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The quantitative range and reproducibility of current serological tests for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are not optimized. Herein, we developed a diagnostic test that detects SARS-CoV-2 IgG and IgM with high quantitativeness and reproducibility and low interference. The system was based on the high-sensitivity chemiluminescence enzyme immunoassay (HISCL) platform and detects IgG and IgM specific to SARS-CoV-2 spike and nucleocapsid proteins. Quantification accuracy and reproducibility were evaluated using serially diluted samples from 60 SARS-CoV-2-infected patients. Assay performance was evaluated using serum samples from the SARS-CoV-2-infected patients and 500 SARS-CoV-2-negative serum samples collected before the emergence of SARS-CoV-2. The system showed high quantification accuracy (range, 10 2 ), high reproducibility (within 5%), and no cross-reaction between SARS1- and MERS-S proteins. Detection accuracy was 98.3% and 93.3% for IgG and IgM against spike proteins and 100% and 71.7% for IgG and IgM against nucleocapsid proteins, respectively. Mean antibody levels were > 10 times that in negative samples upon admission and > 100 times that at convalescent periods. Clinical severity upon admission was not correlated with IgG or IgM levels. This highly quantitative, reproducible assay system with high clinical performance may help analyze temporal serological/immunological profiles of SARS-CoV-2 infection and SARS-CoV-2 vaccine effectiveness.

Coronavirus disease-2019 (COVID-19) remains a critical global health concern. We developed a fully automated, high-throughput competition immunoassay to elucidate how epitope recognition on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) correlates with neutralizing activity. Analysis of clinical samples from both SARS-CoV-2-infected and vaccinated individuals revealed that vaccination elicits significantly higher antibody titers across multiple S1 subunit epitopes compared to natural infection. Notably, median antibody levels against the receptor-binding motif (RBM) exceeded 50% in both cohorts, highlighting the RBM as a key target for antibody induction irrespective of immune origin. Furthermore, the strongest correlation with neutralizing activity was observed for antibodies directed against the broader S1 subunit, indicating that epitopes outside the RBM also contribute to neutralization. These findings underscore the importance of both RBM- and non-RBM-directed antibodies in effective immune defense against SARS-CoV-2. Our assay enables large-scale, reliable quantification of neutralizing antibodies and provides critical insights for developing improved diagnostic antigens and vaccine strategies aimed at eliciting robust, multi-epitope immune responses.

Since 2019, SARS-CoV-2 has undergone mutations, resulting in pandemic and epidemic waves. The SARS-CoV-2 spike protein, crucial for cellular entry, binds to the ACE2 receptor exclusively when its receptor-binding domain (RBD) adopts the up-conformation. However, whether ACE2 also interacts with the RBD in the down-conformation to facilitate the conformational shift to RBD-up remains unclear. Herein, we present the structures of the BA.2.86 and the JN.1 spike proteins bound to ACE2. Notably, we successfully observed the ACE2-bound down-RBD, indicating an intermediate structure before the RBD-up conformation. The wider and mobile angle of RBDs in the up-state provides space for ACE2 to interact with the down-RBD, facilitating the transition to the RBD-up state. The K356T, but not N354-linked glycan, contributes to both of infectivity and neutralizing-antibody evasion in BA.2.86. These structural insights the spike-protein dynamics would help understand the mechanisms underlying SARS-CoV-2 infection and its neutralization. JN.1 lineage is a globally dominant variant of SARS-CoV-2. Here, the authors examine structural insights into the BA.2.86 and JN.1 spike dynamics to help understand the mechanisms underlying SARS-CoV-2 infection and its neutralizing-antibody evasion.

Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions 1 – 3 . However, the players and mechanisms that underlie protease regulation in the intestinal lumen have remained unclear. Here we show that Paraprevotella strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically, Paraprevotella recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis. Paraprevotella colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against Citrobacter rodentium . Moreover, Paraprevotella colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells 4 , 5 . Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection. Colonization of trypsin-degrading commensal bacteria may contribute to the maintenance of intestinal homeostasis and protection against pathogen infection in humans and mice.

CD4⁺ T regulatory cells (Tregs), which express the Foxp3 transcription factor, play a critical role in the maintenance of immune homeostasis. Here, we show that in mice, Tregs were most abundant in the colonic mucosa. The spore-forming component of indigenous intestinal microbiota, particularly clusters IV and XIVa of the genus Clostridium, promoted Treg cell accumulation. Colonization of mice by a defined mix of Clostridium strains provided an environment rich in transforming growth factor-β and affected Foxp3⁺ Treg number and function in the colon. Oral inoculation of Clostridium during the early life of conventionally reared mice resulted in resistance to colitis and systemic immunoglobulin E responses in adult mice, suggesting a new therapeutic approach to autoimmunity and allergy.

Background: The interferon (IFN)-γ release assay (IGRA) has recently been established as a method to evaluate the infection status of tuberculosis instead of the tuberculin skin test. However, indeterminate results can create challenges to interpretation. The IGRA has been available in Japan since 2005, including the recently launched QuantiFERON-TB Gold Plus (QFT-plus) assay. Objectives: The aim of this study was to investigate the clinical features and predictors of indeterminate results by the QFT-plus test in routine practice. Methods: This was a cross-sectional study of 1258 patients. Multivariate logistic regression models were employed to investigate the clinical factors related to indeterminate results by the QFT-plus. Results: Overall, 91.8% of results were found to be conclusive and 8.2% were indeterminate. The QFT-plus indeterminate results were predominantly due to a low level of IFN-γ production by mitogens. Multivariate analysis indicated that an indeterminate result was significantly associated with age, sex, corticosteroid use, autoimmune disease, and inpatient setting. Conclusion: Certain types of individuals are at higher risk of an indeterminate IGRA result. The QFT-plus test for hospitalized patients should be avoided as much as possible, and it is better to perform the test for those patients in outpatient settings.

The reactions of [Rh2(O2CCH3)4(OH2)2] with n-naphthalenecarboxylic acids (n = 1: 1-HNC, n = 2: 2-HNC) afford the dirhodium tetra-μ-(n-naphthoate) complexes [Rh2(1-NC)4] (1) and [Rh2(2-NC)4] (2), respectively. Single crystal X-ray diffraction analyses of [1(OCMe2)2] and [2(OCMe2)2], which were obtained by recrystallization from acetone (OCMe2) solutions of 1 and 2, reveal that the dirhodium cores are coordinated by four equatorially bridging naphthoate ligands and two axial OCMe2 ligands. Density functional theory (DFT) calculation confirmed that (i) the single Rh–Rh bond is formed between the two Rh ions and (ii) the electronic structures between two Rh ions in [1(OCMe2)2] and [2(OCMe2)2] are best described as π4δ2σ2δ*2π*4 and δ2π4σ2δ*2π*4, respectively. Time-dependent DFT (TDDFT) calculations clarify the absorption band characters of [1(OCMe2)2] and [2(OCMe2)2]; the former shows the bands due to d–d and metal–to–metal-ligand charge transfer (MMLCT) excitations in the visible light region, whereas the latter shows the bands due to only d–d excitations in the same region. The electrochemical properties and thermal stabilities of [1(OCMe2)2] and [2(OCMe2)2] were also investigated in this study.

Good syndrome is a rare condition characterized by the presence of thymoma in combination with adult-onset hypogammaglobulinemia. Immunological features of Good syndrome include various immunodeficiencies accompanied with hypogammaglobulinemia. In patients with thymoma, paraneoplastic syndromes including hypogammaglobulinemia worsen the prognosis. We herein describe a patient with advanced-stage type A thymoma who was effectively treated with chemotherapy and exhibited a parallel decrease in the serum level of soluble interleukin-2 receptor (sIL-2R), which depends on cellular immunity. The present case suggests the efficacy of sIL-2R as a potential prognostic biomarker in a subset of patients with Good syndrome. Keywords: thymoma, hypogammaglobulinemia, Good syndrome, soluble interleukin-2 receptors

A novel heteroleptic paddlewheel-type dirhodium (Rh2) complex [Rh2(O2CCH3)3(PABC)] (1; PABC = para-aminobenzenecarboxylate), which has an amino group as a potential donor site for coordination with the metal ion, was synthesized and characterized by 1H NMR, ESI-TOF-MS, infrared spectra, and elemental analysis. The slow evaporation of N,N-dimethylformamide (DMF)-dissolved 1 produces the purple-colored crystalline polymeric species [Rh2(O2CCH3)3 (PABC)(DMF)]n (1P). Single-crystal and powder X-ray diffraction analyses, as well as thermo-gravimetric analysis, clarified that 1P formed a one-dimensional polymeric structure, in which the two axial sites of the Rh2 ion in 1P are coordinated by a DMF molecule and an amino group of the PABC ligand of the neighboring molecule 1, by coordination-induced self-assembly (polymerization) with an Rh-amino bond. The reversible structural change (self-assembly and disassembly transformations) between the discrete species [Rh2(O2CCH3)3(PABC)(DMF)2] (1D; green solution) and the polymeric species 1P (purple solid) was accompanied by a color change, which easily occurred by the dissolution and evaporation procedures with DMF.

A major function of innate immune receptors is to recognize pathogen-associated molecular patterns and then evoke immune responses appropriate to the nature of the invading pathogen(s). Because innate immune cells express various types of these receptors, distinct combinations of signaling pathways are activated in response to a given pathogen. Although the conventional wisdom is that these signaling pathways cooperate with one another to ensure an effective host response, a more nuanced view recognizes antagonism between the individual pathways, where the attenuation of a signaling pathway(s) by others may shape the immune response. In this study, we show that, on Listeria monocytogenes infection, Toll-like receptor-triggered MyD88 signaling pathways suppress type I IFN gene induction, which is detrimental to macrophage bactericidal activity. These pathways target and suppress the IFN regulatory factor 3 (IRF3) transcription factor that is activated by the stimulator of IFN genes–TANK-binding kinase-1 kinase pathway. We also provide evidence for the involvement of the MAPK phosphatase family members, which renders IRF3 hypophosphorylated on Toll-like receptor signaling by enhancing the formation of an MAPK phosphatase–IRF3–TANK-binding kinase-1 ternary complex. This study, therefore, reveals a hitherto unrecognized and important contribution of a beneficial innate signaling interference against bacterial infections.