double positive in ELISA and MCLIA) had detectable circulating IgM antibody against SARS-CoV-2 at 12 months post–disease onset. Notably, numbers of convalescents with positive SARS-CoV-2–specific T-cell responses (≥1 of the SARS-CoV-2 antigen S1, S2, M, and N proteins) were 71/76 (93%) and 67/73 (92%) at 6 and 12 months, respectively. Furthermore, both antibody and T-cell memory levels in the convalescents were positively associated with disease severity.
Conclusions
SARS-CoV-2–specific cellular and humoral immunities are durable at least until 1 year after disease onset.
SARS-CoV-2–specific humoral and T-cell immune memory are present within ~95% and ~90% of convalescents, respectively, until 1 year, with durable neutralizing antibodies and CD8+and CD4+T cells, but decreased IgG and IgM from 6 to 12 months.
As one of the most effective measures to prevent seasonal influenza viruses, annual influenza vaccination is globally recommended. Nevertheless, evidence regarding the impact of repeated vaccination ...to contemporary and future influenza has been inconclusive. A total of 100 subjects singly or repeatedly immunized with influenza vaccines including 3C.2a1 or 3C.3a1 A(H3N2) during 2018–2019 and 2019–2020 influenza season were recruited. We investigated neutralization antibody by microneutralization assay using four antigenically distinct A(H3N2) viruses circulating from 2018 to 2023, and tracked the dynamics of B cell receptor (BCR) repertoire for consecutive vaccinations. We found that vaccination elicited cross‐reactive antibody responses against future emerging strains. Broader neutralizing antibodies to A(H3N2) viruses and more diverse BCR repertoires were observed in the repeated vaccination. Meanwhile, a higher frequency of BCR sequences shared among the repeated‐vaccinated individuals with consistently boosting antibody response was found than those with a reduced antibody response. Our findings suggest that repeated seasonal vaccination could broaden the breadth of antibody responses, which may improve vaccine protection against future emerging viruses.
Zika virus (ZIKV) infection caused neurological complications and male infertility, leading to the accumulation of antigen-specific immune cells in immune-privileged organs (IPOs). Thus, it is ...important to understand the immunological responses to ZIKV in IPOs. We extensively investigated the ZIKV-specific T cell immunity in IPOs in
mice, based on an immunodominant epitope E
tetramer. The distinct kinetics and functions of virus-specific CD8
T cells infiltrated into different IPOs were characterized, with late elevation in the brain and spinal cord. Single epitope E
-specific T cells can account for 20-60% of the total CD8
T cells in the brain, spinal cord, and testicle and persist for at least 90 days in the brain and spinal cord. The E
-specific TCRαβs within the IPOs are featured with the majority of clonotypes utilizing
paired with diverse TRBV chains, but with distinct αβ paired clonotypes in 7 and 30 days post-infection. Specific chemokine receptors,
and
, were selectively expressed in the E
-specific CD8
T cells within the brain and testicle, indicating an IPO-oriented migration of virus-specific CD8
T cells after infection. Overall, this study adds to the understanding of virus-specific CD8
T cell responses for controlling and clearing ZIKV infection in IPOs.IMPORTANCEThe immune-privileged organs (IPOs), such as the central nervous system and testicles, presented pathogenicity and inflammation after Zika virus (ZIKV) infection with infiltrated CD8
T cells. Our data show that CD8
T cells keep up with virus increases and decreases in immune-privileged organs. Furthermore, our study provides the first
comparative analyses of the composition and diversity related to TCRα/β clonotypes across anatomical sites and ZIKV infection phases. We show that the vast majority of TCRα/β clonotypes in tissues utilize
with conservation. Specific chemokine expression, including
and
, was found to be selectively expressed in the E
-specific CD8
T cells within the brain and testicle, indicating an IPO-oriented migration of the virus-specific CD8
T cells after the infection. Our study adds insights into the anti-viral immunological characterization and chemotaxis mechanism of virus-specific CD8
T cells after ZIKV infection in different IPOs.
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