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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit both T cell and B cell immune responses in immunocompetent individuals. However, the mechanisms underlying the antiviral effects mediated by CD4 + T cells are not fully understood. In this study, we analyzed the culture supernatant (SN) from polyclonally stimulated human CD4 + T cells as a model for soluble mediators derived from SARS-CoV-2-stimulated CD4 + T cells. Interestingly, this SN inhibited SARS-CoV-2 propagation in a viral strain- and host cell type-dependent manner. The original wild-type showed the highest susceptibility, whereas the Delta variant exhibited resistance in the human monocyte cell line. In addition, antibody-dependent enhancement (ADE) of infection with the original strain was also abolished in the presence of the SN. The findings showed that the inhibitory effect on viral propagation by the SN was mostly attributed to interferon-γ (IFN-γ) that was present in the SN. These results highlight the potential role of IFN-γ as an anti-SARS-CoV-2 mediator derived from CD4 + T cells, and suggest that we need to understand the SARS-CoV-2 strain-dependent sensitivity to IFN-γ in controlling clinical outcomes. In addition, characterization of new SARS-CoV-2 variants in terms of IFN-γ-sensitivity will have important implications for selecting therapeutic strategies., (© 2024. The Author(s).)

During the COVID-19 pandemic, widespread school closures were implemented globally based on the assumption that transmission among children in the school environment is common. However, evidence regarding secondary infection rates by school type and level of contact is lacking. Our study estimated the frequency of SARS-CoV-2 infection in school settings by examining the positivity rate according to school type and level of contact by using data from a large-scale school-based PCR project conducted in Okinawa, Japan, during 2021-2022. Our results indicate that, despite detection of numerous positive cases, the average number of secondary infections remained relatively low at ≈0.5 cases across all types of schools. Considering the profound effects of prolonged closures on educational access, balancing public health benefits against potential long-term effects on children is crucial.

We estimated the seroprevalence of anti-SARS-COV-2 IgG in different island groups in Okinawa. A cross-sectional sero-survey was repeated in three periods between July 2020 and February 2021. A total of 2683 serum samples were collected from six referral medical centers, each covering a separate region in Okinawa. In the main island, the seroprevalence was 0.0% (0/392, 95% CI: 0.0-0.9), 0.6% (8/1448, 0.2-1.1), and 1.4% (8/582, 0.6-2.7) at the 1 st , 2 nd , and 3 rd sero-survey, respectively. In the remote islands, the seroprevalence was 0.0% (0/144, 95% CI: 0.0-2.5) and 1.6% (2/123, 0.2-5.8) at the 2 nd and 3 rd survey, respectively. The case detection ratio was 2.7 (95% CI: 1.3-5.3) in the main island and 2.8 (0.7-11.1) in the remote islands during the 3 rd survey. The case detection ratio was the highest in people aged 20-29 years (8.3, 95% CI: 3.3-21.4) in the main island and in those aged 50-59 years (14.1, 2.1-92.7) in the remote islands, suggesting under-reporting of clinical cases by the surveillance system in these subgroups. A sero-survey during an emerging infectious disease epidemic can be useful for validating the reliability of the surveillance system by providing the case detection ratio.

In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population., (© 2024 The Author(s). Microbiology and Immunology published by The Societies and John Wiley & Sons Australia, Ltd.)

Purpose: To investigate the long-term outcomes of congenital cataract surgery performed within the first 6 months of life., Setting: 11 ophthalmic surgical sites in Japan., Design: Retrospective chart review., Methods: Medical charts were retrospectively reviewed for 216 eyes of 121 patients. The age at surgery was 2.9 ± 1.7 months, with follow-up duration 13.0 ± 2.3 years. The cohort consisted of 83 cases with bilateral aphakia, 12 with bilateral pseudophakia, 20 with unilateral aphakia, and 6 with unilateral pseudophakia., Results: Surgical intervention within the critical period of visual system development (10 weeks for bilateral and 6 weeks for unilateral cases) led to significantly better final visual acuity than surgery conducted after this time frame. The incidence of secondary glaucoma was similar between groups while the occurrence of visual axis opacification was more frequent with earlier surgery. A forward stepwise multiple regression analysis revealed that the final visual acuity was significantly associated with laterality of cataract (better outcomes in bilateral cases), phakic status (with pseudophakia outperforming aphakia), presence of systemic and ocular comorbidities, and development of secondary glaucoma. Secondary glaucoma was significantly more prevalent in aphakic eyes than pseudophakic eyes., Conclusions: In patients with genuine congenital cataract, surgery within the critical period of visual development results in better final visual acuity, albeit with an increased risk of visual axis opacification. The use of IOL with sophisticated surgical techniques shows promise even in congenital cataract surgery., (Copyright © 2024 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Background: Although several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences in virological characteristics between SARS-CoV-2 and SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat and was found to lack a furin cleavage site (FCS) in the spike (S) protein. The comparison of its virological characteristics with FCS-deleted SARS-CoV-2 (SC2ΔFCS) has not been conducted yet., Methods: We prepared human induced pluripotent stem cell (iPSC)-derived airway and lung epithelial cells and colon organoids as human organ-relevant models. B236, SARS-CoV-2, and artificially generated SC2ΔFCS were used for viral experiments. To investigate the pathogenicity of B236 in vivo, we conducted intranasal infection experiments in hamsters., Findings: In human iPSC-derived airway epithelial cells, the growth of B236 was significantly lower than that of the SC2ΔFCS. A fusion assay showed that the B236 and SC2ΔFCS S proteins were less fusogenic than the SARS-CoV-2 S protein. The infection experiment in hamsters showed that B236 was less pathogenic than SARS-CoV-2 and even SC2ΔFCS. Interestingly, in human colon organoids, the growth of B236 was significantly greater than that of SARS-CoV-2., Interpretation: Compared to SARS-CoV-2, we demonstrated that B236 exhibited a tropism toward intestinal cells rather than respiratory cells. Our results are consistent with a previous report showing that B236 is enterotropic in macaques. Altogether, our report strengthens the assumption that SC2r-CoVs in horseshoe bats replicate primarily in the intestinal tissues rather than respiratory tissues., Funding: This study was supported in part by AMED ASPIRE (JP23jf0126002, to Keita Matsuno, Kazuo Takayama, and Kei Sato); AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers "UTOPIA" (JP223fa627001, to Kei Sato), AMED SCARDA Program on R&D of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED SCARDA Hokkaido University Institute for Vaccine Research and Development (HU-IVReD) (JP223fa627005h0001, to Takasuke Fukuhara, and Keita Matsuno); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP21fk0108574, to Hesham Nasser; JP21fk0108493, to Takasuke Fukuhara; JP22fk0108617 to Takasuke Fukuhara; JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, and Kei Sato; JP21fk0108425, to Kazuo Takayama and Kei Sato; JP21fk0108432, to Kazuo Takayama, Takasuke Fukuhara and Kei Sato; JP22fk0108534, Terumasa Ikeda, and Kei Sato; JP22fk0108511, to Yuki Yamamoto, Terumasa Ikeda, Keita Matsuno, Shinya Tanaka, Kazuo Takayama, Takasuke Fukuhara, and Kei Sato; JP22fk0108506, to Kazuo Takayama and Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410055, to Terumasa Ikeda; and JP22fk0410039, to Kei Sato); AMED Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125008 to Keita Matsuno); AMED CREST (JP21gm1610005, to Kazuo Takayama; JP22gm1610008, to Takasuke Fukuhara; JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to G2P-Japan Consortium, Keita Matsuno, Takasuke Fukuhara and Kei Sato); JST SPRING (JPMJSP2108 to Shigeru Fujita); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103, to Terumasa Ikeda); JSPS KAKENHI Grant-in-Aid for Scientific Research B (21H02736, to Takasuke Fukuhara); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (22K16375, to Hesham Nasser; 20K15767, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to Kei Sato); JSPS Research Fellow DC2 (22J11578, to Keiya Uriu); JSPS Research Fellow DC1 (23KJ0710, to Yusuke Kosugi); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to Terumasa Ikeda); World-leading Innovative and Smart Education (WISE) Program 1801 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Naganori Nao); Ministry of Health, Labour and Welfare (MHLW) under grant 23HA2010 (to Naganori Nao and Keita Matsuno); The Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University (to Kei Sato); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to Terumasa Ikeda and Takasuke Fukuhara); The Tokyo Biochemical Research Foundation (to Kei Sato); Takeda Science Foundation (to Terumasa Ikeda and Takasuke Fukuhara); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Terumasa Ikeda); The Naito Foundation (to Terumasa Ikeda); Hokuto Foundation for Bioscience (to Tomokazu Tamura); Hirose Foundation (to Tomokazu Tamura); and Mitsubishi Foundation (to Kei Sato)., Competing Interests: Declaration of interests Yuki Yamamoto and Tetsuharu Nagamoto are founders and shareholders of HiLung, Inc. Yuki Yamamoto is a co-inventor of patents (PCT/JP2016/057254; "Method for inducing differentiation of alveolar epithelial cells", PCT/JP2016/059786, "Method of producing airway epithelial cells"). Jumpei Ito has consulting fees and honoraria for lectures from Takeda Pharmaceutical Co. Ltd. Kei Sato has consulting fees from Moderna Japan Co., Ltd. and Takeda Pharmaceutical Co. Ltd. and honoraria for lectures from Gilead Sciences, Inc., Moderna Japan Co., Ltd., and Shionogi & Co., Ltd. The other authors declare that no competing interests exist., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells with immunosuppressive functions. It is known that MDSCs are expanded at inflammatory sites after migrating from bone marrow (BM) or spleen (Sp). In chronic inflammatory diseases such as rheumatoid arthritis (RA), previous reports indicate that MDSCs are increased in BM and Sp, but detailed analysis of MDSCs in inflamed joints is very limited., Objective: The purpose of this study is to characterize the MDSCs in the joints of mice with autoimmune arthritis., Methods: We sorted CD11b + Gr1 + cells from joints (Jo), bone marrow (BM) and spleen (Sp) of SKG mice with zymosan (Zym)-induced arthritis and investigated differentially expressed genes (DEGs) by microarray analysis. Based on the identified DEGs, we assessed the suppressive function of CD11b + Gr1 + cells from each organ and their ability to differentiate into osteoclasts., Results: We identified MDSCs as CD11b + Gr1 + cells by flow cytometry and morphological analysis. Microarray analysis revealed that Jo-CD11b + Gr1 + cells had different characteristics compared with BM-CD11b + Gr1 + cells or Sp-CD11b + Gr1 + cells. Microarray and qPCR analysis showed that Jo-CD11b + Gr1 + cells strongly expressed immunosuppressive DEGs ( Pdl1, Arg1, Egr2 and Egr3 ). Jo-CD11b + Gr1 + cells significantly suppressed CD4 + T cell proliferation and differentiation in vitro , which confirmed Jo-CD11b + Gr1 + cells as MDSCs. Microarray analysis also revealed that Jo-MDSCs strongly expressed DEGs of the NF-κB non-canonical pathway ( Nfkb2 and Relb ), which is relevant for osteoclast differentiation. In fact, Jo-MDSCs differentiated into osteoclasts in vitro and they had bone resorptive function. In addition, intra-articular injection of Jo-MDSCs promoted bone destruction., Conclusions: Jo-MDSCs possess a potential to differentiate into osteoclasts which promote bone resorption in inflamed joints, while they are immunosuppressive in vitro ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fujikawa, Sendo, del Peral Fanjul, Yamada, Uto, Yamamoto, Nagamoto, Morinobu and Saegusa.)