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1.
Preprint in English | bioRxiv | ID: ppbiorxiv-496751

ABSTRACT

The use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from COVID-19-convalescent patients, and identified antibodies that exhibited comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns. These antibodies have different profiles against various mutations, which were confirmed by cell-based assay and cryo-electron microscopy. To prevent antibody-dependent enhancement, N297A modification was introduced, and showed a reduction of lung viral RNAs by therapeutic administration in a hamster model. In addition, an antibody cocktail consisting of three antibodies was also administered therapeutically to a macaque model, which resulted in reduced viral titers of swabs and lungs and reduced lung tissue damage scores. These results showed that our antibodies have sufficient antiviral activity as therapeutic candidates.

2.
Preprint in English | medRxiv | ID: ppmedrxiv-22274196

ABSTRACT

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 analysis of an immunologically naive SARS-CoV-2 clinical cohort from the plasma of uninfected controls, mild, and severe infections. A comparison of healthy controls and patient samples showed activation of neutrophil degranulation pathways and formation of neutrophil extracellular trap (NET) complexes that were activated in a subset of the mild infections and more prevalent in severe infections (containing multiple NET proteins in individual patient samples). As a potential mechanism to suppress NET formation, multiple redox enzymes were elevated in the mild and severe symptom population. Analysis of metabolites from the same cohort showed a 24- and 60-fold elevation in plasma L-cystine, the oxidized form of cysteine, which is a substrate of the powerful antioxidant glutathione, in mild and severe patients, respectively. Unique to patients with mild infections, the carnosine dipeptidase modifying enzyme (CNDP1) was up-regulated. The strong protein and metabolite oxidation signatures suggest multiple compensatory pathways working to suppress oxidation and NET formation in SARS-CoV-2 infections.

3.
Ho Namkoong; Ryuya Edahiro; Koichi Fukunaga; Yuya Shirai; Kyuto Sonehara; Hiromu Tanaka; Ho Lee; Takanori Hasegawa; Masahiro Kanai; Tatsuhiko Naito; Kenichi Yamamoto; Ryunosuke Saiki; Takayoshi Hyugaji; Eigo Shimizu; Kotoe Katayama; Kazuhisa Takahashi; Norihiro Harada; Toshio Naito; Makoto Hiki; Yasushi Matsushita; Haruhi Takagi; Ryousuke Aoki; Ai Nakamura; Sonoko Harada; Hitoshi Sasano; Hiroki Kabata; Katsunori Masaki; Hirofumi Kamata; Shinnosuke Ikemura; Shotaro Chubachi; Satoshi Okamori; Hideki Terai; Atsuho Morita; Takanori Asakura; Junichi Sasaki; Hiroshi Morisaki; Yoshifumi Uwamino; Kosaku Nanki; Yohei Mikami; Sho Uchida; Shunsuke Uno; Rino Ishihara; Yuta Matsubara; Tomoyasu Nishimura; Takanori Ogawa; Takashi Ishiguro; Taisuke Isono; Shun Shibata; Yuma Matsui; Chiaki Hosoda; Kenji Takano; Takashi Nishida; Yoichi Kobayashi; Yotaro Takaku; Noboru Takayanagi; Soichiro Ueda; Ai Tada; Masayoshi Miyawaki; Masaomi Yamamoto; Eriko Yoshida; Reina Hayashi; Tomoki Nagasaka; Sawako Arai; Yutaro Kaneko; Kana Sasaki; Etsuko Tagaya; Masatoshi Kawana; Ken Arimura; Kunihiko Takahashi; Tatsuhiko Anzai; Satoshi Ito; Akifumi Endo; Yuji Uchimura; Yasunari Miyazaki; Takayuki Honda; Tomoya Tateishi; Shuji Tohda; Naoya Ichimura; Kazunari Sonobe; Chihiro Sassa; Jun Nakajima; Yasushi Nakano; Yukiko Nakajima; Ryusuke Anan; Ryosuke Arai; Yuko Kurihara; Yuko Harada; Kazumi Nishio; Tetsuya Ueda; Masanori Azuma; Ryuichi Saito; Toshikatsu Sado; Yoshimune Miyazaki; Ryuichi Sato; Yuki Haruta; Tadao Nagasaki; Yoshinori Yasui; Yoshinori Hasegawa; Yoshikazu Mutoh; Tomonori Sato; Reoto Takei; Satoshi Hagimoto; Yoichiro Noguchi; Yasuhiko Yamano; Hajime Sasano; Sho Ota; Yasushi Nakamori; Kazuhisa Yoshiya; Fukuki Saito; Tomoyuki Yoshihara; Daiki Wada; Hiromu Iwamura; Syuji Kanayama; Shuhei Maruyama; Takashi Yoshiyama; Ken Ohta; Hiroyuki Kokuto; Hideo Ogata; Yoshiaki Tanaka; Kenichi Arakawa; Masafumi Shimoda; Takeshi Osawa; Hiroki Tateno; Isano Hase; Shuichi Yoshida; Shoji Suzuki; Miki Kawada; Hirohisa Horinouchi; Fumitake Saito; Keiko Mitamura; Masao Hagihara; Junichi Ochi; Tomoyuki Uchida; Rie Baba; Daisuke Arai; Takayuki Ogura; Hidenori Takahashi; Shigehiro Hagiwara; Genta Nagao; Shunichiro Konishi; Ichiro Nakachi; Koji Murakami; Mitsuhiro Yamada; Hisatoshi Sugiura; Hirohito Sano; Shuichiro Matsumoto; Nozomu Kimura; Yoshinao Ono; Hiroaki Baba; Yusuke Suzuki; Sohei Nakayama; Keita Masuzawa; Shinichi Namba; Ken Suzuki; Nobuyuki Hizawa; Takayuki Shiroyama; Satoru Miyawaki; Yusuke Kawamura; Akiyoshi Nakayama; Hirotaka Matsuo; Yuichi Maeda; Takuro Nii; Yoshimi Noda; Takayuki Niitsu; Yuichi Adachi; Takatoshi Enomoto; Saori Amiya; Reina Hara; Toshihiro Kishikawa; Shuhei Yamada; Shuhei Kawabata; Noriyuki Kijima; Masatoshi Takagaki; Noa Sasa; Yuya Ueno; Motoyuki Suzuki; Norihiko Takemoto; Hirotaka Eguchi; Takahito Fukusumi; Takao Imai; Munehisa Fukushima; Haruhiko Kishima; Hidenori Inohara; Kazunori Tomono; Kazuto Kato; Meiko Takahashi; Fumihiko Matsuda; Haruhiko Hirata; Yoshito Takeda; Hidefumi Koh; Tadashi Manabe; Yohei Funatsu; Fumimaro Ito; Takahiro Fukui; Keisuke Shinozuka; Sumiko Kohashi; Masatoshi Miyazaki; Tomohisa Shoko; Mitsuaki Kojima; Tomohiro Adachi; Motonao Ishikawa; Kenichiro Takahashi; Takashi Inoue; Toshiyuki Hirano; Keigo Kobayashi; Hatsuyo Takaoka; Kazuyoshi Watanabe; Naoki Miyazawa; Yasuhiro Kimura; Reiko Sado; Hideyasu Sugimoto; Akane Kamiya; Naota Kuwahara; Akiko Fujiwara; Tomohiro Matsunaga; Yoko Sato; Takenori Okada; Yoshihiro Hirai; Hidetoshi Kawashima; Atsuya Narita; Kazuki Niwa; Yoshiyuki Sekikawa; Koichi Nishi; Masaru Nishitsuji; Mayuko Tani; Junya Suzuki; Hiroki Nakatsumi; Takashi Ogura; Hideya Kitamura; Eri Hagiwara; Kota Murohashi; Hiroko Okabayashi; Takao Mochimaru; Shigenari Nukaga; Ryosuke Satomi; Yoshitaka Oyamada; Nobuaki Mori; Tomoya Baba; Yasutaka Fukui; Mitsuru Odate; Shuko Mashimo; Yasushi Makino; Kazuma Yagi; Mizuha Hashiguchi; Junko Kagyo; Tetsuya Shiomi; Satoshi Fuke; Hiroshi Saito; Tomoya Tsuchida; Shigeki Fujitani; Mumon Takita; Daiki Morikawa; Toru Yoshida; Takehiro Izumo; Minoru Inomata; Naoyuki Kuse; Nobuyasu Awano; Mari Tone; Akihiro Ito; Yoshihiko Nakamura; Kota Hoshino; Junichi Maruyama; Hiroyasu Ishikura; Tohru Takata; Toshio Odani; Masaru Amishima; Takeshi Hattori; Yasuo Shichinohe; Takashi Kagaya; Toshiyuki Kita; Kazuhide Ohta; Satoru Sakagami; Kiyoshi Koshida; Kentaro Hayashi; Tetsuo Shimizu; Yutaka Kozu; Hisato Hiranuma; Yasuhiro Gon; Namiki Izumi; Kaoru Nagata; Ken Ueda; Reiko Taki; Satoko Hanada; Kodai Kawamura; Kazuya Ichikado; Kenta Nishiyama; Hiroyuki Muranaka; Kazunori Nakamura; Naozumi Hashimoto; Keiko Wakahara; Sakamoto Koji; Norihito Omote; Akira Ando; Nobuhiro Kodama; Yasunari Kaneyama; Shunsuke Maeda; Takashige Kuraki; Takemasa Matsumoto; Koutaro Yokote; Taka-Aki Nakada; Ryuzo Abe; Taku Oshima; Tadanaga Shimada; Masahiro Harada; Takeshi Takahashi; Hiroshi Ono; Toshihiro Sakurai; Takayuki Shibusawa; Yoshifumi Kimizuka; Akihiko Kawana; Tomoya Sano; Chie Watanabe; Ryohei Suematsu; Hisako Sageshima; Ayumi Yoshifuji; Kazuto Ito; Saeko Takahashi; Kota Ishioka; Morio Nakamura; Makoto Masuda; Aya Wakabayashi; Hiroki Watanabe; Suguru Ueda; Masanori Nishikawa; Yusuke Chihara; Mayumi Takeuchi; Keisuke Onoi; Jun Shinozuka; Atsushi Sueyoshi; Yoji Nagasaki; Masaki Okamoto; Sayoko Ishihara; Masatoshi Shimo; Yoshihisa Tokunaga; Yu Kusaka; Takehiko Ohba; Susumu Isogai; Aki Ogawa; Takuya Inoue; Satoru Fukuyama; Yoshihiro Eriguchi; Akiko Yonekawa; Keiko Kan-o; Koichiro Matsumoto; Kensuke Kanaoka; Shoichi Ihara; Kiyoshi Komuta; Yoshiaki Inoue; Shigeru Chiba; Kunihiro Yamagata; Yuji Hiramatsu; Hirayasu Kai; Koichiro Asano; Tsuyoshi Oguma; Yoko Ito; Satoru Hashimoto; Masaki Yamasaki; Yu Kasamatsu; Yuko Komase; Naoya Hida; Takahiro Tsuburai; Baku Oyama; Minoru Takada; Hidenori Kanda; Yuichiro Kitagawa; Tetsuya Fukuta; Takahito Miyake; Shozo Yoshida; Shinji Ogura; Shinji Abe; Yuta Kono; Yuki Togashi; Hiroyuki Takoi; Ryota Kikuchi; Shinichi Ogawa; Tomouki Ogata; Shoichiro Ishihara; Arihiko Kanehiro; Shinji Ozaki; Yasuko Fuchimo; Sae Wada; Nobukazu Fujimoto; Kei Nishiyama; Mariko Terashima; Satoru Beppu; Kosuke Yoshida; Osamu Narumoto; Hideaki Nagai; Nobuharu Ooshima; Mitsuru Motegi; Akira Umeda; Kazuya Miyagawa; Hisato Shimada; Mayu Endo; Yoshiyuki Ohira; Masafumi Watanabe; Sumito Inoue; Akira Igarashi; Masamichi Sato; Hironori Sagara; Akihiko Tanaka; Shin Ohta; Tomoyuki Kimura; Yoko Shibata; Yoshinori Tanino; Takefumi Nikaido; Hiroyuki Minemura; Yuki Sato; Yuichiro Yamada; Takuya Hashino; Masato Shinoki; Hajime Iwagoe; Hiroshi Takahashi; Kazuhiko Fujii; Hiroto Kishi; Masayuki Kanai; Tomonori Imamura; Tatsuya Yamashita; Masakiyo Yatomi; Toshitaka Maeno; Shinichi Hayashi; Mai Takahashi; Mizuki Kuramochi; Isamu Kamimaki; Yoshiteru Tominaga; Tomoo Ishii; Mitsuyoshi Utsugi; Akihiro Ono; Toru Tanaka; Takeru Kashiwada; Kazue Fujita; Yoshinobu Saito; Masahiro Seike; Yosuke Omae; Yasuhito Nannya; Takafumi Ueno; Tomomi Takano; Kazuhiko Katayama; Masumi Ai; Atsushi Kumanogoh; Toshiro Sato; Naoki Hasegawa; Katsushi Tokunaga; Makoto Ishii; Ryuji Koike; Yuko Kitagawa; Akinori Kimura; Seiya Imoto; Satoru Miyano; Seishi Ogawa; Takanori Kanai; Yukinori Okada.
Preprint in English | medRxiv | ID: ppmedrxiv-21256513

ABSTRACT

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5q35 (rs60200309-A at DOCK2) that was associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 x 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

4.
Preprint in English | medRxiv | ID: ppmedrxiv-20235952

ABSTRACT

SARS-CoV-2 genome accumulates point mutations constantly. However, whether non-synonymous mutations affect COVID-19 severity through altering viral protein function remains unknown. SARS-CoV-2 genome sequencing revealed that the number of non-synonymous mutations correlated inversely with COVID-19 severity in Tokyo Metropolitan area. Phylogenic tree analyses identified two predominant groups which were differentiated by a set of six-point mutations (four non-synonymous amino acid mutations). Among them, Pro108Ser in 3 chymotrypsin-like protease (3CLpro) and Pro151Leu in nucleocapsid protein occurred at conserved locations among {beta}-coronaviruses. Patients with these mutations (N = 48) indicated significantly lower odds ratio for developing hypoxia which required supplemental oxygen (odds ratio 0.24 [95% CI 0.07-0.88, p-value = 0.032]) after adjustments for age and sex, versus those lacking this haplotype in the canonical Clade 20B (N = 37). The Pro108Ser 3CLpro enzyme in vitro decreases in the activity by 58%, and the hydrogen/deuterium exchange mass spectrometry reveals that mechanisms for reduced activities involve structural perturbation at the substrate-binding region which is positioned behind and distant from the 108th amino acid residue of the enzyme. This mutant strain rapidly outcompeted pre-existing variants to become predominant in Japan. Our results may benefit the efforts underway to design small molecular compounds or antibodies targeting 3CLpro.

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