Lethality to Ferrets of H5N1 Influenza Viruses Isolated from Humans and Poultry in 2004

Govorkova, Elena A.; Rehg, Jerold E.; Krauss, Scott; Yen, Hui‐Ling; Guan, Yi; Peiris, Malik; Nguyễn, Tiến Dũng; Hanh, Thi H.; Puthavathana, P.; Long, Hoang Thuy; Buranathai, Chantanee; Lim, Wilina; Webster, Robert G.; Hoffmann, Erich

doi:10.1128/jvi.79.4.2191-2198.2005

Cited by 303 publications

(163 citation statements)

References 39 publications

Supporting

Mentioning

154

Contrasting

Order By: Relevance

“…Viral inocula were also administered orally to ferrets 9 to 16 (4 M and 4 F) to represent the ingestion of H5N1-contaminated food or liquid. For comparison, the same dose of virus was also delivered in a large, 500-l volume of inoculum to the nares of sedated animals (ferrets 17 to 24; 6 M and 2 F) to infect the total respiratory tract (TRT), as this method is routinely performed in H5N1 pathogenesis studies (29,30,36). Following inoculation, temperature, weight loss, and activity scores were assessed periodically as an indication of disease severity, and ferrets were euthanized at the predetermined humane endpoint.…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, we infected a further 12 female animals (ferrets 25 and 36) via the URT route to more closely investigate disease signs associated with severe disease outcome and clarify whether neuroinvasion did indeed occur following inoculation by this route. After URT exposure to virus, ferrets 29,30,32,33,35, and 36 were euthanized at the humane endpoint on days 3 to 5 postinfection, and ferrets 25, 26, and 31 were euthanized on day 7. These ferrets were included in the nonsurviving category.…”

Section: Resultsmentioning

confidence: 99%

“…Ferrets develop disease signs similar to those in humans when infected with human isolates of H5N1 virus (29,30). The hematological, metabolic, and physiological changes detected in ferrets over the course of infection and changes found in laboratory samples from infected patients are alike (31).…”

mentioning

confidence: 90%

“…These anatomical pathways for dissemination into systemic organs are potentially influenced by the route of initial infection (36). However, current inoculation methods used to infect ferrets do not accurately reflect natural exposure of humans to the virus (6) because the animals are anesthetized prior to inoculation and are infected with large volumes of viral suspension delivered into the nares (29,30,35,39,41) or directly into the trachea (36). Following these delivery procedures, the inoculum deposits in peripheral lung tissue and, hence, does not model exposure to droplets, which would predominantly deposit in the upper respiratory tract (URT), including the trachea (42).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes

Edenborough

Lowther

Laurie

et al. 2016

J Virol

View full text Add to dashboard Cite

Although avian H5N1 influenza virus has yet to develop the capacity for human-to-human spread, the severity of the rare cases of human infection has warranted intensive follow-up of potentially exposed individuals that may require antiviral prophylaxis. For countries where antiviral drugs are limited, the World Health Organization (WHO) has developed a risk categorization for different levels of exposure to environmental, poultry, or human sources of infection. While these take into account the infection source, they do not account for the likely mode of virus entry that the individual may have experienced from that source and how this could affect the disease outcome. Knowledge of the kinetics and spread of virus after natural routes of exposure may further inform the risk of infection, as well as the likely disease severity. Using the ferret model of H5N1 infection, we compared the commonly used but artificial inoculation method that saturates the total respiratory tract (TRT) with virus to upper respiratory tract (URT) and oral routes of delivery, those likely to be encountered by humans in nature. We show that there was no statistically significant difference in survival rate with the different routes of infection, but the disease characteristics were somewhat different. Following URT infection, viral spread to systemic organs was comparatively delayed and more focal than after TRT infection. By both routes, severe disease was associated with early viremia and central nervous system infection. After oral exposure to the virus, mild infections were common suggesting consumption of virus-contaminated liquids may be associated with seroconversion in the absence of severe disease. IMPORTANCERisks for human H5N1 infection include direct contact with infected birds and frequenting contaminated environments. We used H5N1 ferret infection models to show that breathing in the virus was more likely to produce clinical infection than swallowing contaminated liquid. We also showed that virus could spread from the respiratory tract to the brain, which was associated with end-stage disease, and very early viremia provided a marker for this. With upper respiratory tract exposure, infection of the brain was common but hard to detect, suggesting that human neurological infections might be typically undetected at autopsy. However, viral spread to systemic sites was slower after exposure to virus by this route than when virus was additionally delivered to the lungs, providing a better therapeutic window. In addition to exposure history, early parameters of infection, such as viremia, could help prioritize antiviral treatments for patients most at risk of succumbing to infection. Since the emergence of highly pathogenic avian influenza H5N1 in humans in 1997, outbreaks have occurred sporadically, primarily in populations associated with direct contact with sick birds (1-4). Currently, outbreaks occur in regions where H5N1 is endemic in migratory birds and where a large proportion of the population rear backyard poultry ...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 90%

mentioning

confidence: 99%

See 2 more Smart Citations

Predicting Disease Severity and Viral Spread of H5N1 Influenza Virus in Ferrets in the Context of Natural Exposure Routes

Edenborough

Lowther

Laurie

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…While young adult ferrets (generally 4 to 12 months old) are most frequently used, the age of animals employed can vary depending on the questions addressed in the study, ranging from ferrets that are newly weaned (Յ8 weeks old) to aged ferrets (Ͼ4 years of age) (11,12). The choice of anesthetic used for inoculation and sampling postinoculation (typically ketamine cocktails of various compositions and dosages administered intramuscularly, inhaled isoflurane, or both) can vary between laboratories, leading to differences in the depth of sedation and the respiration rates of sedated animals (13)(14)(15)(16).…”

Section: Standardization Of Materialsmentioning

confidence: 99%

Complexities in Ferret Influenza Virus Pathogenesis and Transmission Models

Belser

Eckert

Tumpey

et al. 2016

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

SUMMARYFerrets are widely employed to study the pathogenicity, transmissibility, and tropism of influenza viruses. However, inherent variations in inoculation methods, sampling schemes, and experimental designs are often overlooked when contextualizing or aggregating data between laboratories, leading to potential confusion or misinterpretation of results. Here, we provide a comprehensive overview of parameters to consider when planning an experiment using ferrets, collecting data from the experiment, and placing results in context with previously performed studies. This review offers information that is of particular importance for researchers in the field who rely on ferret data but do not perform the experiments themselves. Furthermore, this review highlights the breadth of experimental designs and techniques currently available to study influenza viruses in this model, underscoring the wide heterogeneity of protocols currently used for ferret studies while demonstrating the wealth of information which can benefit risk assessments of emerging influenza viruses.

show abstract