Stable and durable antibody responses in SARS-recovered donors vaccinated with inactivated SARS-CoV-2 vaccine.

Whether the immune imprinting caused by severe acute respiratory syndrome coronavirus (SARS-CoV) affects the efficiency of SARS-CoV-2 vaccination has attracted global concern. Little is known about the dynamic changes of antibody response in SARS convalescents inoculated with three doses of inactivated SARS-CoV-2 vaccine although lack of cross-neutralizing antibody response to SARS-CoV-2 in SARS survivors has been reported. We longitudinally examined the neutralizing antibodies (nAbs) against SARS-CoV and SARS-CoV-2 as well as spikes binding IgA, IgG, IgM, IgG1, and IgG3 antibodies in 9 SARS-recovered donors and 21 SARS-naïve donors. Stably higher nAbs and spike antigens-specific IgA, IgG antibodies against SARS-CoV-2 were observed in SARS-recovered donors compared with SARS-naïve donors during the period with two doses of BBIBP-CorV vaccination. However, the third-dose BBIBP-CorV stimulated a sharply and shortly higher increase of nAbs in SARS-naïve donors than in SARS-recovered donors. It is worth noting that, regardless of prior SARS infection, the Omicron subvariants were found to subvert immune responses. Moreover, certain subvariants such as BA.2, BA.2.75, or BA.5 exhibited a high degree of immune evasion in SARS survivors. Interestingly, BBIBP-CorV recalled higher nAbs against SARS-CoV compared with SARS-CoV-2 in SARS-recovered donors. In SARS survivors, a single dose of inactivated SARS-CoV-2 vaccine provoked immune imprinting for the SARS antigen, providing protection against wild-type SARS-CoV-2, and the earlier variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta but not against Omicron subvariants. As such, it is important to evaluate the type and dosage of SARS-CoV-2 vaccine for SARS survivors.

TAK1 of black carp positively regulates IRF7-mediated antiviral signaling in innate immune activation.

Transforming growth factor ß-activated kinase 1 (TAK1) plays a vital role in IL-1-mediated NF-κB, JNK, and p38 activation in human and mammals. However, the function of TAK1 in teleost fish still remains largely unknown. To explore the role of TAK1 during the antiviral innate immune response of teleost fish, TAK1 of black carp (Mylopharyngodon piceus) was cloned and characterized in this paper. The open reading frame (ORF) of black carp TAK1 (bcTAK1) consists of 1626 nucleotides and the predicted bcTAK1 protein contains 541 amino acids, which includes a N-terminal Serine/Threonine protein kinases (S/TKc) and a C-terminal coiled-coil region. bcTAK1 migrated around 75 kDa in immunoblotting assay and was identified as a cytosolic protein by immunofluorescence staining. bcTAK1 transcription in Mylopharyngodon piceus kidney (MPK) cells varied in response to the stimulation of poly (I:C), LPS, grass carp reovirus (GCRV), and spring viremia of carp virus (SVCV). bcTAK1 showed deficient IFN-inducing ability in reporter assay and feeble antiviral activity against GCRV and SVCV in plaque assay. However, when co-expressed with bcIRF7 in EPC cells, bcTAK1 obviously enhanced bcIRF7-mediated IFN promoter induction in reporter assay. Accordingly, the data of plaque assay demonstrated that the antiviral activity of bcIRF7 against both GCRV and SVCV was unregulated by bcTAK1. Thus, the data generated in this study support the conclusion that bcTAK1 up-regulates bcIRF7-mediated antiviral signaling during host innate immune activation, which is reported for the first time in vertebrates.

Identification of Causal Relationships between Gut Microbiota and Influenza a Virus Infection in Chinese by Mendelian Randomization.

Numerous studies have reported a correlation between gut microbiota and influenza A virus (IAV) infection and disease severity. However, the causal relationship between these factors remains inadequately explored. This investigation aimed to assess the influence of gut microbiota on susceptibility to human infection with H7N9 avian IAV and the severity of influenza A (H1N1)pdm09 infection. A two-sample Mendelian randomization analysis was conducted, integrating our in-house genome-wide association study (GWAS) on H7N9 susceptibility and H1N1pdm09 severity with a metagenomics GWAS dataset from a Chinese population. Twelve and fifteen gut microbiotas were causally associated with H7N9 susceptibility or H1N1pdm09 severity, separately. Notably, Clostridium hylemonae and Faecalibacterium prausnitzii were negative associated with H7N9 susceptibility and H1N1pdm09 severity, respectively. Moreover, Streptococcus peroris and Streptococcus sanguinis were associated with H7N9 susceptibility, while Streptococcus parasanguini and Streptococcus suis were correlated with H1N1pdm09 severity. These results provide novel insights into the interplay between gut microbiota and IAV pathogenesis as well as new clues for mechanism research regarding therapeutic interventions or IAV infections. Future studies should concentrate on clarifying the regulatory mechanisms of gut microbiota and developing efficacious approaches to reduce the incidence of IAV infections, which could improve strategy for preventing and treating IAV infection worldwide.

Research Progress into the Biological Functions of IFITM3.

Interferon-induced transmembrane proteins (IFITMs) are upregulated by interferons. They are not only highly conserved in evolution but also structurally consistent and have almost identical structural domains and functional domains. They are all transmembrane proteins and have multiple heritable variations in genes. The IFITM protein family is closely related to a variety of biological functions, including antiviral immunity, tumor formation, bone metabolism, cell adhesion, differentiation, and intracellular signal transduction. The progress of the research on its structure and related functions, as represented by IFITM3, is reviewed.

The truncated IFITM3 facilitates the humoral immune response in inactivated influenza vaccine-vaccinated mice via interaction with CD81.

A single-nucleotide polymorphism (SNP) rs12252-C of interferon-induced transmembrane protein 3 (IFITM3), resulting in a truncated IFITM3 protein lacking 21 N-terminus amino acids, is associated with severe influenza infection in the Chinese population. However, the effect of IFITM3 rs12252-C on influenza vaccination and the underlying mechanism is poorly understood. Here, we constructed a mouse model with a deletion of 21 amino acids at the N-terminus (NΔ21) of IFITM3 and then compared the antibody response between Quadrivalent influenza vaccine (QIV) immunized wild-type (WT) mice and NΔ21 mice. Significantly higher levels of haemagglutination inhibition (HI) titre, neutralizing antibodies (NAb), and immunoglobulin G (IgG) to H1N1, H3N2, B/Victory, and B/Yamagata viruses were observed in NΔ21 mice compared to WT mice. Correspondingly, the numbers of splenic germinal centre (GC) B cells, plasma cells, memory B cells, QIV-specific IgG+ antibody-secreting cells (ASC), and T follicular helper cells (TFH) in NΔ21 mice were higher compared with WT mice. Moreover, the 21-amino-acid deletion caused IFITM3 translocation from the endocytosis compartment to the periphery of cells, which also prevented the degradation of a co-stimulatory molecule of B cell receptor (BCR) CD81 on the cell surface. More importantly, a more interaction was observed between NΔ21 protein and CD81 compared to the interaction between IFITM3 and CD81. Overall, our study revealed a potential mechanism of NΔ21 protein enhancing humoral immune response by relocation to prevent the degradation of CD81, providing insight into SNP affecting influenza vaccination.

DAK inhibits MDA5-mediated signaling in the antiviral innate immunity of black carp.

Dihydroxyacetone kinase (DAK) functions as a negative regulator of melanoma differentiation-associated gene 5 (MDA5)-mediated interferon (IFN) production in human. To explore its role in teleost fish, DAK homologue of black carp (Mylopharyngodon piceus) has been cloned and characterized in this paper. The transcription of black carp DAK (bcDAK) variated in host cells in response to LPS, poly (I:C) and virus stimulation, and bcDAK was majorly distributed in the cytoplasm. Overexpressed bcDAK in EPC cells showed little IFN promoter-inducing ability in the reporter assay and no antiviral activity in plaque assay. When co-expressed with black carp MDA5 (bcMDA5) in EPC cells, bcDAK obviously inhibited bcMDA5-mediated IFN promoter transcription in reporter assay and the antiviral activity in plaque assay. The knockdown of bcDAK enhanced the antiviral activity of the host cells. The association between bcDAK and bcMDA5 has been identified through immunofluorescent staining and co-immunoprecipitation (co-IP) assay. Thus, the data generated in this study support the conclusion that black carp DAK interacts with MDA5 and negatively regulates MDA5-mediated antiviral signaling.