Novel H7N9 Influenza Virus Shows Low Infectious Dose, High Growth Rate, and Efficient Contact Transmission in the Guinea Pig Model

Three waves of human infection with H7N9 influenza viruses have concluded to date, but only viruses within the first wave (iso-lated IMPORTANCE H7N9 influenza viruses, first isolated in 2013, continue to cause human infection and represent an ongoing public health threat.Now entering the fourth wave of human infection, H7N9 viruses continue to exhibit genetic diversity in avian hosts, necessitating continuous efforts to monitor their pandemic potential. However, viruses isolated post-2013 have not been extensively studied, limiting our understanding of potential changes in virus-host adaptation. In order to ensure that current research with firstwave H7N9 viruses still pertains to more recently isolated strains, we compared the relative virulence and transmissibility of H7N9 viruses isolated during the second and third waves, through 2015, in the mouse and ferret models. Our finding that second-and third-wave viruses generally exhibit disease in mammals comparable to that of first-wave viruses strengthens our ability to extrapolate research from the 2013 viruses to current public health efforts. These data further contribute to our understanding of molecular determinants of pathogenicity, transmissibility, and tropism.

Section: Discussionsupporting

confidence: 49%

Section: H7n9 Virus Information and Genetic Diversitymentioning

confidence: 99%

Mammalian Pathogenesis and Transmission of H7N9 Influenza Viruses from Three Waves, 2013-2015

Belser

Creager

Sun

et al. 2016

“…This finding is intriguing as SH2/H7 was isolated from a young adult, whereas SH1/H7 and Anhui/H7 were isolated from older, high-risk subjects with severe infection (1,29). Aside from the differences with H5N1, H7N9 infection still poses a significant threat to human health, especially with the suggestion that these viruses have increased transmissibility versus H5N1 strains (1,30). The reemergence of H7N9 highlights the fact that early diagnosis of infected individuals and outbreak control measures such as closing of the poultry markets may not be sufficient to completely stall an outbreak of H7N9.…”

Section: Discussionmentioning

confidence: 86%

Human H7N9 and H5N1 Influenza Viruses Differ in Induction of Cytokines and Tissue Tropism

Meliopoulos

Karlsson

Kercher

et al. 2014

Since emerging in 2013, the avian-origin H7N9 influenza viruses have resulted in over 400 human infections, leading to 115 deaths to date. Although the epidemiology differs from human highly pathogenic avian H5N1 influenza virus infections, there is a similar rapid progression to acute respiratory distress syndrome. The aim of these studies was to compare the pathological and immunological characteristics of a panel of human H7N9 and H5N1 viruses in vitro and in vivo. Although there were similarities between particular H5N1 and H7N9 viruses, including association between lethal disease and spread to the alveolar spaces and kidney, there were also strain-specific differences. Both H5N1 and H7N9 viruses are capable of causing lethal infections, with mortality correlating most strongly with wider distribution of viral antigen in the lungs, rather than with traditional measures of virus titer and host responses. Strain-specific differences included hypercytokinemia in H5N1 infections that was not seen with the H7N9 infections regardless of lethality. Conversely, H7N9 viruses showed a greater tropism for respiratory epithelium covering nasal passages and nasopharynx-associated lymphoid tissue than H5N1 viruses, which may explain the enhanced transmission in ferret models. Overall, these studies highlight some distinctive properties of H5N1 and H7N9 viruses in different in vitro and in vivo models. IMPORTANCEThe novel avian-origin H7N9 pandemic represents a serious threat to public health. The ability of H7N9 to cause serious lung pathology, leading in some cases to the development of acute respiratory distress syndrome, is of particular concern. Initial reports of H7N9 infection compared them to infections caused by highly pathogenic avian (HPAI) H5N1 viruses. Thus, it is of critical importance to understand the pathology and immunological response to infection with H7N9 compared to HPAI H5N1 viruses. We compared these responses in both in vitro and in vivo models, and found that H5N1 and H7N9 infections exhibit distinct pathological, immunological, and tissue tropism differences that could explain differences in clinical disease and viral transmission.

“…Factors that were controlled in our experiments but vary in nature are known to affect the frequency and timing of dual-transmission events. For example, temperature and humidity (60)(61)(62), preexisting immunity (63)(64)(65)(66), timing and duration of exposure (67), proximity of exposure (68), host species (69), and viral fitness in that host species (41,(70)(71)(72)(73) all impact transmission efficiency and are therefore expected to dictate the likelihood of two independent transmission events leading to coinfection.…”

Section: Discussionmentioning

confidence: 99%

Influenza A Virus Coinfection through Transmission Can Support High Levels of Reassortment

Tao

White

et al. 2015

Self Cite

The reassortment of gene segments between influenza viruses increases genomic diversity and plays an important role in viral evolution. We have shown previously that this process is highly efficient within a coinfected cell and, given synchronous coinfection at moderate or high doses, can give rise to ϳ60 to 70% of progeny shed from an animal host. Conversely, reassortment in vivo can be rendered undetectable by lowering viral doses or extending the time between infections. One might also predict that seeding of transmitted viruses into different sites within the target tissue could limit subsequent reassortment. Given the potential for stochastic factors to restrict reassortment during natural infection, we sought to determine its efficiency in a host coinfected through transmission. Two scenarios were tested in a guinea pig model, using influenza A/Panama/2007/99 (H3N2) virus (wt) and a silently mutated variant (var) thereof as parental virus strains. In the first, coinfection was achieved by exposing a naive guinea pig to two cagemates, one infected with wt and the other with var virus. When such exposure led to coinfection, robust reassortment was typically seen, with 50 to 100% of isolates carrying reassortant genomes at one or more time points. In the second scenario, naive guinea pigs were exposed to a cagemate that had been coinoculated with wt and var viruses. Here, reassortment occurred in the coinoculated donor host, multiple variants were transmitted, and reassortants were prevalent in the recipient host. Together, these results demonstrate the immense potential for reassortment to generate viral diversity in nature. IMPORTANCE Influenza viruses evolve rapidly under selection due to the generation of viral diversity through two mechanisms. The first is the introduction of random errors into the genome by the viral polymerase, which occurs with a frequency of approximately 10؊5 errors/nucleotide replicated. The second is reassortment, or the exchange of gene segments between viruses. Reassortment is known to occur readily under well-controlled laboratory conditions, but its frequency in nature is not clear. Here, we tested the hypothesis that reassortment efficiency following coinfection through transmission would be reduced compared to that seen with coinoculation. Contrary to this hypothesis, our results indicate that coinfection achieved through transmission supports high levels of reassortment. These results suggest that reassortment is not exquisitely sensitive to stochastic effects associated with transmission and likely occurs in nature whenever a host is infected productively with more than one influenza A virus.T he segmented nature of the influenza virus genome allows for ready exchange of genetic material between two viruses that coinfect one cell (1). If the parental viruses differ in all eight gene segments, 256 different progeny viruses can be produced in a single reassortment event. Reassortment between two very distinct strains is typically associated with marked genotypic and ...