研究者詳細 - 上蓑　義典

論文 - 上蓑　義典

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Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019–2020: General view of the pathogens' antibacterial susceptibility

Tokimatsu I., Matsumoto T., Tsukada H., Fujikura Y., Miki M., Morinaga Y., Sato J., Wakamura T., Kiyota H., Tateda K., Yanagisawa H., Sasaki T., Ikeda H., Horikawa H., Takahashi H., Seki M., Mori Y., Takeda H., Kurai D., Hasegawa N., Uwamino Y., Kudo M., Yamamoto M., Nagano Y., Nomura S., Tetsuka T., Hosokai M., Aoki N., Yamamoto Y., Iinuma Y., Mikamo H., Suematsu H., Maruyama T., Kawabata A., Sugaki Y., Nakamura A., Fujikawa Y., Fukumori T., Ukimura A., Kakeya H., Niki M., Yoshida K., Kobashi Y., Tokuyasu H., Yatera K., Ikegami H., Fujita M., Matsumoto T., Yanagihara K., Matsuda J., Hiramatsu K., Shinzato T.

Journal of Infection and Chemotherapy （Journal of Infection and Chemotherapy） 29 （ 8 ） 731 - 743 2023年08月

ISSN 1341321X

The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were β-lactamase-producing ampicillin resistant and β-lactamase-negative ampicillin resistant, respectively. Extended-spectrum β-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-β-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

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Differences among epitopes recognized by neutralizing antibodies induced by SARS-CoV-2 infection or COVID-19 vaccination

Yamamoto S., Yamayoshi S., Ito M., Sakai-Tagawa Y., Nakachi I., Baba R., Kamimoto S., Ogura T., Hagiwara S., Kato H., Nakajima H., Uwamino Y., Yagi K., Sugaya N., Nagai H., Saito M., Adachi E., Koga M., Tsutsumi T., Duong C., Okuda M., Murakami J., Furusawa Y., Ujie M., Iwatsuki-Horimoto K., Yotsuyanagi H., Kawaoka Y.

iScience （iScience） 26 （ 7 ） 107208 2023年07月

SARS-CoV-2 has gradually acquired amino acid substitutions in its S protein that reduce the potency of neutralizing antibodies, leading to decreased vaccine efficacy. Here, we attempted to obtain mutant viruses by passaging SARS-CoV-2 in the presence of plasma samples from convalescent patients or vaccinees to determine which amino acid substitutions affect the antigenicity of SARS-CoV-2. Several amino acid substitutions in the S2 region, as well as the N-terminal domain (NTD) and receptor-binding domain (RBD), affected the neutralization potency of plasma samples collected from vaccinees, indicating that amino acid substitutions in the S2 region as well as those in the NTD and RBD affect neutralization by vaccine-induced antibodies. Furthermore, the neutralizing potency of vaccinee plasma samples against mutant viruses we obtained or circulating viruses differed among individuals. These findings suggest that genetic backgrounds of vaccinees influence the recognition of neutralizing epitopes.

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Healthcare costs for hospitalized COVID-19 patients in a Japanese university hospital: a cross-sectional study.

Uno S, Goto R, Honda K, Tokuda M, Kamata H, Chubachi S, Yamamoto R, Sato Y, Homma K, Uchida S, Namkoong H, Uwamino Y, Sasaki J, Fukunaga K, Hasegawa N

Cost effectiveness and resource allocation : C/E 21 （ 1 ） 43 2023年07月

ISSN 1478-7547

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Single-cell analyses and host genetics highlight the role of innate immune cells in COVID-19 severity

Edahiro R., Shirai Y., Takeshima Y., Sakakibara S., Yamaguchi Y., Murakami T., Morita T., Kato Y., Liu Y.C., Motooka D., Naito Y., Takuwa A., Sugihara F., Tanaka K., Wing J.B., Sonehara K., Tomofuji Y., Wang Q.S., Hasegawa T., Saiki R., Hyugaji T., Shimizu E., Katayama K., Kanai M., Naito T., Sasa N., Yamamoto K., Takahashi K., Harada N., Naito T., Hiki M., Matsushita Y., Takagi H., Ichikawa M., Nakamura A., Harada S., Sandhu Y., Kabata H., Masaki K., Kamata H., Ikemura S., Chubachi S., Okamori S., Terai H., Morita A., Asakura T., Sasaki J., Morisaki H., Uwamino Y., Nanki K., Uchida S., Uno S., Nishimura T., Ishiguro T., Isono T., Shibata S., Matsui Y., Hosoda C., Takano K., Nishida T., Kobayashi Y., Takaku Y., Takayanagi N., Ueda S., Tada A., Miyawaki M., Yamamoto M., Yoshida E., Hayashi R., Nagasaka T., Arai S., Kaneko Y., Sasaki K., Tagaya E., Kawana M., Arimura K., Takahashi K., Anzai T., Ito S., Endo A., Uchimura Y., Miyazaki Y., Honda T., Tateishi T., Tohda S., Ichimura N., Sonobe K., Sassa C.T., Nakajima J., Nakano Y., Nakajima Y., Anan R., Arai R., Kurihara Y., Harada Y., Nishio K., Ueda T., Azuma M., Saito R., Sado T.

Nature Genetics （Nature Genetics） 55 （ 5 ） 753 - 767 2023年05月

ISSN 10614036

Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of >895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell–cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.

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Diagnostic Utility of a Mycobacterium Multiplex PCR Detection Panel for Tuberculosis and Nontuberculous Mycobacterial Infections

Uwamino Y., Aono A., Tomita Y., Morimoto K., Kawashima M., Kamata H., Sasaki Y., Nagai H., Hasegawa N., Mitarai S.

Microbiology spectrum （Microbiology spectrum） 11 （ 3 ） e0516222 2023年04月

The prevalence of nontuberculous mycobacterial diseases is increasing worldwide, and tuberculosis remains highly prevalent. Rapid and accurate microbial diagnoses of both tuberculosis and nontuberculous mycobacterial infections are required. A novel PCR-reverse sequence-specific oligonucleotide probe (PCR-rSSO) method-based mycobacterial detection panel (Myco-Panel) test was developed for the rapid identification of 30 mycobacterial species and subspecies. Clinical respiratory samples were collected from patients with suspected or confirmed tuberculosis and nontuberculous mycobacterial lung disease and those with other respiratory diseases. Myco-Panel tests were performed on the samples, and liquid mycobacterial culture and identification were performed for reference according to housekeeping gene sequences of mycobacteria in positive culture tubes. Furthermore, to assess the detection performance for several mycobacterial species rarely recovered in Japan, the accuracy of the Myco-Panel test was investigated using stock mycobacterial type strains and clinical isolates. A total of 178 clinical respiratory samples were analyzed. The Myco-Panel and sequence-based identification results for mycobacterial cultures were 83.1% concordant (kappa coefficient, 0.785 [95% confidence interval, 0.716 to 0.854]). The Myco-Panel correctly identified 281 of the 283 type strains and clinical isolates tested. The Myco-Panel test could accurately detect several mycobacterial species from clinical respiratory samples and mycobacterial suspensions. Rapid and accurate identification of pathogens using respiratory samples is possible using the Myco-Panel. IMPORTANCE Species identification is important for the diagnosis of mycobacterial infections and decisions on treatment regimens. The Myco-Panel test accurately detects clinically common mycobacterial species that cause respiratory infections from clinical respiratory samples and mycobacterial suspensions. The rapid identification of multiple mycobacterial species will provide clinically useful information for the management of patients. Although we understand that the current diagnostic criteria require mycobacterial culture results in general for the diagnosis of nontuberculous mycobacterial infection, mycobacterial culture examination is a time-consuming process. The detection of potentially causative agents directly from clinical samples will aid in practical diagnosis and decision-making for rapid treatment initiation. This is a new laboratory method for species identification, and evaluating its performance is important.

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Estimating immunity with mathematical models for SARS-CoV-2 after COVID-19 vaccination

Uwamino Y., Nagashima K., Yoshifuji A., Suga S., Nagao M., Fujisawa T., Ryuzaki M., Takemoto Y., Namkoong H., Wakui M., Matsushita H., Hasegawa N., Sato Y., Murata M.

npj Vaccines （npj Vaccines） 8 （ 1 ） 33 2023年03月

Tools that can be used to estimate antibody waning following COVID-19 vaccinations can facilitate an understanding of the current immune status of the population. In this study, a two-compartment-based mathematical model is formulated to describe the dynamics of the anti-SARS-CoV-2 antibody in healthy adults using serially measured waning antibody concentration data obtained in a prospective cohort study of 673 healthcare providers vaccinated with two doses of BNT162b2 vaccine. The datasets of 165 healthcare providers and 292 elderly patients with or without hemodialysis were used for external validation. Internal validation of the model demonstrated 97.0% accuracy, and external validation of the datasets of healthcare workers, hemodialysis patients, and nondialysis patients demonstrated 98.2%, 83.3%, and 83.8% accuracy, respectively. The internal and external validations demonstrated that this model also fits the data of various populations with or without underlying illnesses. Furthermore, using this model, we developed a smart device application that can rapidly calculate the timing of negative seroconversion.

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Multi-omics of NET formation and correlations with CNDP1, PSPB, and L-cystine levels in severe and mild COVID-19 infections

Bramer L.M., Hontz R.D., Eisfeld A.J., Sims A.C., Kim Y.M., Stratton K.G., Nicora C.D., Gritsenko M.A., Schepmoes A.A., Akasaka O., Koga M., Tsutsumi T., Nakamura M., Nakachi I., Baba R., Tateno H., Suzuki S., Nakajima H., Kato H., Ishida K., Ishii M., Uwamino Y., Mitamura K., Paurus V.L., Nakayasu E.S., Attah I.K., Letizia A.G., Waters K.M., Metz T.O., Corson K., Kawaoka Y., Gerbasi V.R., Yotsuyanagi H., Iwatsuki-Horimoto K.

Heliyon （Heliyon） 9 （ 3 ） e13795 2023年03月

ISSN 24058440

The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics and correlative analysis of an immunologically naïve SARS-CoV-2 clinical cohort from blood plasma of uninfected controls, mild, and severe infections. Consistent with previous observations, severe patient populations showed an elevation of pulmonary surfactant levels. Intriguingly, mild patients showed a statistically significant elevation in the carnosine dipeptidase modifying enzyme (CNDP1). Mild and severe patient populations showed a strong elevation in the metabolite L-cystine (oxidized form of the amino acid cysteine) and enzymes with roles in glutathione metabolism. Neutrophil extracellular traps (NETs) were observed in both mild and severe populations, and NET formation was higher in severe vs. mild samples. Our correlative analysis suggests a potential protective role for CNDP1 in suppressing PSPB release from the pulmonary space whereas NET formation correlates with increased PSPB levels and disease severity. In our discussion we put forward a possible model where NET formation drives pulmonary occlusions and CNDP1 promotes antioxidation, pleiotropic immune responses, and vasodilation by accelerating histamine synthesis.

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Humoral and cellular immune response dynamics in Japanese healthcare workers up to six months after receiving a third dose of BNT162b2 monovalent vaccine

Uwamino Y., Yokoyama T., Sato Y., Shibata A., Kurafuji T., Tanabe A., Noguchi M., Arai T., Ohno A., Yokota H., Namkoong H., Nishimura T., Kosaki K., Hasegawa N., Wakui M., Murata M., Matsushita H.

Vaccine （Vaccine） 41 （ 9 ） 1545 - 1549 2023年02月

ISSN 0264410X

Longitudinal data on the immune response from the first dose to several months after the third dose of COVID-19 vaccine are limited. We analyzed the immune response in 406 Japanese healthcare workers who received at least three doses of vaccine. The geometric mean anti-receptor binding domain IgG antibody titers and antigen-stimulated T-cell interferon-gamma levels after 6 months after receiving a third dose were similar to those 8 weeks after receiving a second dose. Humoral and cellular immunity induced by the third dose was more durable than that induced by the second dose. UMIN Clinical Trials Registry ID: UMIN000043340.

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Nasopharyngeal Mycobacterium abscessus Infection: A Case Report and Literature Review

Kaji M., Namkoong H., Nagao G., Azekawa S., Nakagawara K., Tanaka H., Morita A., Asakura T., Kamata H., Uwamino Y., Yoshida M., Fukunaga K., Hasegawa N.

Infection and Drug Resistance （Infection and Drug Resistance） 16 3955 - 3963 2023年

ISSN 1178-6973

Background: Mycobacterium abscessus (M. abscessus) is a rapidly growing bacterium (RGM) that causes refractory pulmonary and extrapulmonary infections. However, studies investigating pharyngeal and laryngeal M. abscessus infections are limited. Case Presentation: A 41-year-old immunocompetent woman complaining of bloody sputum was referred to our hospital. Although her sputum culture tested positive for M. abscessus subsp. abscessus, radiological findings were not indicative of pulmonary infection or sinusitis. Further diagnostic workup, including laryngeal endoscopy and positron emission tomography/computed tomography (PET/CT), confirmed the presence of nasopharyngeal M. abscessus infection. The patient was initially treated with intravenous amikacin, imipenem/ cilastatin, azithromycin, and clofazimine for 28 days, after which the patient was provided with amikacin, azithromycin, clofazimine, and sitafloxacin for four months. After the completion of antibiotic therapy, the patient showed negative results on sputum smear and culture and normal findings on PET/CT and laryngeal endoscopy. Whole-genome sequencing of this strain revealed that it belonged to the ABS-GL4 cluster, which has a functional erythromycin ribosomal methylase gene, although it is not a major lineage in non-cystic fibrosis (CF) patients in Japan and Taiwan and in CF patients in European countries. We conducted a literature review and identified seven patients who developed pharyngeal/laryngeal non-tuberculous mycobacterium (NTM) infection. Four of the eight patients had a history of immunosuppressant use, including steroids. Seven of the eight patients responded well to their treatment regimens. Conclusion: Patients whose sputum culture tests are positive for NTM and who meet the diagnostic criteria for NTM infection but do not have intrapulmonary lesions should be evaluated for otorhinolaryngological infections. Our case series revealed that immunosup-pressant use is a risk factor for pharyngeal/laryngeal NTM infection and that patients with pharyngeal/laryngeal NTM infections respond relatively well to antibiotic therapy.

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Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant

Mise-Omata S., Ikeda M., Takeshita M., Uwamino Y., Wakui M., Arai T., Yoshifuji A., Murano K., Siomi H., Nakagawara K., Ohyagi M., Ando M., Hasegawa N., Saya H., Murata M., Fukunaga K., Namkoong H., Lu X., Yamasaki S., Yoshimura A.

Journal of Immunology （Journal of Immunology） 209 （ 11 ） 2104 - 2113 2022年12月

ISSN 00221767

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR62 circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

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Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant.

Mise-Omata S, Ikeda M, Takeshita M, Uwamino Y, Wakui M, Arai T, Yoshifuji A, Murano K, Siomi H, Nakagawara K, Ohyagi M, Ando M, Hasegawa N, Saya H, Murata M, Fukunaga K, Namkoong H, Lu X, Yamasaki S, Yoshimura A

Journal of immunology (Baltimore, Md. : 1950) 209 （ 11 ） 2104 - 2113 2022年12月

ISSN 0022-1767

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Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant.

Setsuko Mise-Omata, Mari Ikeda, Masaru Takeshita, Yoshifumi Uwamino, Masatoshi Wakui, Tomoko Arai, Ayumi Yoshifuji, Kensaku Murano, Haruhiko Siomi, Kensuke Nakagawara, Masaki Ohyagi, Makoto Ando, Naoki Hasegawa, Hideyuki Saya, Mitsuru Murata, Koichi Fukunaga, Ho Namkoong, Xiuyuan Lu, Sho Yamasaki, Akihiko Yoshimura

Journal of immunology (Baltimore, Md. : 1950) 209 （ 11 ） 2104 - 2113 2022年12月

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

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Age-Stratified Seroprevalence of SARS-CoV-2 Antibodies before and during the Vaccination Era, Japan, February 2020–March 2022

Yamayoshi S., Iwatsuki-Horimoto K., Okuda M., Ujie M., Yasuhara A., Murakami J., Duong C., Hamabata T., Ito M., Chiba S., Kobayashi R., Takahashi S., Mitamura K., Hagihara M., Shibata A., Uwamino Y., Hasegawa N., Ebina T., Izumi A., Kato H., Nakajima H., Sugaya N., Seki Y., Iqbal A., Kamimaki I., Yamazaki M., Kawaoka Y., Furuse Y.

Emerging Infectious Diseases （Emerging Infectious Diseases） 28 （ 11 ） 2198 - 2205 2022年11月

ISSN 10806040

Japan has reported a relatively small number of COVID-19 cases. Because not all infected persons receive diagnostic tests for COVID-19, the reported number must be lower than the actual number of infections. We assessed SARSCoV-2 seroprevalence by analyzing >60,000 samples collected in Japan (Tokyo Metropolitan Area and Hokkaido Prefecture) during February 2020–March 2022. The results showed that ≈3.8% of the population had become seropositive by January 2021. The seroprevalence increased with the administration of vaccinations; however, among the elderly, seroprevalence was not as high as the vaccination rate. Among children, who were not eligible for vaccination, infection was spread during the epidemic waves caused by the SARS-CoV-2 Delta and Omicron variants. Nevertheless, seroprevalence for unvaccinated children <5 years of age was as low as 10% as of March 2022. Our study underscores the low incidence of SARS-CoV-2 infection in Japan and the effects of vaccination on immunity at the population level.

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Assessing anti-SARS-CoV-2 cellular immunity in 571 vaccines by using an IFN-γ release assay

Wakui M., Uwamino Y., Yatabe Y., Nakagawa T., Sakai A., Kurafuji T., Shibata A., Tomita Y., Noguchi M., Tanabe A., Arai T., Ohno A., Yokota H., Uno S., Yamasawa W., Sato Y., Ikeda M., Yoshimura A., Hasegawa N., Saya H., Murata M.

European Journal of Immunology （European Journal of Immunology） 52 （ 12 ） 1961 - 1971 2022年10月

ISSN 00142980

Memory T cell responses have been analyzed only in small cohorts of COVID-19 vaccines. Herein, we aimed to assess anti-SARS-CoV-2 cellular immunity in a large cohort using QuantiFERON assays, which are IFN-γ release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals receiving the viral spike (S) protein-expressing BNT162b2 mRNA vaccine. QuantiFERON assays revealed antigen-specific IFN-γ production in most individuals 8 weeks after the second dose. Simultaneous flow cytometric assays to detect T cells expressing activation-induced markers (AIMs) performed for 28 randomly selected individuals provided data correlating with the QuantiFERON data. Simultaneous IFN-γ enzyme-linked immunospot and AIM assays for another subset of 31 individuals, based on short-term peripheral blood mononuclear cell culture, also indicated a correlation between IFN-γ production and AIM positivity. These observations indicated the acquisition of T cell memory responses and supported the usability of IGRAs to assess cellular immunity. The QuantiFERON results were weakly correlated with serum IgG titers against the receptor-binding domain of the S protein and were associated with pre-vaccination infection and adverse reactions after the second dose. The present study revealed cellular immunity after COVID-19 vaccination, providing insights into the effects and adverse reactions of vaccination.

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Memory B Cells and Memory T Cells Induced by SARS-CoV-2 Booster Vaccination or Infection Show Different Dynamics and Responsiveness to the Omicron Variant.

Journal of immunology (Baltimore, Md. : 1950) 2022年10月

Although the immunological memory produced by BNT162b2 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been well studied and established, further information using different racial cohorts is necessary to understand the overall immunological response to vaccination. We evaluated memory B and T cell responses to the severe acute respiratory syndrome coronavirus 2 spike protein before and after the third booster using a Japanese cohort. Although the Ab titer against the spike receptor-binding domain (RBD) decreased significantly 8 mo after the second vaccination, the number of memory B cells continued to increase, whereas the number of memory T cells decreased slowly. Memory B and T cells from unvaccinated infected patients showed similar kinetics. After the third vaccination, the Ab titer increased to the level of the second vaccination, and memory B cells increased at significantly higher levels before the booster, whereas memory T cells recovered close to the second vaccination levels. In memory T cells, the frequency of CXCR5+CXCR3+CCR6- circulating follicular Th1 was positively correlated with RBD-specific Ab-secreting B cells. For the response to variant RBDs, although 60-80% of memory B cells could bind to the omicron RBD, their avidity was low, whereas memory T cells show an equal response to the omicron spike. Thus, the persistent presence of memory B and T cells will quickly upregulate Ab production and T cell responses after omicron strain infection, which prevents severe illness and death due to coronavirus disease 2019.

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In vitro effects of diazabicyclooctane β-lactamase inhibitors relebactam and nacubactam against three subspecies of Mycobacterium abscessus complex

Misawa K., Nishimura T., Kashimura S., Enoki Y., Taguchi K., Uno S., Uwamino Y., Matsumoto K., Hasegawa N.

International Journal of Antimicrobial Agents （International Journal of Antimicrobial Agents） 60 （ 5-6 ） 106669 - 106669 2022年09月

ISSN 09248579

Background: Mycobacterium abscessus complex (MABC) pulmonary disease is notoriously difficult to treat due to intrinsic resistance to many common antibiotics. MABC is β-lactam-resistant as it produces class A β-lactamases, such as blaMab, which are inhibited by diazabicyclooctane (DBO) β-lactamase inhibitors. Objectives: To investigate the microbiological effects of the combination of β-lactam and DBO β-lactamase inhibitors (relebactam and nacubactam) against MABC and determine if the effects are associated with the MABC subspecies and colony morphotype. Methods: The antimicrobial susceptibility of three type strains and 20 clinical isolates of MABC to the combination of seven β-lactams with relebactam or nacubactam was evaluated using broth microdilution checkerboard assays. For these strains, expression levels of blaMab were assessed using quantitative real-time polymerase chain reaction and genotypic diversity was evaluated using 18-locus variable number tandem repeat assay. Results: Relebactam and nacubactam lowered the minimum inhibitory concentrations of β-lactams, particularly imipenem, meropenem, and tebipenem, against MABC. There was no difference in efficacy of combination treatment between three subspecies, but rough morphotypes tended to be less susceptible than smooth morphotypes. There were no differences in blaMab expression levels and genotypic diversity between the morphotypes. Conclusions: The combination of β-lactam with relebactam or nacubactam improved the efficacy of β-lactams against all MABC subspecies, but higher concentrations of β-lactams were needed for rough morphotypes.

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Identification of trypsin-degrading commensals in the large intestine

Li Y., Watanabe E., Kawashima Y., Plichta D.R., Wang Z., Ujike M., Ang Q.Y., Wu R., Furuichi M., Takeshita K., Yoshida K., Nishiyama K., Kearney S.M., Suda W., Hattori M., Sasajima S., Matsunaga T., Zhang X., Watanabe K., Fujishiro J., Norman J.M., Olle B., Matsuyama S., Namkoong H., Uwamino Y., Ishii M., Fukunaga K., Hasegawa N., Ohara O., Xavier R.J., Atarashi K., Honda K.

Nature （Nature） 609 （ 7927 ） 582 - 589 2022年09月

ISSN 00280836

Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions1–3. 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 cells4,5. 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.

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Dynamics of antibody titers and cellular immunity among Japanese healthcare workers during the 6 months after receiving two doses of BNT162b2 mRNA vaccine

Uwamino Y., Kurafuji T., Takato K., Sakai A., Tanabe A., Noguchi M., Yatabe Y., Arai T., Ohno A., Tomita Y., Shibata A., Yokota H., Yamasawa W., Namkoong H., Sato Y., Hasegawa N., Wakui M., Murata M.

Vaccine （Vaccine） 40 （ 32 ） 4538 - 4543 2022年07月

ISSN 0264410X

Background: The antibody titer is known to wane within months after receiving two doses of the Pfizer-BioNTech BNT162b2 mRNA SARS-CoV-2 vaccine. However, knowledge of the cellular immune response dynamics following vaccination is limited. This study to aimed to determine antibody and cellular immune responses following vaccination, and the incidence and determinants of breakthrough infection. Methods: This prospective cohort study a 6-month follow-up period was conducted among Japanese healthcare workers. All participants received two doses of BNT162b2 vaccine. Anti-SARS-CoV-2 antibody titers and T-cell immune responses were measured in serum samples collected at several timepoints before and after vaccination. Results: A total of 608 participants were included in the analysis. Antibody titers were elevated 3 weeks after vaccination and waned over the remainder of the study period. T-cell immune responses showed similar dynamics. Six participants without predisposing medical conditions seroconverted from negative to positive on the IgG assay for nucleocapsid proteins, indicating breakthrough SARS-CoV-2 infection. Five of the six breakthrough infections were asymptomatic. Conclusions: Both humoral and cellular immunity waned within 6 months after BNT162b2 vaccination. The incidence of asymptomatic breakthrough infection within 6 months after vaccination was approximately one percent. UMIN Clinical Trials Registry ID: UMIN000043340.

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Osteoporosis in nontuberculous mycobacterial pulmonary disease: a cross-sectional study

Tanaka H., Asakura T., Suzuki S., Okamori S., Kusumoto T., Ogawa T., Uno S., Morita A., Lee H., Namkoong H., Kamata H., Sato Y., Uwamino Y., Nishimura T., Ishii M., Fukunaga K., Hasegawa N.

BMC Pulmonary Medicine （BMC Pulmonary Medicine） 22 （ 1 ） 202 - 202 2022年05月

Background: Since nontuberculous mycobacterial pulmonary disease (NTM-PD) is common in middle-aged/elderly slender women at risk of osteoporosis, we hypothesized that NTM-PD could be associated with osteoporosis. The study aimed to evaluate the prevalence of osteoporosis in patients with NTM-PD compared with that in the general population and determine the factors associated with osteoporosis in the subjects, including the serum estradiol (E2) and 25-hydroxyvitamin D (25OHD) levels. Methods: We have recruited 228 consecutive adult patients with NTM-PD from a prospective cohort study at the Keio University Hospital, who had no history of osteoporosis or osteoporosis-associated bone fracture but underwent dual-energy X-ray absorptiometry-based bone mineral density (BMD) evaluation from August 2017–September 2019. The E2 and 25OHD levels were measured in 165 patients with available stored serum samples. We performed multivariable logistic regression analyses for osteopenia and osteoporosis. Results: Osteoporosis (T-score ≤ − 2.5) and osteopenia (T-score − 1 to − 2.5) were diagnosed in 35.1% and 36.8% of patients with NTM-PD, respectively. Compared with the general population, the proportion of osteoporosis was significantly higher in 50–59-, 60–69-, and 70–79-year-old women with NTM-PD. Multivariable analysis revealed that older age (adjusted odds ratio [aOR] for 1-year increase = 1.12; 95% confidence interval [CI] = 1.07–1.18), female sex (aOR = 36.3; 95% CI = 7.57–174), lower BMI (aOR for 1 kg/m2 decrease = 1.37; 95% CI = 1.14–1.65), and chronic Pseudomonas aeruginosa (PA) infection (aOR = 6.70; 95% CI = 1.07–41.8) were independently associated with osteoporosis. Additionally, multivariable analysis in 165 patients whose serum E2 and 25OHD levels were measured showed that both low E2 levels (< 10 pg/mL) and lower 25OHD levels were independently associated with osteoporosis. Conclusions: Middle-aged/elderly women with NTM-PD have a higher prevalence of osteoporosis than the general population. BMD screening should be considered in NTM-PD, especially in older females with severe diseases such as chronic PA infection and lower BMI, and low serum E2 and 25OHD levels.

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The effect of the E484K mutation of SARS-CoV-2 on the neutralizing activity of antibodies from BNT162b2 vaccinated individuals

Uwamino Y., Yokoyama T., Shimura T., Nishimura T., Sato Y., Wakui M., Kosaki K., Hasegawa N., Murata M.

Vaccine （Vaccine） 40 （ 13 ） 1928 - 1931 2022年03月

ISSN 0264410X

The reduced vaccine efficacy against the SARS-CoV-2 variant lineage B. 1.351 (beta variant) containing the E484K and N501Y mutations is well known. The E484K mutation in SARS-CoV-2 is thought to be responsible for weakened humoral immunity. Vaccine efficacy against the R.1 lineage, which contains the E484K mutation but not the N501Y mutation, is uncertain. Serum samples were collected from 100 healthy Japanese participants three weeks after receiving the second dose of the BNT162b2 vaccine, and serum neutralization antibody titers were measured against five SARS-CoV-2 variants. The geometric mean neutralization titers measured for the original and R.1 lineages were equivalent (91.90 ± 2.40 and 102.67 ± 2.28, respectively), whereas a low titer was measured for the beta variant (18.03 ± 1.92). Although further investigations with other variant strains and serum samples are essential, our results imply that the weakened humoral response is not caused solely by the E484K mutation. (UMIN000043340).

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