Experimental Infection of Macaques with a Wild Water Bird-Derived Highly Pathogenic Avian Influenza Virus (H5N1)

Fujiyuki, Tomoko; Yoneda, Misako; Yasui, Fumihiko; Kuraishi, Takeshi; Hattori, Satoshi; Kwon, Hyun-jeong; Munekata, Keisuke; Kiso, Yuri; Kida, Hiroshi; Kohara, Michinori; Kai, Chieko

doi:10.1371/journal.pone.0083551

Cited by 6 publications

(14 citation statements)

References 25 publications

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“…As a control, 4 ml of the virus solution was administered through multiple routes by the conventional method, that is, by the intranasal (0.4 ml each to the left and right nostril), intraoral (0.4 ml each to the left and right tonsil), intraocular (0.1 ml per eye), and intratracheal (2.2 ml using a tracheal catheter) routes (defined as 'the conventional method group'). The virus dose of 4 × 10 7 PFU of influenza virus was chosen for inoculation because a similar virus dose has been widely used in previous studies to infect NHPs to ensure the greatest likelihood of virus infection and replication in the inoculated animals 6,15,[17][18][19] .…”

Section: Resultsmentioning

confidence: 99%

Experimental infection of Cynomolgus Macaques with highly pathogenic H5N1 influenza virus through the aerosol route

Watanabe

Iwatsuki‐Horimoto

Kiso

et al. 2018

Sci Rep

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Several animal models are used to study influenza viruses. Intranasal inoculation of animals with a liquid inoculum is one of the main methods used to experimentally infect animals with influenza virus; however, this method does not reflect the natural infection with influenza virus by contact or aerosol route. Aerosol inhalation methods have been established with several influenza viruses for mouse and ferret models, but few studies have evaluated inoculation routes in a nonhuman primates (NHP) model. Here, we performed the experimental infection of NHPs with a highly pathogenic H5N1 influenza virus via the aerosol route and demonstrated that aerosol infection had no effect on clinical outcome, but caused broader infection throughout all of the lobes of the lung compared with a non-aerosolized approach. Aerosol infection therefore represents an option for inoculation of NHPs in future studies.

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Section: Resultsmentioning

confidence: 99%

Experimental infection of Cynomolgus Macaques with highly pathogenic H5N1 influenza virus through the aerosol route

Watanabe

Iwatsuki‐Horimoto

Kiso

et al. 2018

Sci Rep

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“…A significant issue with nonhuman primate studies to date is that unlike human disease, infection causes death in only a small minority of animals (21–23, 26). All published nonhuman primate studies have used an inoculation method involving application of virus in liquid suspension (21–26) or via large droplets (27) into the trachea, often in combination with other mucosal routes. These delivery methods are unlikely to expose target cells in the alveoli to significant quantities of virus because liquid suspensions and/or large droplets are cleared by the mucociliary apparatus of the upper respiratory tract.…”

Section: Introductionmentioning

confidence: 99%

Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques

Wonderlich

Swan

Bissel

et al. 2017

The Journal of Immunology

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Human infections with highly pathogenic avian influenza A (H5N1) virus are frequently fatal but the mechanisms of disease remain ill-defined. H5N1 infection is associated with intense production of proinflammatory cytokines, but whether this cytokine storm is the main cause of fatality or is a consequence of extensive virus replication that itself drives disease remains controversial. Conventional intratracheal inoculation of a liquid suspension of H5N1 influenza virus in nonhuman primates likely results in efficient clearance of virus within the upper respiratory tract and rarely produces severe disease. We reasoned that small particle aerosols of virus would penetrate the lower respiratory tract and blanket alveoli where target cells reside. We show that inhalation of aerosolized H5N1 influenza virus in cynomolgus macaques results in fulminant pneumonia that rapidly progresses to acute respiratory distress syndrome with a fatal outcome reminiscent of human disease. Molecular imaging revealed intense lung inflammation coincident with massive increases in proinflammatory proteins and interferon-α in distal airways. Aerosolized H5N1 exposure decimated alveolar macrophages, which were widely infected and caused marked influx of interstitial macrophages and neutrophils. Extensive infection of alveolar epithelial cells caused apoptosis and leakage of albumin into airways, reflecting loss of epithelial barrier function. These data establish inhalation of aerosolized virus as a critical source of exposure for fatal human infection and reveal that direct viral effects in alveoli mediate H5N1 disease. This new nonhuman primate model will advance vaccine and therapeutic approaches to prevent and treat human disease caused by highly pathogenic avian influenza viruses.

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“…To examine the protective effects of rMV-Ed-H5HA or rMV-HL-Vko-H5HA against H5N1 infection, we challenged the vaccinated monkeys with H5N1 (A/whooper swan/Hokkaido/1/2008 clade 2.3.2.1) as previously described 13 . We monitored their body temperature, respiratory rate, heart rate, bodyweight, and appetite.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we developed a candidate HPAIV vaccine based on the MV vector. We generated rMV expressing an HPAIV antigen and evaluated its efficacy on the challenge with a wild HPAIV (H5N1) strain in a previously established model of HPAIV infection in non-human primate 13 .…”

Section: Introductionmentioning

confidence: 99%

Efficacy of recombinant measles virus expressing highly pathogenic avian influenza virus (HPAIV) antigen against HPAIV infection in monkeys

Fujiyuki

Horie

Yoneda

et al. 2017

Sci Rep

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Highly pathogenic avian influenza virus (HPAIV) is a serious threat not only to domestic fowls but also to humans. Vaccines inducing long-lasting immunity against HPAIV are required. In the present study, we generated recombinant measles virus (MV) expressing the hemagglutinin protein of HPAIV without the multibasic site necessary for its pathogenicity in chickens using the backbone of an MV vaccine strain (rMV-Ed-H5HA) or a wild-type MV-derived mutant (rMV-HL-Vko-H5HA). We examined protective efficacy of the candidate vaccines in the monkey infection model by the challenge with a HPAIV (H5N1). Cynomolgus monkeys inoculated with the candidate vaccines produced both anti-H5 HA and anti-MV antibodies. They recovered earlier from influenza symptoms than unvaccinated monkeys after the challenge with the HPAIV strain. Chest radiography and histopathological analyses confirmed less severe pneumonia in the vaccinated monkeys. Vaccination tended to suppress viral shedding and reduced the interleukin-6 levels in the lungs. Furthermore, the vaccination with rMV-Ed-H5HA of monkeys with pre-existing anti-MV immunity induced the production of anti-H5 HA antibodies. These results suggest that both candidate vaccines effectively reduce disease severity in naïve hosts, and that rMV-Ed-H5HA is a particularly good candidate vaccine against HPAIV infection.

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Experimental Infection of Macaques with a Wild Water Bird-Derived Highly Pathogenic Avian Influenza Virus (H5N1)

Cited by 6 publications

References 25 publications

Experimental infection of Cynomolgus Macaques with highly pathogenic H5N1 influenza virus through the aerosol route

Experimental infection of Cynomolgus Macaques with highly pathogenic H5N1 influenza virus through the aerosol route

Widespread Virus Replication in Alveoli Drives Acute Respiratory Distress Syndrome in Aerosolized H5N1 Influenza Infection of Macaques

Efficacy of recombinant measles virus expressing highly pathogenic avian influenza virus (HPAIV) antigen against HPAIV infection in monkeys

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