Details of a Researcher - Asakura, Takanori

Papers - Asakura, Takanori

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Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease.

Takafumi Kato*, Takanori Asakura*, Caitlin E Edwards, Hong Dang, Yu Mikami, Kenichi Okuda, Gang Chen, Ling Sun, Rodney C Gilmore, Padraig Hawkins, Gabriela De la Cruz, Michelle R Cooley, Alexis B Bailey, Stephen M Hewi, Daniel S Chertow, Alain C Borczuk, Steven Salvatore, Fernando J Martinez, Leigh B Thorne, Frederic B Askin, Camille Ehre, Scott H Randell, Wanda K O'Neal, Ralph S Baric, Richard C Boucher

American journal of respiratory and critical care medicine 206 ( 11 ) 1336 - 1352 2022.12

ISSN 1073449X

RATIONALE: The incidence and sites of mucus accumulation, and molecular regulation of mucin gene expression, in COVID-19 lung disease have not been reported. OBJECTIVES: Characterize incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. METHODS: Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by AB-PAS and immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. SARS-CoV-2-infected human bronchial epithelial (HBE) cultures were utilized to investigate mechanisms of SARS-CoV-2-induced mucin expression and synthesis and test candidate countermeasures. MEASUREMENTS AND MAIN RESULTS: MUC5B and variably MUC5AC RNA levels were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the sub-acute/chronic disease phase following SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of COVID-19 subjects in both morphologically identified bronchioles and microcysts, and MUC5B accumulated in damaged alveolar spaces. SARS-CoV-2-infected HBE cultures exhibited peak titers 3 days post inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days post inoculation. SARS-CoV-2 infection of HBE cultures induced expression of EGFR ligands and inflammatory cytokines (e.g., IL-1α/β) associated with mucin gene regulation. Inhibiting EGFR/IL-1R pathways, or dexamethasone administration, reduced SARS-CoV-2-induced mucin expression. CONCLUSIONS: SARS-CoV-2 infection is associated with a high prevalence of distal airspace mucus accumulation and increased MUC5B expression in COVID-19 autopsy lungs. HBE culture studies identified roles for EGFR and IL-1R signaling in mucin gene regulation post SARS-CoV-2 infection. These data suggest that time-sensitive mucolytic agents, specific pathway inhibitors, or corticosteroid administration may be therapeutic for COVID-19 lung disease. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Characteristics of hospitalized patients with COVID-19 during the first to fifth waves of infection: a report from the Japan COVID-19 Task Force.

Ho Lee, Shotaro Chubachi, Ho Namkoong, Takanori Asakura, Hiromu Tanaka, Shiro Otake, Kensuke Nakagawara, Atsuho Morita, Takahiro Fukushima, Mayuko Watase, Tatsuya Kusumoto, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Koji Murakami, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

BMC infectious diseases 22 ( 1 ) 935 - 935 2022.12

ISSN 2186-5884

BACKGROUND: We aimed to elucidate differences in the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan, by COVID-19 waves, from conventional strains to the Delta variant. METHODS: We used secondary data from a database and performed a retrospective cohort study that included 3261 patients aged ≥ 18 years enrolled from 78 hospitals that participated in the Japan COVID-19 Task Force between February 2020 and September 2021. RESULTS: Patients hospitalized during the second (mean age, 53.2 years [standard deviation {SD}, ± 18.9]) and fifth (mean age, 50.7 years [SD ± 13.9]) COVID-19 waves had a lower mean age than those hospitalized during the other COVID-19 waves. Patients hospitalized during the first COVID-19 wave had a longer hospital stay (mean, 30.3 days [SD ± 21.5], p < 0.0001), and post-hospitalization complications, such as bacterial infections (21.3%, p < 0.0001), were also noticeable. In addition, there was an increase in the use of drugs such as remdesivir/baricitinib/tocilizumab/steroids during the latter COVID-19 waves. In the fifth COVID-19 wave, patients exhibited a greater number of presenting symptoms, and a higher percentage of patients required oxygen therapy at the time of admission. However, the percentage of patients requiring invasive mechanical ventilation was the highest in the first COVID-19 wave and the mortality rate was the highest in the third COVID-19 wave. CONCLUSIONS: We identified differences in clinical characteristics of hospitalized patients with COVID-19 in each COVID-19 wave up to the fifth COVID-19 wave in Japan. The fifth COVID-19 wave was associated with greater disease severity on admission, the third COVID-19 wave had the highest mortality rate, and the first COVID-19 wave had the highest percentage of patients requiring mechanical ventilation.

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The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

Wang Q.S., Edahiro R., Namkoong H., Hasegawa T., Shirai Y., Sonehara K., Tanaka H., Lee H., Saiki R., Hyugaji T., Shimizu E., Katayama K., Kanai M., Naito T., Sasa N., Yamamoto K., Kato Y., Morita T., 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., Miyazaki Y., Sato R., Haruta Y., Nagasaki T., Yasui Y., Hasegawa Y., Mutoh Y., Kimura T., Sato T.

Nature Communications 13 ( 1 ) 2022.12

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

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

Hiromu Tanaka, Takanori Asakura, Shoji Suzuki, Satoshi Okamori, Tatsuya Kusumoto, Takunori Ogawa, Shunsuke Uno, Atsuho Morita, Ho Lee, Ho Namkoong, Hirofumi Kamata, Yasunori Sato, Yoshifumi Uwamino, Tomoyasu Nishimura, Makoto Ishii, Koichi Fukunaga, Naoki Hasegawa

BMC pulmonary medicine 22 ( 1 ) 202 - 202 2022.12

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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Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study.

Kensuke Nakagawara, Shotaro Chubachi, Ho Namkoong, Hiromu Tanaka, Ho Lee, Shuhei Azekawa, Shiro Otake, Takahiro Fukushima, Atsuho Morita, Mayuko Watase, Kaori Sakurai, Tatsuya Kusumoto, Takanori Asakura, Katsunori Masaki, Hirofumi Kamata, Makoto Ishii, Naoki Hasegawa, Norihiro Harada, Tetsuya Ueda, Soichiro Ueda, Takashi Ishiguro, Ken Arimura, Fukuki Saito, Takashi Yoshiyama, Yasushi Nakano, Yoshikazu Mutoh, Yusuke Suzuki, Ryuya Edahiro, Koji Murakami, Yasunori Sato, Yukinori Okada, Ryuji Koike, Yuko Kitagawa, Katsushi Tokunaga, Akinori Kimura, Seiya Imoto, Satoru Miyano, Seishi Ogawa, Takanori Kanai, Koichi Fukunaga

Respiratory research 23 ( 1 ) 315 - 315 2022.12

ISSN 14659921

BACKGROUND: Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. METHODS: This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. RESULTS: Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11-0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43-4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. CONCLUSIONS: Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

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Clinical utility of whole body diffusion-weighted imaging in an immunocompetent adult with atypical cat scratch disease.

Jin Kagatani, Takanori Asakura, Katsutoshi Sekine, Hiromi Watanabe, Miki Kawada, Kiyofumi Ohkusu, Takashi Koyama

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 28 ( 11 ) 1558 - 1561 2022.11

ISSN 1341321X

BACKGROUND: Cat scratch disease (CSD) is an infectious disease caused by Bartonella henselae. CSD follows a typical course, characterized by regional lymphadenopathy. In atypical CSD, the lesions spread to systemic organs and can cause fever of unknown origin (FUO). A previous study showed the usefulness of whole-body magnetic resonance imaging (WB-MRI) without diffusion-weighted imaging (DWI) in the diagnosis of FUO, but there are no studies on the clinical utility of whole-body DWI (WB-DWI). We herein report the case of an immunocompetent young man in whom contrast-enhanced CT-unidentifiable multiple liver abscess and osteomyelitis were successfully detected by WB-DWI. Follow up with a liver biopsy helped confirm an atypical CSD diagnosis. CASE PRESENTATION: A 23-year-old previously healthy man was admitted for a 19-day history of high fever despite 3-day treatment by azithromycin. His physical examination was unremarkable and contrast-enhanced CT showed only a low attenuated area in the right lobe of the liver, indicating a cyst. WB-DWI revealed multiple nodular lesions of hypo-diffusion in the liver, spine, and pelvic region. The biopsy specimens of the liver abscess showed no evidence of tuberculosis/malignancy and the polymerase chain reaction (PCR) test of liver abscess aspirate showed positive findings for B. henselae, confirming the diagnosis of CSD. He completed minocycline monotherapy for a total of 60 days without any deterioration. CONCLUSIONS: WB-DWI can be useful for the diagnosis of atypical CSD with hepatic and bone involvement, which can cause FUO in young immunocompetent adults.

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SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice.

Kenneth H Dinnon 3rd, Sarah R Leist, Kenichi Okuda, Hong Dang, Ethan J Fritch, Kendra L Gully, Gabriela De la Cruz, Mia D Evangelista, Takanori Asakura, Rodney C Gilmore, Padraig Hawkins, Satoko Nakano, Ande West, Alexandra Schäfer, Lisa E Gralinski, Jamie L Everman, Satria P Sajuthi, Mark R Zweigart, Stephanie Dong, Jennifer McBride, Michelle R Cooley, Jesse B Hines, Miriya K Love, Steve D Groshong, Alison VanSchoiack, Stefan J Phelan, Yan Liang, Tyler Hether, Michael Leon, Ross E Zumwalt, Lisa M Barton, Eric J Duval, Sanjay Mukhopadhyay, Edana Stroberg, Alain Borczuk, Leigh B Thorne, Muthu K Sakthivel, Yueh Z Lee, James S Hagood, Jason R Mock, Max A Seibold, Wanda K O'Neal, Stephanie A Montgomery, Richard C Boucher, Ralph S Baric

Science translational medicine 14 ( 664 ) eabo5070 2022.09

ISSN 19466234

A subset of individuals who recover from coronavirus disease 2019 (COVID-19) develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal tissue samples. The mouse-adapted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute to clinical recovery phases. At 15 to 120 days post-virus clearance, pulmonary histologic findings included subpleural lesions composed of collagen, proliferative fibroblasts, and chronic inflammation, including tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal up-regulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

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DOCK2 is involved in the host genetics and biology of severe COVID-19

Namkoong H., Edahiro R., Takano T., Nishihara H., Shirai Y., Sonehara K., Tanaka H., Azekawa S., Mikami Y., Lee H., Hasegawa T., Okudela K., Okuzaki D., Motooka D., Kanai M., Naito T., Yamamoto K., Wang Q.S., Saiki R., Ishihara R., Matsubara Y., Hamamoto J., Hayashi H., Yoshimura Y., Tachikawa N., Yanagita E., Hyugaji T., Shimizu E., Katayama K., Kato Y., Morita T., Takahashi K., Harada N., Naito T., Hiki M., Matsushita Y., Takagi H., Aoki R., Nakamura A., Harada S., Sasano H., 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.

Nature 609 ( 7928 ) 754 - 760 2022.09

ISSN 00280836

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

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SARS-CoV-2 infection of airway cells causes intense viral and cell shedding, two spreading mechanisms affected by IL-13.

Cameron B Morrison, Caitlin E Edwards, Kendall M Shaffer, Kenza C Araba, Jason A Wykoff, Danielle R Williams, Takanori Asakura, Hong Dang, Lisa C Morton, Rodney C Gilmore, Wanda K O'Neal, Richard C Boucher, Ralph S Baric, Camille Ehre

Proceedings of the National Academy of Sciences of the United States of America 119 ( 16 ) e2119680119 2022.04

ISSN 00278424

Significance Gaining insights into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) high transmissibility and the role played by inflammatory mediators in viral proliferation are critical to investigating new therapeutic targets against COVID-19. Electron microscopy reveals important SARS-CoV-2 features, including the combination of large, rapidly released viral clusters and the massive shedding of epithelial cells packed with virions. Interleukin-13 (IL-13), a Th2 cytokine up-regulated in allergic asthma and associated with less severe COVID-19, protects against SARS-CoV-2 viral and cell shedding. Using gene expression analyses and biochemical assays, IL-13 is shown to affect viral entry, replication, and cell-to-cell transmission. Given the broad spectrum of COVID-19 clinical symptoms, it is important to elucidate intrinsic factors that modulate viral load and spreading mechanisms.

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Protease-anti-protease compartmentalization in SARS-CoV-2 ARDS: Therapeutic implications.

Oisin F McElvaney, Takanori Asakura, Suzanne L Meinig, Jose L Torres-Castillo, Robert S Hagan, Claudie Gabillard-Lefort, Mark P Murphy, Leigh B Thorne, Alain Borczuk, Emer P Reeves, Ross E Zumwalt, Yu Mikami, Tomas P Carroll, Kenichi Okuda, Grace Hogan, Oliver J McElvaney, Jennifer Clarke, Natalie L McEvoy, Patrick W Mallon, Cormac McCarthy, Ger Curley, Matthew C Wolfgang, Richard C Boucher, Noel G McElvaney

EBioMedicine 77 103894 - 103894 2022.03

BACKGROUND: Interleukin-6 (IL-6) is elevated in SARS-CoV-2 infection. IL-6 regulates acute-phase proteins, such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the protease-anti-protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS) compared to non-SARS-CoV-2 ARDS (nsARDS) and the effects of tocilizumab (IL-6 receptor antagonist) on anti-protease defence in SARS-CoV-2 infection. METHODS: Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma, airway tissue and tracheal secretions (TA) of people with SARS-CoV-2 ARDS or nsARDS. AAT and IL-6 levels were evaluated in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab. FINDINGS: AAT plasma levels doubled in SARS-CoV-2 ARDS. In lung parenchyma AAT levels were increased, as was the percentage of neutrophils involved in NET formation. A protease-anti-protease imbalance was detected in TA with active NE and no active AAT. The airway anti-protease, secretory leukoprotease inhibitor was decreased in SARS-CoV-2-infected lungs and cleaved in TA. In nsARDS, plasma AAT levels were elevated but TA samples had less AAT cleavage, with no detectable active NE in most samples. Induction of AAT in ARDS occurred mainly through IL-6. Tocilizumab down-regulated AAT during SARS-CoV-2 infection. INTERPRETATION: There is a protease-anti-protease imbalance in the airways of SARS-CoV-2-ARDS patients. This imbalance is a target for anti-protease therapy. FUNDING: NIH Serological Sciences Network, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

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A model of persistent post SARS-CoV-2 induced lung disease for target identification and testing of therapeutic strategies.

Kenneth H Dinnon, Sarah R Leist, Kenichi Okuda, Hong Dang, Ethan J Fritch, Kendra L Gully, Gabriela De la Cruz, Mia D Evangelista, Takanori Asakura, Rodney C Gilmore, Padraig Hawkins, Satoko Nakano, Ande West, Alexandra Schäfer, Lisa E Gralinski, Jamie L Everman, Satria P Sajuthi, Mark R Zweigart, Stephanie Dong, Jennifer McBride, Michelle R Cooley, Jesse B Hines, Miriya K Love, Steve D Groshong, Alison VanSchoiack, Stefan J Phelan, Yan Liang, Tyler Hether, Michael Leon, Ross E Zumwalt, Lisa M Barton, Eric J Duval, Sanjay Mukhopadhyay, Edana Stroberg, Alain Borczuk, Leigh B Thorne, Muthu K Sakthivel, Yueh Z Lee, James S Hagood, Jason R Mock, Max A Seibold, Wanda K O'Neal, Stephanie A Montgomery, Richard C Boucher, Ralph S Baric

bioRxiv : the preprint server for biology 2022.02

COVID-19 survivors develop post-acute sequelae of SARS-CoV-2 (PASC), but the mechanistic basis of PASC-associated lung abnormalities suffers from a lack of longitudinal samples. Mouse-adapted SARS-CoV-2 MA10 produces an acute respiratory distress syndrome (ARDS) in mice similar to humans. To investigate PASC pathogenesis, studies of MA10-infected mice were extended from acute disease through clinical recovery. At 15-120 days post-virus clearance, histologic evaluation identified subpleural lesions containing collagen, proliferative fibroblasts, and chronic inflammation with tertiary lymphoid structures. Longitudinal spatial transcriptional profiling identified global reparative and fibrotic pathways dysregulated in diseased regions, similar to human COVID-19. Populations of alveolar intermediate cells, coupled with focal upregulation of pro-fibrotic markers, were identified in persistently diseased regions. Early intervention with antiviral EIDD-2801 reduced chronic disease, and early anti-fibrotic agent (nintedanib) intervention modified early disease severity. This murine model provides opportunities to identify pathways associated with persistent SARS-CoV-2 pulmonary disease and test countermeasures to ameliorate PASC.

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Development of Rheumatoid Arthritis in Cavitary Mycobacterium avium Pulmonary Disease: A Case Report of Successful Treatment with CTLA4-Ig (Abatacept).

Hiromu Tanaka, Takanori Asakura, Jun Kikuchi, Makoto Ishii, Ho Namkoong, Yuko Kaneko, Koichi Fukunaga, Naoki Hasegawa

Infection and drug resistance 15 91 - 97 2022

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often develops in patients with rheumatoid arthritis (RA), especially during immunosuppressive treatment, including biological disease-modifying antirheumatic drugs. NTM-PD is associated with airway lesions such as bronchiectasis, which is frequently seen in RA patients. Distinguishing which diseases cause the pulmonary lesion is difficult. However, there are limited reports of the development of RA during the follow-up of NTM-PD and how biological agents should be administered in these conditions, especially with cavitary lesions. Case Presentation: A 62-year-old woman with hemosputum was referred to our hospital, where she was diagnosed with Mycobacterium avium pulmonary disease. She began treatment with several antibiotics, including clarithromycin, ethambutol, rifampicin, and amikacin. In the course of treatment, M. avium became macrolide-resistant. Five years after beginning antibiotic treatment, she felt arthralgia in the fingers and wrists and had a high titer of rheumatoid factor and anticitrullinated peptide antibody, with which we diagnosed RA. Methotrexate, prednisolone, and iguratimod were subsequently administered, but the activity of RA gradually worsened. Meanwhile, M. avium changed to a macrolide-susceptible strain, her sputum smear results remained almost negative, and the NTM-PD disease was well controlled with antimicrobial therapy, despite her having cavitary lesions. Therefore, we started using CTLA4-Ig (abatacept). RA symptoms were substantially ameliorated. The pulmonary lesions and NTM-PD worsened mildly, but her pulmonary symptoms were stable. Conclusion: Physicians should be mindful of the etiologies of bronchiectasis, including RA, even in patients with a long-term history of treatment for bronchiectasis and NTM-PD. When NTM-PD is well controlled, even with remaining cavitary lesions, abatacept may be an option for patients with RA based on a comprehensive assessment of disease progression using NTM sputum smear/culture, computed tomography findings, and treatment response.

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Early-Phase Adverse Effects and Management of Liposomal Amikacin Inhalation for Refractory Mycobacterium avium Complex Lung Disease in Real-World Settings.

Atsuho Morita, Ho Namkoong, Kazuma Yagi, Takanori Asakura, Makoto Hosoya, Hiromu Tanaka, Ho Lee, Takunori Ogawa, Tatsuya Kusumoto, Shuhei Azekawa, Kensuke Nakagawara, Hirofumi Kamata, Makoto Ishii, Koichi Fukunaga, Hiroyuki Ozawa, Naoki Hasegawa

Infection and drug resistance 15 4001 - 4011 2022

Purpose: Amikacin liposome inhalation suspension (ALIS), which efficiently allows amikacin to reach the pulmonary periphery for effect while minimising systemic adverse effects, was recently approved for treating Mycobacterium avium complex (MAC) infections. The international Phase 3 open-label clinical trials showed promising results, contributing to sputum culture conversion, but few studies have examined the efficacy and adverse effects of ALIS using real-world data. We identified the clinical outcome and adverse effects of ALIS in the early phase of treatment, for more effective and safe use in clinical practice. Patients and Methods: The study population consisted of patients with MAC lung disease (MAC-LD), introduced to ALIS therapy after July 2021 at Keio University Hospital due to poor response to multidrug therapy. The sputum smear/culture results, symptoms, adverse effects, and the serum amikacin concentrations of the early phase of ALIS inhalation therapy were examined. Results: A total of 11 patients (9 women; median age 64.6 years) were included in this study. The median disease duration of MAC-LD was 13.7 years, and all patients exhibited a positive culture at the beginning of ALIS inhalation. Three of the six patients (50.0%) who were initially sputum-smear-positive were confirmed to have become sputum-smear-negative within one month, including one culture conversion. ALIS inhalation therapy caused some adverse effects in nine patients (81.8%); however, no serious systemic adverse effects were observed. The most common adverse effect was hoarseness (72.7%), which mostly occurred around 1 week after initiation. The medians of peak serum amikacin concentrations were 1.4 and 2.3 μg/mL for the first and third inhalations, respectively. Trough serum concentrations just before the third inhalation were <1.2 μg/mL in all patients. Conclusion: ALIS therapy might be a treatment option for patients with refractory MAC infection with long disease duration and a poor response to guideline-based therapy.

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Mapping the human genetic architecture of COVID-19

Niemi M.E.K., Karjalainen J., Liao R.G., Neale B.M., Daly M., Ganna A., Pathak G.A., Andrews S.J., Kanai M., Veerapen K., Fernandez-Cadenas I., Schulte E.C., Striano P., Marttila M., Minica C., Marouli E., Karim M.A., Wendt F.R., Savage J., Sloofman L., Butler-Laporte G., Kim H.N., Kanoni S., Okada Y., Byun J., Han Y., Uddin M.J., Smith G.D., Willer C.J., Buxbaum J.D., Mehtonen J., Finucane H., Cordioli M., Martin A.R., Zhou W., Pasaniuc B., Julienne H., Aschard H., Shi H., Yengo L., Polimanti R., Ghoussaini M., Schwartzentruber J., Dunham I., Chwialkowska K., Francescatto M., Trankiem A., Balaconis M.K., Davis L., Lee S., Priest J., Renieri A., Sankaran V.G., van Heel D., Deelen P., Brent Richards J., Nakanishi T., Biesecker L., Eric Kerchberger V., Kenneth Baillie J., Mari F., Bernasconi A., Ceri S., Canakoglu A., Wolford B., Faucon A., Dutta A.K., Schurmann C., Harry E., Birney E., Nguyen H., Nasir J., Kaunisto M., Solomonson M., Dueker N., Vadgama N., Limou S., Rahmouni S., Mbarek H., Darwish D., Uddin M.M., Albertos R., Pérez-Tur J., Li R., Folkersen L., Moltke I., Koelling N., Teumer A., Kousathanas A., Utrilla A., Verdugo R.A., Zárate R., Medina-Gómez C., Gómez-Cabrero D., Carnero-Montoro E., Cadilla C.L., Moreno-Estrada A., Garmendia A., Moya L., Sedaghati-Khayat B.

Nature 600 ( 7889 ) 472 - 477 2021.12

ISSN 00280836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

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ADAM10 Partially Protects Mice against Influenza Pneumonia by Suppressing Specific Myeloid Cell Population.

Satoshi Okamori, Makoto Ishii, Takanori Asakura, Shoji Suzuki, Ho Namkoong, Shizuko Kagawa, Ahmed E Hegab, Kazuma Yagi, Hirofumi Kamata, Tatsuya Kusumoto, Takunori Ogawa, Hayato Takahashi, Masaki Yoda, Keisuke Horiuchi, Naoki Hasegawa, Koichi Fukunaga

American journal of physiology. Lung cellular and molecular physiology 321 ( 5 ) L872 - L884 2021.11

ISSN 10400605

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contribute to various immune responses; however, the role of ADAM10 in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. Adam10flox/flox/Lyz2-Cre (Adam10ΔLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines such as TNF-α, IL-1b, and CCL2 were increased in bronchoalveolar lavage fluid from Adam10ΔLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocytes/macrophages-like phenotype, were significantly increased in the lungs of Adam10ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10ΔLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10ΔLyz2 mice than in control mice, while an arginase-1 inhibitor improved the prognosis of Adam10ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

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Clinical Features and Prognosis of Nontuberculous Mycobacterial Pleuritis: A Multicenter Retrospective Study.

Kazuma Yagi, Akihiro Ito, Keiji Fujiwara, Eriko Morino, Isano Hase, Yasushi Nakano, Takanori Asakura, Koji Furuuchi, Atsuho Morita, Takahiro Asami, Ho Namkoong, Fumitake Saito, Kozo Morimoto, Makoto Ishii, Yasunori Sato, Hiroki Tateno, Kazumi Nishio, Yoshitaka Oyamada, Koichi Fukunaga, Haruhito Sugiyama, Tadashi Ishida, Atsuyuki Kurashima, Naoki Hasegawa

Annals of the American Thoracic Society 18 ( 9 ) 1490 - 1497 2021.09

ISSN 23296933

RATIONALE: The clinical features and prognosis of nontuberculous mycobacterial (NTM) pleuritis and pleural effusion combined with NTM lung disease (NTM-LD) remain unclear. OBJECTIVES: To investigate the clinical features and prognosis of NTM pleuritis. METHODS: This retrospective observational study included patients with NTM pleuritis from January 2001 to June 2018 across eight hospitals in Japan. NTM pleuritis was defined by a positive culture of NTM from pleural effusion. We matched patients with Mycobacterium complex lung disease (MAC-LD) without pleuritis by sex and age to obtain comparative data and investigated the association between clinical parameters and prognosis. RESULTS: We identified 64 patients with NTM pleuritis (median age, 73 years; 37 female). The median follow-up duration was 11 months, and 27 patients died. Patients with MAC pleuritis had a significantly worse survival compared to matched patients with MAC-LD without pleuritis. Multivariate analysis revealed that pleuritis (adjusted hazard ratio [aHR], 6.99; 95% confidence interval [CI], 2.58-19.00) and underlying pulmonary diseases (aHR, 3.01; 95% CI, 1.44-6.28) were independently associated with all-cause mortality in MAC-LD patients. CONCLUSIONS: The prognosis of MAC pleuritis is poorer than that of MAC-LD without pleuritis. Pleuritis is an independent prognostic factor in patients with MAC-LD.

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Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease.

Ho Namkoong, Yosuke Omae, Takanori Asakura, Makoto Ishii, Shoji Suzuki, Kozo Morimoto, Yosuke Kawai, Katsura Emoto, Andrew J Oler, Eva P Szymanski, Mitsunori Yoshida, Shuichi Matsuda, Kazuma Yagi, Isano Hase, Tomoyasu Nishimura, Yuka Sasaki, Takahiro Asami, Tetsuya Shiomi, Hiroaki Matsubara, Hisato Shimada, Junko Hamamoto, Byung Woo Jhun, Su-Young Kim, Hee Jae Huh, Hong-Hee Won, Manabu Ato, Kenjiro Kosaki, Tomoko Betsuyaku, Koichi Fukunaga, Atsuyuki Kurashima, Hervé Tettelin, Hideki Yanai, Surakameth Mahasirimongkol, Kenneth N Olivier, Yoshihiko Hoshino, Won-Jung Koh, Steven M Holland, Katsushi Tokunaga, Naoki Hasegawa

The European respiratory journal 58 ( 2 ) 2021.08

ISSN 09031936

RATIONALE: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. OBJECTIVES: We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. METHODS: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. RESULTS: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10-13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10-12, OR 0.54) and European (p=5.12×10-03, OR 0.63) ancestry. CONCLUSIONS: We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

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Longitudinal validity and prognostic significance of the St George's Respiratory Questionnaire in Mycobacterium avium complex pulmonary disease

Takunori Ogawa, Takanori Asakura, Shoji Suzuki, Satoshi Okamori, Tatsuya Kusumoto, Yasunori Sato, Ho Namkoong, Hirofumi Kamata, Makoto Ishii, Koichi Fukunaga, Naoki Hasegawa

Respiratory Medicine (Elsevier BV) 185 106515 - 106515 2021.08

ISSN 09546111

Background: Although previous cross-sectional studies showed the feasibility and clinical association of the St. George's Respiratory Questionnaire (SGRQ) in Mycobacterium avium complex pulmonary disease (MAC-PD), its longitudinal validity is poorly understood. We aimed to determine the longitudinal validity and prognostic significance of SGRQ. Methods: In this prospective observational study conducted between May 2012 and August 2018, we evaluated 269 enrolled patients with MAC-PD and examined associations between baseline SGRQ total scores and mortality or clinical variables (anchors), including serum C-reactive protein levels and pulmonary function test results. Results: Age- and sex-matched SGRQ scores indicated significantly greater impairment in patients with MAC-PD than in the general population (P < 0.001). On multivariable Cox proportional hazards regression analysis, the SGRQ total score ≥25 was an independent risk factor for mortality (adjusted hazard ratio, 5.90; 95% confidence interval, 1.65–37.7) as well as age, body mass index, and forced vital capacity (FVC). Mixed-effect model results showed a significant association between SGRQ symptom/total scores and forced expiratory volume in 1 s (FEV<inf>1</inf>), FVC, and diffusing carbon monoxide capacity. Older age, a positive smear, non-nodular/bronchiectatic form, and cavity regions were associated with SGRQ total score deterioration. Patients with a greater decline from baseline FEV<inf>1</inf> (% predicted) exhibited significantly worse impairment in the SGRQ total score (mean ± SE, 4.69 ± 10.9 points, P = 0.001). Conclusions: SGRQ showed longitudinal validity in assessing disease severity and was sensitive to changes in patients with MAC-PD, especially changes in %FEV<inf>1.</inf> The SGRQ total score may be an important prognostic factor.

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Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia.

Kenichi Okuda, Hong Dang, Yoshihiko Kobayashi, Gianni Carraro, Satoko Nakano, Gang Chen, Takafumi Kato, Takanori Asakura, Rodney C Gilmore, Lisa C Morton, Rhianna E Lee, Teresa Mascenik, Wei-Ning Yin, Selene Margarita Barbosa Cardenas, Yvonne K O'Neal, Caroline E Minnick, Michael Chua, Nancy L Quinney, Martina Gentzsch, Carlton W Anderson, Andrew Ghio, Hirotoshi Matsui, Takahide Nagase, Lawrence E Ostrowski, Barbara R Grubb, John C Olsen, Scott H Randell, Barry R Stripp, Purushothama Rao Tata, Wanda K O'Neal, Richard C Boucher

American journal of respiratory and critical care medicine 203 ( 10 ) 1275 - 1289 2021.05

ISSN 1073449X

RATIONALE: Identification of the specific cell types expressing CFTR is required for precision medicine therapies for cystic fibrosis (CF). However, a full characterization of CFTR expression in normal human airway epithelia is missing. OBJECTIVES: To identify the cell types that contribute to CFTR expression and function within the proximal-distal axis of the normal human lung. METHODS: Single cell RNA-seq (scRNA-seq) was performed on freshly isolated human large and small airway epithelial cells. Single cell-based RNA in situ hybridization (scRNA-ISH) and quantitative RT-PCR (scqRT-PCR) were performed for validation. In vitro culture systems correlated CFTR function to cell types. Lentiviruses were used for cell-type specific transduction of wild-type CFTR in CF cells. MEASUREMENTS AND MAIN RESULTS: scRNA-seq identified secretory cells as dominating CFTR expression in normal human large and particularly small airway superficial epithelia, followed by basal cells. Ionocytes expressed the highest CFTR levels but were rare, while expression in ciliated cells was infrequent and low. scRNA-ISH, and scqRT-PCR confirmed the scRNA-seq findings. CF lungs exhibited distributions of CFTR and ionocytes similar to normal controls. CFTR-mediated Cl- secretion in culture tracked secretory cell, not ionocyte, densities. Further, the nucleotide-purinergic regulatory system that controls CFTR-mediated hydration was associated with secretory cells, and not ionocytes. Lentiviral transduction of wild-type CFTR produced CFTR-mediated Cl- secretion in CF airway secretory cells but not ciliated cells. CONCLUSIONS: Secretory cells dominate CFTR expression and function in human airway superficial epithelia. CFTR therapies may need to restore CFTR function to multiple cell types, with a focus on secretory cells.

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Complete Genome Sequence of Mycobacterium heckeshornense JCM 15655T, Closely Related to a Pathogenic Nontuberculous Mycobacterial Species, Mycobacterium xenopi.

Mitsunori Yoshida, Hanako Fukano, Takanori Asakura, Masato Suzuki, Yoshihiko Hoshino

Microbiology resource announcements 10 ( 10 ) 2021.03

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