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High Pathogenicity of Influenza A (H10N8) Virus in Mice.

ABSTRACT: Three human cases of H10N8 virus infections were initially reported in China in late 2013 and early 2014, two of which were fatal. This was the first time the H10N8 subtype has been detected in humans, and the pathogenicity of this virus remains under characterized. We first assessed its pathogenicity by infecting BALB/c mice with two H10N8 isolates, A/Jiangxi-Donghu/346-1/2013 and A/Chicken/Jiangxi/102/2013. The human isolate (H346-1) demonstrated stronger capability of replication and induced higher cytokine response in vivo than the chicken isolate (C102). In addition, H346-1 was fatal to mice, while all mice (N = 14) in C102-infected group survived during the infection course without weight loss. We hypothesized that the 627K mutation in the PB2 gene (PB2-K627) in H346-1 was associated with high pathogenicity in mice. Taken together, this study based on mouse model provides some insight into understanding the pathogenicity of the emerging viruses in mammals.

SUBMITTER: Chen H

PROVIDER: S-EPMC4674259 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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High Pathogenicity of Influenza A (H10N8) Virus in Mice.

Chen Haiying H Huang Lihong L Li Hui H Zhou Xianfeng X Li Huanan H Sun Na N Qi Wenbao W Xiao Chencheng C Ni Xiansheng X Liu Mingbin M Liao Ming M

The American journal of tropical medicine and hygiene 20150908 6

Three human cases of H10N8 virus infections were initially reported in China in late 2013 and early 2014, two of which were fatal. This was the first time the H10N8 subtype has been detected in humans, and the pathogenicity of this virus remains under characterized. We first assessed its pathogenicity by infecting BALB/c mice with two H10N8 isolates, A/Jiangxi-Donghu/346-1/2013 and A/Chicken/Jiangxi/102/2013. The human isolate (H346-1) demonstrated stronger capability of replication and induced ...[more]

PMID: 26350451

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Project description:UnlabelledA novel avian-origin influenza A/H7N9 virus infecting humans was first identified in March 2013 and, as of 30 May 2013, has caused 132 human infections leading to 33 deaths. Phylogenetic studies suggest that this virus is a reassortant, with the surface hemagglutinin (HA) and neuraminidase (NA) genes being derived from duck and wild-bird viruses, respectively, while the six "internal gene segments" were derived from poultry H9N2 viruses. Here we determine the pathogenicity of a human A/Shanghai/2/2013 (Sh2/H7N9) virus in healthy adult mice in comparison with that of A/chicken/Hong Kong/HH8/2010 (ck/H9N2) virus, highly pathogenic avian influenza (HPAI) A/Hong Kong/483/1997 (483/H5N1) virus, and a duck influenza A H7N9 virus of different genetic derivation, A/duck/Jiangxi/3286/2009 (dk/H7N9). Intranasal infection of mice with Sh2/H7N9 virus doses of 10(3), 10(4), and 10(5) PFU led to significant weight loss without fatality. This virus was more pathogenic than dk/H7N9 and ck/H9N2 virus, which has six internal gene segments that are genetically similar to Sh2/H7N9. Sh2/H7N9 replicated well in the nasal cavity and lung, but there was no evidence of virus dissemination beyond the respiratory tract. Mice infected with Sh2/H7N9 produced higher levels of proinflammatory cytokines in the lung and serum than did ck/H9N2 and dk/H7N9 but lower levels than 483/H5N1. Cytokine induction was positively correlated with virus load in the lung at early stages of infection. Our results suggest that Sh2/H7N9 virus is able to replicate and cause disease in mice without prior adaptation but is less pathogenic than 483/H5N1 virus.ImportanceAn H7N9 virus isolate causing fatal human disease was found to be more pathogenic for mice than other avian H9N2 or H7N9 viruses but less pathogenic than the highly pathogenic avian influenza virus (HPAI) H5N1. Similarly, the ability of Sh2/H7N9 to elicit proinflammatory cytokines in the lung and serum of mice was intermediate to ck/H9N2 and dk/H7N9 on the one hand and HPAI H5N1 on the other. These findings accord with the observed epidemiology in humans, in whom, as with seasonal influenza viruses, H7N9 viruses cause severe disease predominantly in older persons while HPAI H5N1 can cause severe respiratory disease and death in children and young adults.

Project description:UnlabelledThe recently identified H7N9 influenza A virus has caused severe economic losses and worldwide public concern. Genetic analysis indicates that its six internal genes all originated from H9N2 viruses. However, the H7N9 virus is more highly pathogenic in humans than H9N2, which suggests that the internal genes of H7N9 have mutated. To analyze which H7N9 virus internal genes contribute to its high pathogenicity, a series of reassortants was generated by reverse genetics, with each virus containing a single internal gene of the typical A/Anhui/1/2013 (H7N9) (AH-H7N9) virus in the genetic background of the A/chicken/Shandong/lx1023/2007 (H9N2) virus. The replication ability, polymerase activity, and pathogenicity of these viruses were then evaluated in vitro and in vivo. These recombinants displayed high genetic compatibility, and the H7N9-derived PB2, M, and NP genes were identified as the virulence genes for the reassortants in mice. Further investigation confirmed that the PB2 K627 residue is critical for the high pathogenicity of the H7N9 virus and the reassortant containing the H7N9-derived PB2 segment (H9N2-AH/PB2). Notably, the H7N9-derived PB2 gene displayed greater compatibility with the H9N2 genome than that of H7N9, endowing the H9N2-AH/PB2 reassortant with greater viability and virulence than the parental H7N9 virus. In addition, the H7N9 virus, with the exception of the H9N2 reassortants, could effectively replicate in human A549 cells. Our results indicate that PB2, M, and NP are the key virulence genes, together with the surface hemagglutinin (HA) and neuraminidase (NA) proteins, contributing to the high infectivity of the H7N9 virus in humans.ImportanceTo date, the novel H7N9 influenza A virus has caused 437 human infections, with approximately 30% mortality. Previous work has primarily focused on the two viral surface proteins, HA and NA, but the contribution of the six internal genes to the high pathogenicity of H7N9 has not been systematically studied. Here, the H9N2 virus was used as a genetic backbone to evaluate the virulence genes of H7N9 virus in vitro and in vivo. Our data indicate that the PB2, M, and NP genes play important roles in viral infection in mice and, together with HA and NA, contribute to the high infectivity of the H7N9 virus in humans.

Dataset Information

High Pathogenicity of Influenza A (H10N8) Virus in Mice.

Publications

High Pathogenicity of Influenza A (H10N8) Virus in Mice.

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