376
1.
OIE. 2018. OIE Situation Report for Avian Influenza.1-12.
377
2.
Li C, Chen H. 2014. Enhancement of influenza virus transmission by gene reassortment.
378
379
Curr Top Microbiol Immunol 385:185-204.
3.
Ottmann M, Duchamp MB, Casalegno JS, Frobert E, Moules V, Ferraris O, Valette M,
380
Escuret V, Lina B. 2010. Novel influenza A(H1N1) 2009 in vitro reassortant viruses with
381
oseltamivir resistance. Antivir Ther 15:721-726.
382
4.
383
Neumann G, Noda T, Kawaoka Y. 2009. Emergence and pandemic potential of swineorigin H1N1 influenza virus. Nature 459:931-939.
384
5.
OIE. 2017. OIE Situation Report for Avian Influenza 1-14.
385
6.
Jiang H, Wu P, Uyeki TM, He J, Deng Z, Xu W, Lv Q, Zhang J, Wu Y, Tsang TK, Kang
386
M, Zheng J, Wang L, Yang B, Qin Y, Feng L, Fang VJ, Gao GF, Leung GM, Yu H,
17
387
Cowling BJ. 2017. Preliminary Epidemiologic Assessment of Human Infections With
388
Highly Pathogenic Avian Influenza A(H5N6) Virus, China. Clin Infect Dis 65:383-388.
389
7.
Bi Y, Tan S, Yang Y, Wong G, Zhao M, Zhang Q, Wang Q, Zhao X, Li L, Yuan J, Li H,
390
Li H, Xu W, Shi W, Quan C, Zou R, Li J, Zheng H, Yang L, Liu WJ, Liu D, Wang H,
391
Qin Y, Liu L, Jiang C, Liu W, Lu L, Gao GF, Liu Y. 2019. Clinical and immunological
392
characteristics of human infections with H5N6 avian influenza virus. Clin Infect Dis
393
68:1100-1109. doi:10.1093/cid/ciy681.
394
8.
Sun H, Pu J, Wei Y, Sun Y, Hu J, Liu L, Xu G, Gao W, Li C, Zhang X, Huang Y, Chang
395
KC, Liu X, Liu J. 2016. Highly Pathogenic Avian Influenza H5N6 Viruses Exhibit
396
Enhanced Affinity for Human Type Sialic Acid Receptor and In-Contact Transmission in
397
Model Ferrets. J Virol 90:6235-6243.
398
9.
Hui KP, Chan LL, Kuok DI, Mok CK, Yang ZF, Li RF, Luk GS, Lee EF, Lai JC, Yen
399
HL, Zhu H, Guan Y, Nicholls JM, Peiris JS, Chan MC. 2017. Tropism and innate host
400
responses of influenza A/H5N6 virus: an analysis of ex vivo and in vitro cultures of the
401
human respiratory tract. Eur Respir J 49:pii: 1601710. doi: 10.1183/13993003.01710-
402
2016.
403
10.
Zhao Z, Guo Z, Zhang C, Liu L, Chen L, Zhang C, Wang Z, Fu Y, Li J, Shao H, Luo Q,
404
Qian J, Liu L. 2017. Avian Influenza H5N6 Viruses Exhibit Differing Pathogenicities
405
and Transmissibilities in Mammals. Sci Rep 7:16280.
406
11.
Herfst S, Mok CKP, van den Brand JMA, van der Vliet S, Rosu ME, Spronken MI, Yang
407
Z, de Meulder D, Lexmond P, Bestebroer TM, Peiris JSM, Fouchier RAM, Richard M.
408
2018. Human Clade 2.3.4.4 A/H5N6 Influenza Virus Lacks Mammalian Adaptation
18
409
Markers and Does Not Transmit via the Airborne Route between Ferrets. mSphere 3: pii:
410
e00405-17. doi: 10.1128/mSphere.00405-17.
411
12.
412
413
Hussain M, Galvin HD, Haw TY, Nutsford AN, Husain M. 2017. Drug resistance in
influenza A virus: the epidemiology and management. Infect Drug Resist 10:121-134.
13.
Gaymard A, Charles-Dufant A, Sabatier M, Cortay JC, Frobert E, Picard C, Casalegno JS,
414
Rosa-Calatrava M, Ferraris O, Valette M, Ottmann M, Lina B, Escuret V. 2016. Impact
415
on antiviral resistance of E119V, I222L and R292K substitutions in influenza A viruses
416
bearing a group 2 neuraminidase (N2, N3, N6, N7 and N9). J Antimicrob Chemother
417
71:3036-3045.
418
14.
Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM, Centers for Disease C,
419
Prevention. 2011. Antiviral agents for the treatment and chemoprophylaxis of influenza
420
recommendations of the Advisory Committee on Immunization Practices (ACIP).
421
MMWR Recomm Rep 60:1-24.
422
15.
Dong G, Peng C, Luo J, Wang C, Han L, Wu B, Ji G, He H. 2015. Adamantane-resistant
423
influenza a viruses in the world (1902-2013): frequency and distribution of M2 gene
424
mutations. PLoS One 10:e0119115.
425
16.
Itoh Y, Shichinohe S, Nakayama M, Igarashi M, Ishii A, Ishigaki H, Ishida H, Kitagawa
426
N, Sasamura T, Shiohara M, Doi M, Tsuchiya H, Nakamura S, Okamatsu M, Sakoda Y,
427
Kida H, Ogasawara K. 2015. Emergence of H7N9 Influenza A Virus Resistant to
428
Neuraminidase Inhibitors in Nonhuman Primates. Antimicrob Agents Chemother
429
59:4962-4973.
430
431
17.
Arikata M, Itoh Y, Okamatsu M, Maeda T, Shiina T, Tanaka K, Suzuki S, Nakayama M,
Sakoda Y, Ishigaki H, Takada A, Ishida H, Soda K, Pham VL, Tsuchiya H, Nakamura S,
19
432
Torii R, Shimizu T, Inoko H, Ohkubo I, Kida H, Ogasawara K. 2012. Memory immune
433
responses against pandemic (H1N1) 2009 influenza virus induced by a whole particle
434
vaccine in cynomolgus monkeys carrying Mafa-A1*052:02. PLoS One 7:e37220.
435
18.
Pham VL, Nakayama M, Itoh Y, Ishigaki H, Kitano M, Arikata M, Ishida H, Kitagawa N,
436
Shichinohe S, Okamatsu M, Sakoda Y, Tsuchiya H, Nakamura S, Kida H, Ogasawara K.
437
2013. Pathogenicity of pandemic H1N1 influenza A virus in immunocompromised
438
cynomolgus macaques. PLoS One 8:e75910.
439
19.
Hiono T, Okamatsu M, Matsuno K, Haga A, Iwata R, Nguyen LT, Suzuki M, Kikutani Y,
440
Kida H, Onuma M, Sakoda Y. 2017. Characterization of H5N6 highly pathogenic avian
441
influenza viruses isolated from wild and captive birds in the winter season of 2016-2017
442
in Northern Japan. Microbiol Immunol 61:387-397.
443
20.
Okamatsu M, Ozawa M, Soda K, Takakuwa H, Haga A, Hiono T, Matsuu A, Uchida Y,
444
Iwata R, Matsuno K, Kuwahara M, Yabuta T, Usui T, Ito H, Onuma M, Sakoda Y, Saito
445
T, Otsuki K, Ito T, Kida H. 2017. Characterization of Highly Pathogenic Avian Influenza
446
Virus A(H5N6), Japan, November 2016. Emerg Infect Dis 23:691-695.
447
21.
Choi WS, Jeong JH, Kwon JJ, Ahn SJ, Lloren KKS, Kwon HI, Chae HB, Hwang J, Kim
448
MH, Kim CJ, Webby RJ, Govorkova EA, Choi YK, Baek YH, Song MS. 2018.
449
Screening for Neuraminidase Inhibitor Resistance Markers among Avian Influenza
450
Viruses of the N4, N5, N6, and N8 Neuraminidase Subtypes. J Virol 92:pii: e01580-17.
451
doi: 10.1128/JVI.01580-17.
452
22.
De Jong MD, Ison MG, Monto AS, Metev H, Clark C, O'Neil B, Elder J, McCullough A,
453
Collis P, Sheridan WP. 2014. Evaluation of intravenous peramivir for treatment of
454
influenza in hospitalized patients. Clin Infect Dis 59:e172-85.
20
455
23.
456
457
Yang. Z-F, Mok. CKP, Peiris. JSM, Zhong. N-S. 2015. Human Infection with a Novel
Avian Influenza A(H5N6) Virus. N Engl J Med 373:487-489.
24.
Shieh WJ, Blau DM, Denison AM, Deleon-Carnes M, Adem P, Bhatnagar J, Sumner J,
458
Liu L, Patel M, Batten B, Greer P, Jones T, Smith C, Bartlett J, Montague J, White E,
459
Rollin D, Gao R, Seales C, Jost H, Metcalfe M, Goldsmith CS, Humphrey C, Schmitz A,
460
Drew C, Paddock C, Uyeki TM, Zaki SR. 2010. 2009 pandemic influenza A (H1N1):
461
pathology and pathogenesis of 100 fatal cases in the United States. Am J Pathol 177:166-
462
175.
463
25.
Liem NT, Nakajima N, Phat le P, Sato Y, Thach HN, Hung PV, San LT, Katano H,
464
Kumasaka T, Oka T, Kawachi S, Matsushita T, Sata T, Kudo K, Suzuki K. 2008. H5N1-
465
infected cells in lung with diffuse alveolar damage in exudative phase from a fatal case in
466
Vietnam. Jpn J Infect Dis 61:157-160.
467
26.
Feng Y, Hu L, Lu S, Chen Q, Zheng Y, Zeng D, Zhang J, Zhang A, Chen L, Hu Y,
468
Zhang Z. 2015. Molecular pathology analyses of two fatal human infections of avian
469
influenza A(H7N9) virus. J Clin Pathol 68:57-63.
470
27.
Gao R, Pan M, Li X, Zou X, Zhao X, Li T, Yang H, Zou S, Bo H, Xu J, Li S, Zhang M,
471
Li Z, Wang D, Zaki SR, Shu Y. 2016. Post-mortem findings in a patient with avian
472
influenza A (H5N6) virus infection. Clin Microbiol Infect 22:574 e1-5.
473
28.
474
475
476
Betakova T, Kostrabova A, Lachova V, Turianova L. 2017. Cytokines Induced During
Influenza Virus Infection. Curr Pharm Des 23:2616-2622.
29.
Van Reeth K. 2000. Cytokines in the pathogenesis of influenza. Vet Microbiol 74:109116.
21
477
30.
Kitano M, Itoh Y, Ishigaki H, Nakayama M, Ishida H, Pham VL, Arikata M, Shichinohe
478
S, Tsuchiya H, Kitagawa N, Kobayashi M, Yoshida R, Sato A, Le QM, Kawaoka Y,
479
Ogasawara K. 2014. Efficacy of repeated intravenous administration of peramivir against
480
highly pathogenic avian influenza A (H5N1) virus in cynomolgus macaques. Antimicrob
481
Agents Chemother 58:4795-4803.
482
31.
De Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJ, Chau TN, Hoang DM, Chau
483
NV, Khanh TH, Dong VC, Qui PT, Cam BV, Ha do Q, Guan Y, Peiris JS, Chinh NT,
484
Hien TT, Farrar J. 2006. Fatal outcome of human influenza A (H5N1) is associated with
485
high viral load and hypercytokinemia. Nat Med 12:1203-1207.
486
32.
Szretter KJ, Gangappa S, Belser JA, Zeng H, Chen H, Matsuoka Y, Sambhara S, Swayne
487
DE, Tumpey TM, Katz JM. 2009. Early control of H5N1 influenza virus replication by
488
the type I interferon response in mice. J Virol 83:5825-5834.
489
33.
Liu Q, Ma J, Strayer DR, Mitchell WM, Carter WA, Ma W, Richt JA. 2014. Emergence
490
of a novel drug resistant H7N9 influenza virus: evidence based clinical potential of a
491
natural IFN-alpha for infection control and treatment. Expert Rev Anti Infect Ther
492
12:165-169.
493
34.
494
495
Sato M, Hashimoto K, Kawasaki Y, Hosoya M. 2018. Immune response after a single
intravenous peramivir administration in children with influenza. Antivir Ther 23:435-441.
35.
Ilyushina NA, Govorkova EA, Russell CJ, Hoffmann E, Webster RG. 2007. Contribution
496
of H7 haemagglutinin to amantadine resistance and infectivity of influenza virus. J Gen
497
Virol 88:1266-1274.
22
498
36.
Togo Y, Hornick RB, Felitti VJ, Kaufman ML, Dawkins AT, Jr., Kilpe VE, Claghorn JL.
499
1970. Evaluation of therapeutic efficacy of amantadine in patients with naturally
500
occurring A2 influenza. JAMA 211:1149-1156.
501
37.
Kandeil A, Kayed A, Moatasim Y, Webby RJ, McKenzie PP, Kayali G, Ali MA. 2017.
502
Genetic characterization of highly pathogenic avian influenza A H5N8 viruses isolated
503
from wild birds in Egypt. J Gen Virol 98:1573-1586.
504
38.
Levite M. 2016. Dopamine and T cells: dopamine receptors and potent effects on T cells,
505
dopamine production in T cells, and abnormalities in the dopaminergic system in T cells
506
in autoimmune, neurological and psychiatric diseases. Acta Physiol (Oxf) 216:42-89.
507
39.
Kocks JR, Davalos-Misslitz AC, Hintzen G, Ohl L, Forster R. 2007. Regulatory T cells
508
interfere with the development of bronchus-associated lymphoid tissue. J Exp Med
509
204:723-734.
510
40.
Kitano M, Itoh Y, Kodama M, Ishigaki H, Nakayama M, Nagata T, Ishida H, Tsuchiya H,
511
Torii R, Baba K, Yoshida R, Sato A, Ogasawara K. 2010. Establishment of a cynomolgus
512
macaque model of influenza B virus infection. Virology 407:178-184.
513
41.
Chen F, Liu Z, Wu W, Rozo C, Bowdridge S, Millman A, Van Rooijen N, Urban JF, Jr.,
514
Wynn TA, Gause WC. 2012. An essential role for TH2-type responses in limiting acute
515
tissue damage during experimental helminth infection. Nat Med 18:260-266.
516
23
517
Table 1. Virus titers in swab samples of cynomolgus macaques infected with H5N6 and
518
treated with antiviral drugs.
Virus titers (Log10TCID50/mL)
Sample a
Treatment
Animal
Days after virus inoculation
≤ 0.83
2.50
2.67
1.83
2.00
3.44
4.83
3.00
1.50
2.33
3.50
3.50
3.67
3.23
3.50
1.50
≤ 0.67
O2
3.83
≤ 0.67
2.00
≤ 1.23
O3
≤ 1.33
P1
≤ 1.33
P2
3.50
≤ 1.00
≤ 1.00
≤ 0.67
P3
4.00
< 0.67
< 1.00
S1b
Saline
S2
S3
O1
Oseltamivir
Nasal
swab
Peramivir
Amantadine
Saline
Oseltamivir
Trachea
swab
Peramivir
Amantadine
Saline
Bronchial
swab
Oseltamivir
3.50
2.67
3.83
3.23
≤ 0.67
A1
3.50
A2
≤ 1.33
A3
1.67
≤ 1.5
≤ 1.77
≤ 1.33
2.23
2.50
2.23
≤ 1.50
≤ 1.77
2.50
2.33
≤ 1.00
≤ 1.33
S1
4.67
3.33
1.67
2.00
≤ 0.67
S2
3.67
≤ 1.00
≤ 0.67
≤ 0.67
S3
2.50
2.50
≤ 0.75
1.83
≤ 0.67
≤ 0.67
≤ 1.83
≤ 0.83
2.50
≤ 1.44
<1
O1
2.67
2.83
O2
3.50
2.00
2.00
O3
4.33
3.77
2.33
P1
2.5
2.67
≤ 1.5
P2
4.00
≤ 1.00
≤ 1.44
P3
4.50
2.77
20
1.83
≤ 2.17
3.33
2.67
≤ 1.23
≤ 1.67
≤1.00
≤ 1.50
2.63
≤ 1.50
2.50
A1
5.67
A2
4.50
A3
4.67
3.50
2.33
3.50
2.23
S1
3.67
4.00
1.67
2.83
1.50
2.67
S2
5.00
3.00
≤ 1.00
≤ 1.00
1.67
≤ 1.50
S3
2.00
2.50
2.67
2.23
1.50
O1
1.83
2.50
2.00
≤ 0.67
O2
4.00
≤ 1.00
2.23
≤ 0.83
O3
3.33
2.50
≤ 1.23
≤ 0.67
24
Peramivir
Amantadine
P1
3.00
2.50
2.00
≤ 1.50
≤ 1.00
P2
4.33
3.50
≤ 0.67
P3
4.67
3.00
1.38
A1
3.67
3.00
≤ 1.00
≤ 1.00
2.23
A2
4.50
≤ 1.23
≤ 1.77
< 1.50
3.50
≤ 2.25
A3
4.00
2.33
≤ 1.33
3.23
3.00
2.25
≤ 1.00
519
520
: Sampling organs.
521
: Macaque identification.
522
<: No CPE-positive well in quadruplicate culture. A detection limit was 0.67 log10TCID50/mL.
523
≤ 0.67: One CPE-positive well in quadruplicate culture with the undiluted samples was
524
observed.
525
526
samples and one with 10-fold diluted sample.
527
≤ 1: Two CPE-positive wells in quadruplicate culture with undiluted sample were observed.
528
≤1.23: Three CPE-positive wells were observed in quadruplicate culture: two with undiluted
529
sample and one with 10-fold diluted sample.
530
≤1.33: Three CPE-positive wells in quadruplicate culture with undiluted sample were observed.
531
≤ 1.44: Four CPE-positive wells were observed in quadruplicate culture: two with undiluted
532
sample; one with 10-fold diluted sample and one with 100-fold diluted sample.
533
534
sample and two with 10-fold diluted sample.
535
536
sample; one with 10-fold diluted sample and one with 1000-fold diluted sample.
537
538
sample and two with 10-fold diluted sample.
539
540
sample; one with 10-fold diluted sample and two with 100-fold diluted sample.
541
542
sample; three with 10-fold diluted sample.
543
544
≤ 0.83: Two CPE-positive wells were observed in quadruplicate culture: one with undiluted
≤ 1.5: Four CPE-positive wells were observed in quadruplicate culture: two with undiluted
≤ 1.67: Five CPE-positive wells were observed in quadruplicate culture: three with undiluted
≤ 1.77: Five CPE-positive wells were observed in quadruplicate culture: three with undiluted
≤ 1.83: Six CPE-positive wells were observed in quadruplicate culture: three with undiluted
≤ 2.17: Six CPE-positive wells were observed in quadruplicate culture: three with undiluted
≤ 2.25: Seven CPE-positive wells were observed in quadruplicate culture: three with undiluted
sample; two with 10-fold diluted sample and two with 100-fold diluted sample.
25
545
Figure legends
546
Fig 1. Symptoms of cynomolgus macaques challenged with A/black swan/Akita/1/2016
547
(H5N6).
548
Cynomolgus macaques (n = 3) were inoculated with the virus on day 0. (a) Averages and
549
standard deviations of body temperature and (b) heart rate were determined by using a telemetry
550
probe system during the night (from 8:00 p.m. to 8:00 a.m.) and data were adjusted to day -1. (c,
551
d) Averages and standard deviations of food consumption and body weight are shown. (c) Food
552
consumption was estimated by the following formation: food consumption = [(number of pellets
553
given in the morning - number of pellets left at night)/number of pellets given in the morning] ×
554
100 (%). (d) Body weight was monitored every day. Statistical differences among groups are
555
calculated with an ANOVA multi-comparison test.
556
557
Fig
558
swan/Akita/1/2016 (H5N6).
559
H&E staining of lung tissues collected 7 days after virus infection. Representative photos of
560
cynomolgus macaques treated with saline (a), oseltamivir (b), peramivir (c) and amantadine (d).
561
Black arrow heads point neutrophils. Bars, 50 μm.
2.
Viral
pneumonia
in
cynomolgus
macaques
challenged
with
A/black
562
563
Fig 3. Peripheral blood cell populations and cytokine/chemokine responses in cynomolgus
564
macaques challenged with A/black swan/Akita/1/2016 (H5N6).
565
(a-d) Concentrations in peripheral blood cells collected on the indicated days: (a) total leukocytes,
566
(b) granulocytes, (c) monocytes, and (d) lymphocytes. (e-h) Levels of cytokines/chemokines in
567
plasma after virus infection. The average values and standard deviations were shown.
26
568
569
Fig 4. Efficacy of antiviral drugs against A/black swan/Akita/1/2016 (H5N6) virus in vitro.
570
MDCK cells were infected with the virus at a multiplicity of infection (MOI) of 0.01 and
571
cultured with antiviral drugs of various concentrations: (a) oseltamivir, (b, d) peramivir, and (c)
572
amantadine. Sensitivity of the inoculum virus (a-c) and the virus recovered from a tonsil of
573
macaque P2 on day 7 (d) was examined. The supernatant of each well was collected at 24 h and
574
48 h after virus infection. Then virus titers in the supernatants were determined by the Reed
575
Muench method. Averages and standard deviations of three independent experiments were
576
shown in a-c. Averages and standard deviations of triplicate culture were shown in d. EC50
577
values were calculated by "Quest Graph™ EC50 Calculator." AAT Bioquest, Inc, 03 Feb. 2020,
578
https://www.aatbio.com/tools/ec50-calculator. The asterisks show significant differences in virus
579
titers with treatment at each antiviral drug concentration and without treatment (0 μg/mL)
580
(Student’s t-test, *: P < 0.05, **:P<0.01).
27
...
論文の公開元へ
