Avian influenza virus

Avian influenza viruses do not typically replicate efficiently in humans, indicating direct transmission of avian influenza virus to humans is unlikely. However, since 1997, several cases of human infections with different subtypes (H5N1, H7N7, and H9N2) of avian influenza viruses have been identified and raised the pandemic potential of avian influenza virus in humans. Although circumstantial evidence of human to human transmission exists, the novel avian-origin influenza viruses isolated from humans lack the ability to transmit efficiently from person-to-person. However, the on-going human infection with avian-origin H5N1 viruses increases the likelihood of the generation of human-adapted avian influenza virus with pandemic potential. Thus, a better understanding of the biological and genetic basis of host restriction of influenza viruses is a critical factor in determining whether the introduction of a novel influenza virus into the human population will result in a pandemic. In this article, we review current knowledge of type A influenza virus in which all avian influenza viruses are categorized.     

(Highly pathogenic) avian influenza as a zoonotic agent

Zoonotic agents challenging the world every year afresh are influenza A viruses. In the past, human pandemics caused by influenza A viruses had been occurring periodically. Wild aquatic birds are carriers of the full variety of influenza virus A subtypes, and thus, most probably constitute the natural reservoir of all influenza A viruses. Whereas avian influenza viruses in their natural avian reservoir are generally of low pathogenicity (LPAIV), some have gained virulence by mutation after transmission and adaptation to susceptible gallinaceous poultry. Those so-called highly pathogenic avian influenza viruses (HPAIV) then cause mass die-offs in susceptible birds and lead to tremendous economical losses when poultry is affected. Besides a number of avian influenza virus subtypes that have sporadically infected mammals, the HPAIV H5N1 Asia shows strong zoonotic characteristics and it was transmitted from birds to different mammalian species including humans. Theoretically, pandemic viruses might derive directly from avian influenza viruses or arise after genetic reassortment between viruses of avian and mammalian origin. So far, HPAIV H5N1 already meets two conditions for a pandemic virus: as a new subtype it has been hitherto unseen in the human population and it has infected at least 438 people, and caused severe illness and high lethality in 262 humans to date (August 2009). The acquisition of efficient human-to-human transmission would complete the emergence of a new pandemic virus. Therefore, fighting H5N1 at its source is the prerequisite to reduce pandemic risks posed by this virus. Other influenza viruses regarded as pandemic candidates derive from subtypes H2, H7, and H9 all of which have infected humans in the past. Here, we will give a comprehensive overview on avian influenza viruses in concern to their zoonotic potential.     

Novel human H7N9 influenza virus in China

Outbreaks of H7N9 avian influenza in humans in 5 provinces and 2 municipalities of China have reawakened concern that avian influenza viruses may again cross species barriers to infect the human population and thereby initiate a new influenza pandemic. Evolutionary analysis shows that human H7N9 influenza viruses originated from the H9N2, H7N3 and H11N9 avian viruses, and that it is as a novel reassortment influenza virus. This article reviews current knowledge on 11 subtypes of influenza A virus from human which can cause human infections.     

Influenza pandemic planning

In this article the most important properties of influenza A viruses are described to understand influenza pandemics. There are at least three possibilities: (1) By reassortment between an avian and the prevailing human influenza A virus viruses with a new surface are created, against which no neutralizing antibodies are present in the human population. Such a virus can spread immediately worldwide. (2) Viruses, which have been present in the human population some time ago, reappear and infect the new generation, which has not been in contact with this virus before. (3) An avian influenza virus crosses the species barrier to humans and forms there a new stable lineage. In relation to pandemic planning, the first possibility can be more or less excluded, since the now-a-days human influenza A viruses have evolved so far away from their original source, the avian influenza viruses, that the formation of a well-growing and well-spreading reassortant is practically not possible anymore. Point two is a dangerous possibility, in that, e.g., a human H2N2 virus could reappear, which had disappeared in 1968 from the human population. The third possibility is at the moment the most dangerous situation, if, e.g., a highly neurotropic H5N1 virus from Southeast Asia crosses the species barrier to humans. An infection with such a pandemic virus presumably cannot be treated efficiently by antivirals. In such a situation only a rapid vaccination would be successful. In this respect in the last year important results have been obtained by using the reverse genetics. Meanwhile in about 50 countries there have been drawn up pandemic-preparedness plans.     

Avian and swine influenza viruses: our current understanding of the zoonotic risk

The introduction of swine or avian influenza (AI) viruses in the human population can set the stage for a pandemic, and many fear that the Asian H5N1 AI virus will become the next pandemic virus. This article first compares the pathogenesis of avian, swine and human influenza viruses in their natural hosts. The major aim was to evaluate the zoonotic potential of swine and avian viruses, and the possible role of pigs in the transmission of AI viruses to humans. Cross-species transfers of swine and avian influenza to humans have been documented on several occasions, but all these viruses lacked the critical capacity to spread from human-to-human. The extreme virulence of H5N1 in humans has been associated with excessive virus replication in the lungs and a prolonged overproduction of cytokines by the host, but there remain many questions about the exact viral cell and tissue tropism. Though pigs are susceptible to several AI subtypes, including H5N1, there is clearly a serious barrier to infection of pigs with such viruses. AI viruses frequently undergo reassortment in pigs, but there is no proof for a role of pigs in the generation of the 1957 or 1968 pandemic reassortants, or in the transmission of H5N1 or other wholly avian viruses to humans. The major conclusion is that cross-species transmission of influenza viruses per se is insufficient to start a human influenza pandemic and that animal influenza viruses must undergo dramatic but largely unknown genetic changes to become established in the human population.     

Human‐infecting influenza A (H9N2) virus: A forgotten potential pandemic strain?

Continuously emergence of human infection with avian influenza A virus poses persistent threat to human health, as illustrated in H5N1, H7N9 and recent surge of H9N2 infections. Long‐term prevalence of H9N2 avian influenza A virus in China and adjacent regions favours the interspecies transmissions from avian to human. Establishment of multiple genotypes of H9N2 variants in this region contributes to the emergence of novel H7N9 and H10N8 viruses which caused human fatalities. Recent increasing human infection with H9N2 virus in China highlights the necessity to closely monitor the interspecies transmission events. Available human H9N2 sequences revealed that Y280/G9 lineage was responsible for the most of human cases. Presence of adaptive mutations beyond the human‐like receptor binding was indicative of the capacity of readily infecting new hosts without prior adaptation. Moreover, enlarged host range of H9N2 virus in this region substantially increased the transmission among mammals. Meanwhile, serological surveys implied human was more susceptible to H9N2 infection, compared with panzootic H5 and H7 subtype avian influenza virus. Thus, control at the source will be the ultimate and effective option for H9N2 pandemic preparedness. This review comprehensively summarized recent updates on H9N2 human infections, aiming to shed light on the prevention strategies against this strain with pandemic potential.     

Public health risk from avian influenza viruses

Since 1997, avian influenza (AI) virus infections in poultry have taken on new significance, with increasing numbers of cases involving bird-to-human transmission and the resulting production of clinically severe and fatal human infections. Such human infections have been sporadic and are caused by H7N7 and H5N1 high-pathogenicity (HP) and H9N2 low-pathogenicity (LP) AI viruses in Europe and Asia. These infections have raised the level of concern by human health agencies for the potential reassortment of influenza virus genes and generation of the next human pandemic influenza A virus. The presence of endemic infections by H5N1 HPAI viruses in poultry in several Asian countries indicates that these viruses will continue to contaminate the environment and be an exposure risk with human transmission and infection. Furthermore, the reports of mammalian infections with H5N1 AI viruses and, in particular, mammal-to-mammal transmission in humans and tigers are unprecedented. However, the subsequent risk for generating a pandemic human strain is unknown. More international funding from both human and animal health agencies for diagnosis or detection and control of AI in Asia is needed. Additional funding for research is needed to understand why and how these AI viruses infect humans and what pandemic risks they pose.     

禽流感感染人的分子机制研究进展

禽流感病毒可以感染多种动物,包括人、猪、鸟、马、海豹、鲸和雪貂等。流感病毒在不同的宿主存在一定的屏障,但禽流感毒株能突破宿主屏障直接感染人,造成死亡。因此流感病毒的变异和病毒如何选择物种跨越物种流行的机制,对预防和控制流感的爆发是非常重要的。本文综述病毒毒力的分子生物学基础、禽流感染人的分子机制研究进展及在控制禽流感方面的研究。     

H9N2亚型禽流感病毒的研究现状

H9N2亚型禽流感病毒已在世界范围内的禽类中分离确认,并被证实可以传播到人类和低等哺乳类动物。对于它存在的潜在危害已经越来越多地受到关注,相关的研究也相继开展。许多遗传进化的分析为禽或猪流感可以直接感染人提供了证据,通过在人体的适应或与人流感病毒基因重组,可以形成新的病毒株,引起人类流感疫情暴发。文章提示应当密切监控H9N2亚型禽流感病毒,防止人类流感大流行。     

H10亚型禽流感病毒全球谱系分析

本文借助于GenBank中的Influenza Virus Resource和已发表的相关文献报道,对H10亚型禽流感病毒在全球和中国的流行谱系、流行情况和致病性进行了分析。全球H10亚型主要存在北美和欧亚2个谱系。H10病毒的HA受体结合位点分析表明,其倾向于结合α-2,3-唾液酸受体,属于典型的禽流感病毒特征。对H10病毒的HA裂解位点分析表明,大部分H10病毒具有低致病特性。综合分析认为,目前H10N8出现大规模流行的可能性不大,但仍需要提高警惕、加强监测。     

Phylogenetic evolution of swine-origin human influenza virus: a pandemic H1N1 2009

The knowledge of the genome constellation in pandemic influenza A virus H1N1 2009 from different countries and different hosts is valuable for monitoring and understanding of the evolution and migration of these strains. The complete genome sequences of selected worldwide distributed influenza A viruses are publicly available and there have been few longitudinal genome studies of human, avian and swine influenza A viruses. All possible to download SIV sequences of influenza A viruses available at GISAID Platform (Global Initiative on Sharing Avian Influenza Data) were analyzed firstly through the web servers of the Influenza Virus Resource in NCBI. Phylogenetic study of circulating human pandemic H1N1 virus indicated that the new variant possesses a distinctive evolutionary trait. There is no one way the pandemic H1N1 have acquired new genes from other distinguishable viruses circulating recently in local human, pig or domestic poultry populations from various geographic regions. The extensive genetic diversity among whole segments present in pandemic H1N1 genome suggests that multiple introduction of virus have taken place during the period 1999-2009. The initial interspecies transmission could have occurred in the long-range past and after it the reassortants steps lead to three lineages: classical SIV prevalent in the North America, avian-like SIV in Europe and avian-like related SIV in Asia. This analysis contributes to the evidence that pigs are not the only hosts playing the role of "mixing vessel", as it was suggested for many years.     

Serological Evidence of Pandemic H1N1 Influenza Virus Infections in Greek Swine

The introduction of the 2009 pandemic H1N1 (pH1N1) influenza virus in pigs changed the epidemiology of influenza A viruses (IAVs) in swine in Europe and the rest of the world. Previously, three IAV subtypes were found in the European pig population: an avian‐like H1N1 and two reassortant H1N2 and H3N2 viruses with human‐origin haemagglutinin (HA) and neuraminidase proteins and internal genes of avian decent. These viruses pose antigenically distinct HAs, which allow the retrospective diagnosis of infection in serological investigations. However, cross‐reactions between the HA of pH1N1 and the HAs of the other circulating H1 IAVs complicate serological diagnosis. The prevalence of IAVs in Greek swine has been poorly investigated. In this study, we examined and compared haemagglutination inhibition (HI) antibody titres against previously established IAVs and pH1N1 in 908 swine sera from 88 herds, collected before and after the 2009 pandemic. While we confirmed the historic presence of the three IAVs established in European swine, we also found that 4% of the pig sera examined after 2009 had HI antibodies only against the pH1N1 virus. Our results indicate that pH1N1 is circulating in Greek pigs and stress out the importance of a vigorous virological surveillance programme.     

Studies on influenza viruses H10N4 and H10N7 of avian origin in mink

An influenza A virus, A/mink/Sweden/84 (H10N4), was isolated from farmed mink during an outbreak of respiratory disease, histopathologically characterised by severe interstitial pneumonia. The virus was shown to be of recent avian origin and closely related to concomitantly circulating avian influenza virus. Serological investigations were used to link the isolated virus to the herds involved in the disease outbreak. Experimental infection of adult mink with the virus isolate from the disease outbreak reproduced the disease signs and pathological lesions observed in the field cases. The mink influenza virus also induced an antibody response and spread between mink by contact. The same pathogenesis in mink was observed for two avian influenza viruses of the H10N4 subtype, circulating in the avian population. When mink were infected with the prototype avian H10 influenza virus, A/chicken/Germany/N/49, H10N7, the animals responded with antibody production and mild pulmonary lesions but neither disease signs nor contact infections were observed. Detailed studies, including demonstration of viral antigen in situ by immunohistochemistry, of the sequential development of pathological lesions in the mink airways after aerosol exposure to H10N4 or H10N7 revealed that the infections progress very similarly during the first 24h, but are distinctly different at later stages. The conclusion drawn is that A/mink/Sweden/84, but not A/chicken/Germany/N/49, produces a multiple-cycle replication in mink airways. Since the viral distribution and pathological lesions are very similar during the initial stages of infection we suggest that the two viruses differ in their abilities to replicate and spread within the mink tissues, but that their capacities for viral adherence and entry into mink epithelial cells are comparable.     

Genetic analysis of human and swine influenza A viruses isolated in Northern Italy during 2010–2015

Influenza A virus (IAV) infection in swine plays an important role in the ecology of influenza viruses. The emergence of new IAVs comes through different mechanisms, with the genetic reassortment of genes between influenza viruses, also originating from different species, being common. We performed a genetic analysis on 179 IAV isolates from humans (n. 75) and pigs (n. 104) collected in Northern Italy between 2010 and 2015, to monitor the genetic exchange between human and swine IAVs. No cases of human infection with swine strains were noticed, but direct infections of swine with H1N1pdm09 strains were detected. Moreover, we pointed out a continuous circulation of H1N1pdm09 strains in swine populations evidenced by the introduction of internal genes of this subtype. These events contribute to generating new viral variants—possibly endowed with pandemic potential—and emphasize the importance of continuous surveillance at both animal and human level.     

Classic fowl plague--a review

Highly pathogenic avian influenza (HPAI) represents a severe form of generalized avian influenza which is characterized by a rapid and severe course of disease and a very high mortality. All poultry species are susceptible. Turkeys and chickens are most vulnerable. There are no pathognomonic symptoms or specific pathological alterations. The disease is caused by avian influenza virus strains of the subtypes H5 or H7. These viruses arise spontaneously from apathogenic progenitors by insertional mutation in the HA gene. Until recently, outbreaks of HPAI were rare events, however, they have been found to cause increasing losses over the past few years. Since 2003, a widespread occurrence of HPAI has been registered in southeast Asia, and some countries are endemically infected with HPAIV strain H5N1. In six countries this virus has also caused fatal human infections. This has sparked fears that this agent may be the progenitor of a new pandemic influenza virus. During summer 2005 the disease has slowly spread westward. Isolated outbreaks have been reported from Kazakhstan, Russia, Romania, Turkey, Croatia and Ukraine. Migratory birds have been tentatively accused for spreading the infection along their flyways.     

Recent developments in avian influenza research: epidemiology and immunoprophylaxis

Influenza A viruses have been isolated from humans, from several other mammalian species and a wide variety of avian species, among which, wild aquatic birds represent the natural hosts of influenza viruses. The majority of the possible combinations of the 15 haemagglutinin (HA) and nine neuraminidase (NA) subtypes recognized have been identified in isolates from domestic and wild birds. Infection of birds can cause a wide range of clinical signs, which may vary according to the host, the virus strain, the host's immune status, the presence of any secondary exacerbating microorganisms and environmental factors. Most infections are inapparent, especially in waterfowl and other wild birds. In contrast, infections caused by viruses of H5 and H7 subtypes can be responsible for devastating epidemics in poultry. Despite the warnings to the poultry industry about these viruses, in 1997 an avian H5N1 influenza virus was directly transmitted from birds to humans in Hong Kong and resulted in 18 confirmed infections, thus strengthening the pandemic threat posed by avian influenza (AI). Indeed, reassortant viruses, harbouring a combination of avian and human viral genomes, have been responsible for major pandemics of human influenza. These considerations warrant the need to continue and broaden efforts in the surveillance of AI. Control programmes have varied from no intervention, as in the case of the occurrence of low pathogenic (LP) AI (LPAI) viruses, to extreme, expensive total quarantine-slaughter programmes carried out to eradicate highly pathogenic (HP) AI (HPAI) viruses. The adoption of a vaccination policy, targeted either to control or to prevent infection in poultry, is generally banned or discouraged. Nevertheless, the need to boost eradication efforts in order to limit further spread of infection and avoid heavy economic losses, and advances in modern vaccine technologies, have prompted a re-evaluation of the potential use of vaccination in poultry as an additional tool in comprehensive disease control strategies. This review presents a synthesis of the most recent research on AI that has contributed to a better understanding of the ecology of the virus and to the development of safe and efficacious vaccines for poultry.     

Interspecies transmission of influenza viruses: H5N1 virus and a Hong Kong SAR perspective

This account takes stock of events and involvements, particularly on the avian side of the influenza H5N1 'bird flu' incident in Hong Kong SAR in 1997. It highlights the role of the chicken in the many live poultry markets as the source of the virus for humans. The slaughter of chicken and other poultry across the SAR seemingly averted an influenza pandemic. This perspective from Hong Kong SAR marks the coming-of-age of acceptance of the role of avian hosts as a source of pandemic human influenza viruses and offers the prospect of providing a good baseline for influenza pandemic preparedness in the future. Improved surveillance is the key. This is illustrated through the H9N2 virus which appears to have provided the 'replicating' genes for the H5N1 virus and which has since been isolated in the SAR from poultry, pigs and humans highlighting its propensity for interspecies transmission.     

"Constanze": a trinational project on avian influenza in wild birds at Lake Constance

When highly pathogenic avian influenza H5N1 (HPAI H5N1) arrived at Lake Constance in February 2006, little was known about its ecology and epidemiology in wild birds. In order to prevent virus transmission from wild birds to poultry, the adjacent countries initiated the tri-national, interdisciplinary research program ?Constanze? to investigate avian influenza infections in water birds at Lake Constance. In collaboration with government agencies scientists examined the prevalence of AI virus in the region of Lake Constance for a period of 33 months, compared the effectiveness of different surveillance methods and analysed the migration behaviour of water birds. Although virus introduction from regions as far as the Ural Mountains seemed possible based on the migration behaviour of certain species, no influenza A viruses of the highly pathogenic subtype H5N1 (HPAIV) was found. However, influenza A viruses of different low pathogenic subtypes were isolated in 2.2 % of the sampled birds (swabs). Of the different surveillance methods utilised in the program the sampling of so called sentinel birds was particularly efficient.     

Avian influenza: eradication from commercial poultry is still not in sight

Avian influenza viruses are highly infectious micro-organisms that primarily affect birds. Nevertheless, they have also been isolated from a number of mammals, including humans. Avian influenza virus can cause large economic losses to the poultry industry because of its high mortality. Although there are pathogenic variants with a low virulence and which generally cause only mild, if any, clinical symptoms, the subtypes H5 and H7 can mutate from a low to a highly virulent (pathogenic) virus and should be taken into consideration in eradication strategies. The primary source of infection for commercial poultry is direct and indirect contact with wild birds, with waterfowl forming a natural reservoir of the virus. Live-poultry markets, exotic birds, and ostriches also play a significant role in the epidemiology of avian influenza. The secondary transmission (i.e., between poultry farms) of avian influenza virus is attributed primarily to fomites and people. Airborne transmission is also important, and the virus can be spread by aerosol in humans. Diagnostic tests detect viral proteins and genes. Virus-specific antibodies can be traced by serological tests, with virus isolation and identification being complementary procedures. The number of outbreaks of avian influenza seems to be increasing - over the last 5 years outbreaks have been reported in Italy, Hong Kong, Chile, the Netherlands, South Korea, Vietnam, Japan, Thailand, Cambodia, Indonesia, Laos, China, Pakistan, United States of America, Canada, South Africa, and Malaysia. Moreover, a growing number of human cases of avian influenza, in some cases fatal, have paralleled the outbreaks in commercial poultry. There is great concern about the possibility that a new virus subtype with pandemic potential could emerge from these outbreaks. From the perspective of human health, it is essential to eradicate the virus from poultry; however, the large number of small-holdings with poultry, the lack of control experience and resources, and the international scale of transmission and infection make rapid control and long-term prevention of recurrence extremely difficult. In the Western world, the renewed interest in free-range housing carries a threat for future outbreaks. The growing ethical objections to the largescale culling of birds require a different approach to the eradication of avian influenza.