Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive ...therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium’s protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.
Avian Coronavirus in Wild Aquatic Birds CHU, Daniel K. W; LEUNG, Connie Y. H; GILBERT, Martin ...
Journal of Virology,
12/2011, Letnik:
85, Številka:
23
Journal Article
A novel H7N9 influenza A virus first detected in March 2013 has since caused more than 130 human infections in China, resulting in 40 deaths. Preliminary analyses suggest that the virus is a ...reassortant of H7, N9 and H9N2 avian influenza viruses, and carries some amino acids associated with mammalian receptor binding, raising concerns of a new pandemic. However, neither the source populations of the H7N9 outbreak lineage nor the conditions for its genesis are fully known. Using a combination of active surveillance, screening of virus archives, and evolutionary analyses, here we show that H7 viruses probably transferred from domestic duck to chicken populations in China on at least two independent occasions. We show that the H7 viruses subsequently reassorted with enzootic H9N2 viruses to generate the H7N9 outbreak lineage, and a related previously unrecognized H7N7 lineage. The H7N9 outbreak lineage has spread over a large geographic region and is prevalent in chickens at live poultry markets, which are thought to be the immediate source of human infections. Whether the H7N9 outbreak lineage has, or will, become enzootic in China and neighbouring regions requires further investigation. The discovery here of a related H7N7 influenza virus in chickens that has the ability to infect mammals experimentally, suggests that H7 viruses may pose threats beyond the current outbreak. The continuing prevalence of H7 viruses in poultry could lead to the generation of highly pathogenic variants and further sporadic human infections, with a continued risk of the virus acquiring human-to-human transmissibility.
We assessed the effect of closing live poultry markets in China on influenza A(H7N9) virus detection and viability. Intensive sampling was carried out before, during, and after a 2-week citywide ...market closure; the markets were cleaned and disinfected at the beginning of the closure period. Swab samples were collected at different sites within the markets and tested for H7N9 by real-time reverse transcription PCR and culture. During the closure, H7N9 viral RNA detection and isolation rates in retail markets decreased by 79% (95% CI 64%-88%) and 92% (95% CI 58%-98%), respectively. However, viable H7N9 virus could be cultured from wastewater samples collected up to 2 days after the market closure began. Our findings indicates that poultry workers and the general population are constantly exposed to H7N9 virus at these markets and that market closure and disinfection rapidly reduces the amount of viable virus.
Mongolia combines a near absence of domestic poultry, with an abundance of migratory waterbirds, to create an ideal location to study the epidemiology of highly pathogenic avian influenza virus ...(HPAIV) in a purely wild bird system. Here we present the findings of active and passive surveillance for HPAIV subtype H5N1 in Mongolia from 2005–2011, together with the results of five outbreak investigations. In total eight HPAIV outbreaks were confirmed in Mongolia during this period. Of these, one was detected during active surveillance employed by this project, three by active surveillance performed by Mongolian government agencies, and four through passive surveillance. A further three outbreaks were recorded in the neighbouring Tyva Republic of Russia on a lake that bisects the international border. No HPAIV was isolated (cultured) from 7,855 environmental fecal samples (primarily from ducks), or from 2,765 live, clinically healthy birds captured during active surveillance (primarily shelducks, geese and swans), while four HPAIVs were isolated from 141 clinically ill or dead birds located through active surveillance. Two low pathogenic avian influenza viruses (LPAIV) were cultured from ill or dead birds during active surveillance, while environmental feces and live healthy birds yielded 56 and 1 LPAIV respectively. All Mongolian outbreaks occurred in 2005 and 2006 (clade 2.2), or 2009 and 2010 (clade 2.3.2.1); all years in which spring HPAIV outbreaks were reported in Tibet and/or Qinghai provinces in China. The occurrence of outbreaks in areas deficient in domestic poultry is strong evidence that wild birds can carry HPAIV over at least moderate distances. However, failure to detect further outbreaks of clade 2.2 after June 2006, and clade 2.3.2.1 after June 2010 suggests that wild birds migrating to and from Mongolia may not be competent as indefinite reservoirs of HPAIV, or that HPAIV did not reach susceptible populations during our study.
Genetic factors affect an individual's risk of developing obesity, but in most cases each genetic variant has a small effect. Discovery of genes that regulate obesity may provide clues about its ...underlying biological processes and point to new ways the disease can be treated. Preclinical animal models facilitate genetic discovery in obesity because environmental factors can be better controlled compared with the human population. We studied inbred mouse strains to identify novel genes affecting obesity and glucose metabolism. BTBR T+
/J (BTBR) mice are fatter and more glucose intolerant than C57BL/6J (B6) mice. Prior genetic studies of these strains identified an obesity locus on chromosome 2. Using congenic mice, we found that obesity was affected by a ∼316 kb region, with only two known genes, pyruvate dehydrogenase kinase 1 (
) and integrin α 6 (
). Both genes had mutations affecting their amino acid sequence and reducing mRNA levels. Both genes have known functions that could modulate obesity, lipid metabolism, insulin secretion, and/or glucose homeostasis. We hypothesized that genetic variation in or near
or
causing reduced
and
expression would promote obesity and impaired glucose tolerance. We used knockout mice lacking
or
fed an obesigenic diet to test this hypothesis. Under the conditions we studied, we were unable to detect an individual contribution of either
or
to body weight. During our studies, with conditions outside our control, we were unable to reproduce some of our previous body weight data. However, we identified a previously unknown role for
in cardiac cholesterol metabolism providing the basis for future investigations. The studies described in this paper highlight the importance and the challenge using physiological outcomes to study obesity genes in mice.
Highlights • HPAI H5N1 viruses undergo antigenic changes. • These antigenic changes may lead to loss of protection against poultry vaccines. • The needs to monitor the H5N1 viruses’ susceptibility to ...vaccine induced immunity. • A lack of serologic HI reactivity may not always mean lack of vaccine protection. • There is a need for challenge studies in vaccinated poultry.
The mechanism for the pathogenesis of H5N1 infection in humans remains unclear. This study reveals that cyclooxygenase-2 (COX-2) was strongly induced in H5N1-infected macrophages in vitro and in ...epithelial cells of lung tissue samples obtained during autopsy of patients who died of H5N1 disease. Novel findings demonstrated that COX-2, along with tumor necrosis factor α and other proinflammatory cytokines were hyperinduced in epithelial cells by secretory factors from H5N1-infected macrophages in vitro. This amplification of the proinflammatory response is rapid, and the effects elicited by the H5N1-triggered proinflammatory cascade are broader than those arising from direct viral infection. Furthermore, selective COX-2 inhibitors suppress the hyperinduction of cytokines in the proinflammatory cascade, indicating a regulatory role for COX-2 in the H5N1-hyperinduced host proinflammatory cascade. These data provide a basis for the possible development of novel therapeutic interventions for the treatment of H5N1 disease, as adjuncts to antiviral drugs.
Avian H9N2 influenza A virus has caused repeated human infections in Asia since 1998. Here we report that an H9N2 influenza virus infected a 5-year-old child in Hong Kong in 2003. To identify the ...possible source of the infection, the human isolate and other H9N2 influenza viruses isolated from Hong Kong poultry markets from January to October 2003 were genetically and antigenically characterized. The findings of this study show that the human H9N2 influenza virus, A/Hong Kong/2108/03, is of purely avian origin and is closely related to some viruses circulating in poultry in the markets of Hong Kong. The continued presence of H9N2 influenza viruses in poultry markets in southern China increases the likelihood of avian-to-human interspecies transmission.
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