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About 70% of microbial agents causing outbreaks of emerging infectious diseases in humans originate directly from animals. Among respiratory virus infections, the influenza A viruses H5N1 and H7N9 from avian species, and the severe acute respiratory syndrome coronavirus from bats have caused large epidemics–. Atypical bacterial pathogens causing community-acquired pneumonia include Chlamydophila psittaci from psittacine birds and Coxiella burnetti from livestock and other animals. However, human outbreaks due to zoonotic bacteria associated with the emergence of a novel animal virus in the animal host were not previously documented.
In November 2012, an outbreak of human psittacosis affecting six staff members occurred at the New Territories North Animal Management Centre (NTNAMC) in Hong Kong. The human outbreak was preceded by an outbreak of avian chlamydiosis among the detained Mealy Parrots (Amazona farinose). Although birds in the tropical and sub-tropical areas are commonly infected with C. psittaci, most infected birds are asymptomatic,. Large human outbreaks are rare even among bird handlers. Although co-infection of C. psittaci and viruses has been reported in outbreaks of avian species–, no virus-bacterium co-infection of implicated avian species has ever been reported in outbreaks of human psittacosis. In this study, we sought to investigate viruses that cause avian co-infection, which may have led to this outbreak of psittacosis.
Waterbirds and shorebirds of the orders Anseriformes (mainly ducks, geese and swans) and Charadriiformes (mainly gulls, terns and waders) are considered the natural host reservoirs of LPAI viruses (see Fig. 1). In wild birds LPAI viruses predominantly infect epithelial cells of the intestinal tract, and are subsequently excreted in the faeces. However, infection of wild birds with LPAI viruses is typically sub-clinical and occurs in the absence of obvious lesions,,. Every year, LPAI viruses cause outbreaks amongst waterbirds. These outbreaks are most commonly associated with the increased presence of juvenile, immunologically naïve birds in the population and occur during migration when contact rates between, and within, populations are high. The relatively high virus prevalence in waterbirds may be due, in part, to virus transmission through the faecal–oral route via surface waters.
A case was defined as a staff member working at the NTNAMC who was hospitalized for respiratory tract infection between November 1 and November 30, 2012, and confirmed to have C. psittaci infection by polymerase chain reaction (PCR) and/or a four-fold rise in serum microimmunofluorescent antibody titer against C. psittaci (Focus Diagnostics, Cypress, California, USA).
Influenza A viruses (Family Orthomyxoviridae) impose a large burden on both human and animal health worldwide. Influenza A viruses can be categorised into different subtypes based on genetic and antigenic differences in the two surface glycoproteins of the virus, the haemagglutinin (HA) and neuraminidase (NA). Wild waterfowl and shorebirds are the natural reservoirs of influenza A virus and can be infected with viruses harbouring combinations of 16 different HA subtypes and nine different NA subtypes. Recently, two novel influenza A virus subtypes (H17N10 and H18N11) have been identified in rectal swabs collected from the little yellow-shouldered bat [Sturnira lilium] and the flat-faced fruit-eating bat [Artibeus jamaicensis planirostris],,. Influenza viruses of this subtype have not been isolated from any other animal order and it is unknown whether these viruses might be able to cross the species barrier. In contrast, there is significant inter-species transmission of influenza viruses from waterbirds, such that animals ranging from domestic poultry to humans can also become infected. Accordingly, infection with influenza virus has wide-reaching ramifications. For example, whilst some influenza virus strains are largely asymptomatic in chickens (and are hence referred to as low pathogenic avian influenza [LPAI] viruses) others cause severe disease in chickens that is often fatal within 48 h (and are hence referred to as highly pathogenic avian influenza [HPAI] viruses). Outbreaks of HPAI viruses can cause devastation for the poultry industry resulting in the mass slaughter of millions of birds. Similarly, outbreaks of influenza viruses amongst thoroughbred horses have disrupted numerous race meetings and resulted in the death of infected horses. In humans, seasonal influenza viruses are a significant cause of morbidity and mortality and constitute an economic burden of $10.4 billion dollars per year in the U.S.A. alone. The diversity and complexity of influenza virus infections across so many different animal species suggests that a one-health approach is the only comprehensive way to reduce the burden of disease. Here, we seek to highlight how influenza viruses spread from their natural avian hosts to mammals, and what the virus needs to overcome in order to ensure the success of these inter-species transmission events. We highlight the consequences that this inter-species transmission has, not only for human health, but also for the health of wild animals and the success of industries such as poultry farming.
Influenza A virus (IAV) has caused significant morbidity and mortality globally in humans, with an estimated 14 pandemics that have occurred since the 1500s.1 Wild aquatic birds are well known to be the natural reservoirs for IAV subtypes harbouring H1–H16 subtypes,2, 3, 4 with the exception of H17 and H18 subtypes that were recently discovered in bats.5, 6 The phylogenetic relationships of all IAV subtypes are displayed in Fig. 1. In addition to its natural reservoir species, influenza viruses infect a wide range of hosts including canids, equids, humans and swine.2 IAVs’ ability to generate novel gene constellations through reassortment between subtypes poses a risk for immune escape in these new hosts.7 Furthermore, IAV undergoes rapid genetic and antigenic evolution, which makes vaccination control difficult in humans and other domestic species.
In addition to human pandemics that have emerged from avian and swine hosts, there are also repeated spillover events from domesticated animals, primarily poultry and swine, that pose a significant threat to human health.8, 9, 10, 11, 12, 13, 14 Direct transmission of IAV from a wild avian source to humans is rare, as there has only been a single report of laboratory‐confirmed human infection with H5N1 contracted through close contact with dead and infected wild swan in Azerbaijan.15 However, there is serological evidence of H5N1 infection among Alaskan hunters who handled dead wild avian species,16 indicating that exposure to IAVs from wild birds through close contact can potentially cause infection. More notably, viral genes that are similar to the 1918‐like H1N1 avian virus were recently detected in the influenza gene pools of wild birds, raising the potential for the re‐emergence of a 1918‐like pandemic virus.17 Furthermore, due to increasing human encroachment of wildlife habitats, the potential of a wild‐source threat becomes more relevant, as is seen with the emergence of other pathogens such as human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus and the more recent Zaire‐variant Ebola virus in Western Africa.18, 19, 20, 21
In this review, we discuss the current knowledge of ecological and molecular determinants responsible for interspecies transmission of IAV, with specific focus on avian‐derived influenza subtypes involved in zoonotic and epizootic transmission to other hosts (see Fig. 2).
Avian influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. Influenza viruses are classified into groups A, B and C according to differences in the nucleocapsid and matrix protein.2 The type A viruses were divided into haemagglutinin (H) and neuraminidase (N) subtypes based on the surface glycoproteins.3,4 Up until to now, 16 H and 9 N subtypes have been reported (Fig. 1).5,6 All influenza subtypes can be found in waterfowl, but only the H 1-3 and N 1-2 subtypes were known to infect humans; in particular, the H5N1 subtype is highly pathogenic and endemic in Asian nations including Mainland China. In 1997, the H5N1 virus was first isolated from a three-year-old boy in Hong Kong,7 and new genotypes of H5N1 virus have continually emerged in Mainland China.8 H5N1 virus infection has three features. First, the area where avian influenza cases occurred did not have animal plague and the cases of H5N1 showed dissemination in Mainland China.9 Secondly, the outbreak was mainly distributed in Central, East China and South China; in South China the outbreak was more serious. Third, the virus pathogenicity was strong. The H5N1 subtypes not only caused the death of fowl, ducks, goose and turkey, but also caused human morbidity(Fig. 2).10-12
Influenza A virus infects many animals such as humans, pigs, horses, marine mammals, and birds. In avian species, most influenza virus infections cause mild localized infections of the respiratory and intestinal tract, but highly pathogenic strains such as H5N1 cause system infections in which mortality may reach 100%. In humans, influenza viruses cause a highly contagious acute respiratory disease that resulted in epidemic and pandemic disease in humans.
Three types of influenza viruses, types A, B, and C are known and they belong to a family of single-stranded negative-sense enveloped RNA viruses called Orthomyxoviridae. The viral genome is comprised of eight RNA segments (seven in Type C). Influenza A viruses can be classified into subtypes based on antigenic differences in the two surface glycoproteins, namely, hemagglutinin (HA) and neuraminidase (NA) which are required for viral attachment and cellular release. Other major viral proteins include the nucleoprotein (NP) which is the main structural protein, membrane proteins (M1 and M2), polymerase proteins (PA, PB1 and PB2), and non-structural proteins (NS1 and NS2). Currently, sixteen subtypes of HA (H1-H16) and nine NA (N1-N9) antigenic variants are known in influenza A virus mostly related with veterinary significance, with only three subtypes circulating in humans (H1N1, H1N2, and H3N2). However, in recent years, the pathogenic H5N1 subtype of avian influenza A has been reported to cross the species barrier and infect humans as documented in Hong Kong in 1997 and 2003. Since late 2003, the H5N1 avian A influenza in poultry reached epidemic proportions with reports of serious outbreaks in several Asian countries including Vietnam, Thailand, South Korea, Laos, Cambodia, Indonesia, Japan and Malaysia that resulted in massive culling of millions of poultry which had severe economic repercussions.
As a result, H5N1 avian influenza A virus represents a potential danger to human health not only in Asia but to the world. Therefore, in addition to containment procedures, sensitive detection assays for early diagnosis are vital to lower the chances of spread and reduce the risk of development into an epidemic. Current methods employed to detect H5N1 subtypes include various polymerase chain reaction (PCR) assays and antigen tests using various fluorescence and enzyme-linked immunoassays. However, these assays are reported to be low in specificity and sensitivity, and clinically, the low sensitivity of these diagnostics may limit the usefulness for reliable detection of influenza A (H5N1) virus in humans. Therefore, there is an urgent need for improved, validated, sensitive diagnostic tests for rapid and early diagnosis. In this study, we describe the development of a nucleic acid detection test that is rapid, specific and sensitive, thus allowing greatly improved detection of the H5N1 avian influenza A virus.
Influenza A virus is a common cause of respiratory disease in swine. The virus also infects other species including humans and birds. Influenza A viruses are classified into different subtypes based on the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). So far, 17 different HA and 10 different NA subtypes have been described. The predominant swine influenza virus (SIV) subtypes worldwide are H1N1, H1N2 and H3N2, all of which show considerable diversity within each subtype. Until the emergence of the pandemic influenza A (H1N1) 2009 (H1N1pdm09) virus, which possesses a “classical-swine” H1 HA gene, the European H1N1 SIV belonged exclusively to the “avian-like” lineage of SIV with all eight gene segments of avian origin or they were reassortants hereof retaining the “avian-like” H1 HA. European H3N2 SIV are human-avian reassortants retaining the HA and NA genes from human H3N2 virus, whereas the remaining gene segments originate from “avian-like” H1N1 SIV. H1N2, which is the most recently recognized new European SIV subtype, was first reported from Great Britain in 1995. This virus possessed an HA closely related to that of human A/England/80-like H1N1 viruses, an NA probably derived from a swine H3N2 virus, and internal gene segments of avian origin. Subsequent spread of related “human-like” H1N2 viruses has been reported from several European countries (Italy and France, Belgium, Germany and Spain) including reassortments containing HA from the “human-like” H1N2. “Human-like” H1N2 viruses (so-called delta clade viruses) have also been reported from North America but other H1N2 viruses that are circulating in North America and Asia contain HA genes of “classical-swine” H1N1 origin descending from the very first SIVs, which were isolated from pigs in USA in 1930 and resemble human viruses responsible for the 1918 Spanish flu pandemic. Since the emergence of the H1N1pdm09 virus in swine, several descendant reassortant viruses have been recognized, including H1N2 with all genes from the pandemic virus except the N2 and an H1N2 with HA and NA from the “human-like” swine H1N2 and the rest of the genes from H1N1pdm09 virus. H1N2 viruses with “avian-like” H1 have earlier been reported from France and Italy, but without having been established in the regional pig populations. In Denmark, the H1N2 subtype was first recognized in a lung tissue sample from a pig with coughing, fever and panting, showing indications of bronchopneumonia. This pig was submitted to the National Veterinary Institute for diagnosis of SIV in 2003. The detected virus (A/swine/Denmark/12687/2003(H1N2) had an “avian-like” H1, and this reassorted H1N2 subtype has since then continuously been detected from lung tissue and nasal swabs from Danish pigs throughout the country, and is now established in Denmark (unpublished data). Prior to 2003, only the H1N1 and H3N2 subtypes had been isolated in Denmark. The “avian-like” H1N2 has been reported previously from Sweden and Italy. The aim of the present study was to make a genetic characterization of the Danish reassorted “avian-like” H1N2 virus and to compare the cross-protection and infection dynamics of the reassorted “avian-like” H1N2 with the older endemic “avian-like” H1N1 virus.
The confirmed cases of avian influenza A (H5N1) in humans since 2003 have been listed in Table 1.13-15 From this table, it was found that the avian influenza plague had been reported in several cities of Mainland China in 2003 and 2004. However, no cases had been diagnosed in humans.16 At the same time it was also found that most cases appeared in females, which may be associated with genotype, although to determine the true reason required further research, and the frequencies of H5N1 infection among humans have not been reported. Human influenza is transmitted by way of the inhalation of infectious droplets and droplet nuclei by direct or indirect contact.17 There were three primary routes for the transmission of avian influenza, the first of which was by contact with the domestic fowl market; the second by bird migrations; and the third was by the transmission from fowl to mammals. Additionally, the infected birds, which were captured, led to poultry infection, although this type of transmission was merely a possibility. Avian influenza usually involves horizontal transmission, while the vertical transmission of the virus has not been discovered. However, the H5N2 subtype has been isolated from chicken eggs, indicating a possibility for vertical transmission.18 For human influenza A (H5N1), the main transmission routes were from birds to humans and from the environment to humans. Human-to-human transmission of influenza A (H5N1) has been suggested in several household clusters, and there was also one case of possible child-to-mother transmission. Intimate contact without the use of protective measures was implicated, and no case of human-to-human transmission by small-particle aerosols was identified.19 In 1997, human-to-human transmission apparently did not occur through social contact, and serologic studies of exposed health care workers showed that the transmission was inefficient. Recently, some researchers have suggested that the animal virus strains may be adapting to humans by accumulating nonsynonymous (amino acid-changing) substitutions in key proteins (e.g. surface glycoprotein).20 However, epidemiologic and virologic studies are needed to confirm whether avian influenza viruses have acquired the capacity for human infection by adaptive evolution. To date, the risk of nosocomial transmission to health care workers has been low.
There are sixteen recognized serological subtypes of type A influenza virus hemagglutinin (H1 through H16) and 9 type A neuraminidase subtypes (N1 through N9). Among the combinatorial diversity of 144 possible A/HN subtypes, relatively few subtypes have been identified as causes of human disease. Four pandemic outbreaks in the last century, one catastrophic, appear to have introduced the subsequently prevalent seasonal human influenza virus subtypes A/H1N1 (Spanish flu, 1918), A/H2N2 (Asian flu, 1957), A/H3N2 (Hong Kong flu, 1968), and A/H1N1 again (Swine flu, 1976; Russian flu, 1977). The current year 2009 has been marked by a late season pandemic-scale emergence of a novel A/H1N1 outbreak strain, raising immediate concerns for public health as well as for pork and poultry production industries worldwide.
As with the few common subtypes of human type A influenza viruses, there are similarly few subtypes of type A influenza viruses that are associated with most influenza infections of swine, horses or dogs. In distinct contrast, wildfowl species are natural hosts and a global reservoir for the majority of possible influenza A/HN subtypes. Many of these variant strains appear to be associated with endemic infections, often asymptomatic in avian hosts. Incidental infections of humans by avian influenza viruses have been documented for avian influenza subtypes A/H5N1, A/H7N2, A/H7N3, A/H7N7, A/H9N2, A/H10N7 and A/H11N9. Recent outbreaks of “bird flu” may foreshadow an eventual pandemic outbreak, in the emergence of strains and variants with enhanced pathogenicity, virulence and transmissibility in human hosts. Examples of such outbreaks include A/H5N1 Hong Kong, 1997; H9N2 Hong Kong, 1999; A/H7N7 Netherlands, 2003; A/H5N1 Southeast Asia, 2004. Some avian A/H5 and A/H7 strains of influenza virus are recognized as highly pathogenic (HP) in domestic poultry and concerns arise that this phenotype may carry over to infections of humans. Since 1997, human infections associated with the Eurasian-African lineage of A/H5N1 HP avian influenza virus have been associated with 467 documented cases in 15 countries with high mortality (282 deaths) [2; updated 30 December 2009].
Fortunately, infectious transmission of such avian influenza virus strains between humans continues to be limited. However, history suggests that further evolution of these or other type A influenza strains could emerge as a next pandemic strain. Similarly, variant type A influenza virus strains have emerged from time to time, imposing serious costs and burdens upon poultry and livestock production.
Because the natural history and the molecular biology of influenza viruses reflect such viral genome diversity, there is a critical need for rapid, sensitive, specific, and informative assays to detect and characterize any subtype of influenza virus. Benchmark standard methods that employ propagation of virus in cell culture or in embryonating chicken eggs, with assays using panels of specific serological reagents, or reverse transcriptase polymerase chain reaction (RT-PCR)-based assays, using panels of short oligonucleotide primers and probes, are either slow and time consuming, or expensive. As prevailing strains of avian influenza continue to evolve and diverge, diagnostic assays that are based only on specific recognition of short signature sequences or peptide biomarker loci will increasingly fail, through false-positive and/or false-negative results. This will adversely impact critical decision-making.
This report describes a re-sequencing pathogen microarray (RPM)-based assay for simultaneous detection, identification and characterization of any subtype of type A human or avian influenza virus, based on rapid, sensitive and specimen-specific determination of nucleotide sequences from viral hemagglutinin, neuraminidase, and other genes.
The influenza A virus (FluA) is a negative-sense, single-stranded RNA virus belonging to the family Orthomyxoviridae. FluA is further classified on the basis of two surface glycoproteins, hemagglutinin (H) and neuraminidase (N) [1, 2]. All subtypes of FluA comprise various combinations of the H and N glycoproteins. Sixteen H subtypes (H1-H16) and nine N subtypes (N1-N9) have been characterized in avian species, while the H17N10 subtype is found in bats [3, 4]. Most subtypes of FluA virus such as H5 and H7 subtypes are not pathogenic in poultry, but outbreaks in poultry and wild birds are correlated with the highly virulent FluA virus, which can cause severe economic losses owing to massive numbers of deaths of domestic poultry [4–6].
Human infections are generally associated with the H1, H2, and H3 subtypes, although sporadic cases or outbreaks of avian FluA subtypes H5N1, H7N2, H7N3, H7N7, H10N8, H10N7, and H9N2 have resulted from direct transmissions from domestic poultry and wild birds to humans. Most patients infected with these subtypes exhibit mild symptoms, such as conjunctivitis and acute upper respiratory tract infections associated with fever and sore throat, with or without gastrointestinal symptoms. However, the H5N1 virus exhibits a high mortality rate of over 50%, the H7N7 virus has caused one fatality, and three deaths have resulted from the H10N8 virus [3, 5, 6].
The avian influenza A (H7N9) virus has been found in poultry and birds, although no human infections have been documented, and its pathogenicity was found to be low in previous studies. Since February 2013, a novel, reassortant avian influenza A (H7N9) virus associated with human deaths has emerged in eastern China [10, 11]. Up to February 28, 2014, this novel, highly virulent H7N9 virus for humans has infected over 381 patients who presented with influenza-like illness (ILI) and severe acquired pneumonia, resulting in 118 deaths. It will be a challenge to control the H7N9 outbreak in humans before it spreads further. Currently, sporadic cases, but no evident outbreaks, of this novel virus have been documented in wild birds and poultry, and there is some limited evidence of human-to-human transmission during unprotected exposure, and there are no vaccines for humans.
Thus, early detection and isolation of suspected patients are the most effective measures to control and prevent further transmission of the virus. Here, we report a multiplex real-time RT-PCR assay allowing the simultaneous detection and discrimination of universal FluA strains and the novel H7N9 subtype in a single test tube. The results showed that the sensitivity and specificity of this assay was comparable to a protocol recommended by the World Health Organization (WHO).
The presence of all subtypes influenza A viruses in wild aquatic birds poses serious health risks to a wide range of animal species. Influenza A viruses are enveloped, single-, negative-stranded and segmented RNA viruses belonging to the Orthomyxoviridae family; they are highly infectious respiratory pathogens in their respective natural hosts. All 16 known hemagglutinin (HA) and 9 neuraminidase (NA) subtypes of influenza A viruses have been isolated from wild waterfowl and seabirds (Webster et al, 2006). Although some of these subtypes are non-pathogenic/non-virulent within their natural hosts and have been present in these animal reservoirs for many centuries, various subtypes are highly virulent within their natural host species and to other species (Webby et al, 2007). For example, the changing role of the highly pathogenic avian influenza virus (HPAIV) H5N1 subtype in both wild and domestic ducks has recently been documented as a potential public health hazard because they are zoonotic agents with the theoretical ability – after genetic adaptation – of a human-to-human transmission, i.e., the start of a human epidemic/pandemic (Hulse-Post et al, 2005).
The ecology of influenza A viruses is dynamic and complex involving multiple host species and viral genes. Commercial poultry farms, “wet markets,” (where live birds and other animals are sold), backyard poultry farms, commercial and family poultry slaughtering facilities, swine farms, human dietary habits and the global trade in exotic animals have all been implicated in the spread of influenza A viruses (Greger, 2006). The “wet markets” of Southeast Asia, where people, pigs, ducks, geese and chickens (and occasionally other animals) are in close proximity pose a particular danger to public health (Webster, 2004; Bush, 2005; Greenfeld, 2006; Lau et al, 2007).
Scientific opinion differs on the probability of future sustained human-to-human transmission, e.g., for H5N1 HPAIV, as well as on which viruses pose the greatest threat to humanity and to other species (Hilleman, 2002). The prevailing scientific view regarding a possible H5N1 epidemic is that sustained human-to-human transmission will occur at some unknown future date and that a prediction on the future virulence of H5N1 viruses to humans is very difficult to make. The H5N1 HPAIVs are possibly the greatest threat at the moment, although H1, H2, H3, H7 and H9 avian-derived viruses are also strong contenders as causes of potential epidemics in various species, including humans (Hilleman, 2002; Wan et al, 2008). This review will conclude that an avian influenza virus transmitted via pigs to humans poses a significant risk to cause a new influenza pandemic, possibly on the disturbing scale of the human influenza pandemic experienced during 1918-1920 (H1N1 “Spanish Flu”). Before investigating the role of swine in the influenza A viruses, it is necessary to consider the challenge which influenza A viruses pose to both human and animal health.
Increasing morbidity from zoonoses is a significant problem in terms of global health, and they are currently considered exotic in Europe. Zoonoses are infectious or parasitic diseases transmitted by animals to humans (Spahr et al. 2018). These infections as aetiological factors can develop in humans in several ways:
by the digestive tract, where the microorganism gets into the body via infected feed (meat) or water, which is quite often in large-scale farming. Therefore, Escherichia and Salmonella transmission to people occurs mainly through ingestion or frequent contact with infected birds. The above microorganisms can live in the external environment for a long period of time without damage to the pathogenic properties.by skin laceration; a break in the continuity of the skin promotes infection by pathogens of the staphylococci and streptococci families. In addition, the infection is intensified by the release of toxins into the host system.by the respiratory system (by inhalation of dust in which the pathogens are raised); infection occurs through direct contact of a healthy individual with contaminated excretion or through indirect contact (low hygiene at the slaughterhouse) with contaminated faeces and secretion on bird feathers (Hugh-Jones and de Vos 2002).
Humans are more susceptible to zoonoses carried by mammals than birds, and they share more diseases with them. This sharing is due to a higher degree of similarity between the intracellular environment of mammals (to which they belong), rather than birds. Many microorganisms need proper conditions and parameters to determine their host, for example, the presence of its receptor on the surface of the cells. These receptors can serve as a site for attachment and penetration into cells, which provides a pathway for the development of infection. The above situation determines the susceptibility of one animal species to a pathogen and resistance of another species. Vectors, such as insects, are also involved in the transmission of various pathogens, which may have an effect on the immune system. In the case of infecting a human with an avian zoonosis, the course of the disease is usually severe with general life-threatening symptoms. People who have been infected with an avian zoonosis require in-hospital treatment in isolation. Avian zoonoses in humans may end in death or a chronic disease requiring prolonged administration of antibiotics (Hugh-Jones and de Vos 2002).
Hence, the aim of this work is to present the aetiological factors of bird zoonoses, which are currently the most threatening to the European population. In addition, the epidemiological and economic analysis of the above infections in humans is presented. In general, zoonoses from birds can be divided by the type of the infectious agent: bacterial, viral and fungal.
Myanmar lies in the western region of mainland Southeast Asia. Agriculture is the backbone of the Myanmar economy, and poultry farming is one of the country’s major industries. In association with the recent economic development of Myanmar, the total number of raised chickens has increased over the last decade. In order to provide a stable supply of poultry products, the development of farm biosecurity measures is required, and it is important that farmers and veterinarians are aware of these measures. Infectious respiratory diseases have severe impacts on the poultry industry. Avian influenza and Newcastle disease are major threats to the poultry industry, and these diseases have been reported in Myanmar [2–4]. Other respiratory pathogens, such as mycoplasmas and infectious bronchitis virus (IBV), have not been investigated in Myanmar, although clinical signs suggesting contagious respiratory diseases have been detected, according to local veterinarians’ observations. These diseases cause considerable economic losses worldwide, and vaccines for their prevention have been developed. It is important to determine the genotypes and/or serotypes of each pathogen circulating in Myanmar to inform vaccination programs.
Avian mycoplasmosis is caused by several pathogenic mycoplasmas. Among them, Mycoplasma gallisepticum (MG) and M. synoviae (MS) are the most impactful to the poultry industry. MG infections usually cause chronic respiratory disorders and are characterized by sneezing, coughing, and snicks as well as nasal and ocular discharges [5, 6]. MS infections most frequently occur as subclinical upper respiratory tract infections and may cause air sac disease. MS results in infectious synovitis, an acute to chronic infectious disease of chickens. The co-infection by MG or MS with respiratory virus infections, such as IBV and Newcastle disease, can exacerbate the disease conditions. Both MG and MS infections cause considerable economic losses in the poultry industry by reducing weight gains and meat quality in broilers, causing severe drops in egg production in layers, and increasing embryo mortality in breeders.
Infectious bronchitis (IB) is a severe acute disease of poultry caused by IBV, which primarily infects the respiratory tracts, with respiratory disease being the most frequent sign. In addition, IBV can infect the kidneys and reproductive tracts and consequently cause kidney damage and decrease in egg production. Generally, IB is controlled by serotype-specific vaccines. The identification of field isolates is necessary for appropriate vaccinations because these vaccines exhibit little cross-reactivity among different serotypes [10, 11].
In this study, we performed molecular detection of MG, MS, and IBV in chickens from poultry farms at the outskirts of three large cities in Myanmar: Mandalay and Pyin Oo Lwin in February 2018 and Yangon in May 2018. In addition, by analyzing genetic characteristics, we detected at least three genotypes of IBV existing in Myanmar. To our knowledge, this is the first report using molecular analysis to detect MG, MS, and IBV in Myanmar.
Wild birds have been recognized as important reservoir hosts harboring and amplifying emerging zoonotic viruses such as avian influenza A viruses and West Nile virus. In the northeastern USA, the Delaware Bay area is crucial for the annual migration of shorebird and gull species that feed on the horseshoe crab eggs found in abundance thanks to the coinciding spawning season (for review see). Avian influenza virus isolation rates from shorebirds and gulls during spring migration are significantly higher in this area than in other surveillance sites,,. This observation prompted us to assess the ability to detect other, novel viruses in shorebirds during the spring migration.
Infectious bronchitis (IB), an acute, highly contagious viral upper respiratory disease of chickens, is one of the most economically significant diseases hampering the intensive poultry industry worldwide. IB affects chickens of all ages, causing respiratory, reproductive, and renal manifestations. Although control of IBV infection is primarily achieved through live attenuated vaccines, the infection is difficult to contain because immunization with different serotypes of the virus do not necessarily cross-protect against other serotypes. Within an infected poultry flock, quick and accurate detection of the presence of the virus is imperative to properly vaccinate uninfected flocks. In addition, rapid differentiation of IBV infection from other upper respiratory tract diseases (e.g., avian influenza, Newcastle disease, infectious laryngotracheitis, avian mycoplasmosis) is important so that appropriate measures can be taken in a timely manner.
IB is a disease that negatively impacts the poultry industry of developing countries. For instance, in Morocco, IB continues to be an uncontrolled problem [4–6] due to the lack of in-country diagnostic capabilities that can be performed quickly and interpreted easily by local staff in potentially underequipped or otherwise challenging environments.
The causative agent of IB, infectious bronchitis virus (IBV), is a member of the species Avian coronavirus, genus Gammacoronavirus, family Coronaviridae. IBV is an enveloped, positive-sense, single-stranded RNA virus (genome length = 27.6 kb), expressing three major structural proteins: the nucleocapsid protein (N) surrounding the viral RNA, the membrane glycoprotein (M), and the spike glycoprotein (S) located on the surface of the viral envelope. The S protein contains two post-translational subunits, S1 and S2.
Current diagnostic assays for IBV include virus isolation in embryonated eggs, tracheal organ culture, cell culture immunoassays, and molecular assays that detect viral RNA. Virus isolation has been considered to be the reference standard. However, such isolations are expensive and time consuming because several passages may be required to detect the virus. Immunoassays use IBV-specific monoclonal antibodies to detect the virus in direct or indirect fluorescent antibody and enzyme-linked immunosorbent assay (ELISA) formats. Although faster and simpler than virus isolation, immunoassays tend to lack specificity and sensitivity. None of these immunoassays detect all strains or types of IBV [11–13]. Molecular assays, such as reverse transcriptase-polymerase chain reaction (RT-PCR), for the detection of IBV are commonly used because highly specific and sensitive results can be obtained in a timely manner. Molecular assays detect viral RNA directly from a clinical sample or from virus isolated in a laboratory host system. When RT-PCR is used to amplify the spike glycoprotein (S) of IBV, the assay can be coupled with restriction fragment length polymorphism analysis or nucleic acid sequencing to identify serotypes of the virus [2, 10, 12–16]. More recently, many fluorescent probe-based real-time RT-PCR assays have been developed to detect IBV strains [2, 3, 9, 10, 15, 17]. Real-time TaqMan RT-PCR assays have been developed that amplify a fragment of the 5′ untranslated region of the IBV genome to detect turkey coronaviruses and IBV or that target the N gene for IBV detection.
Unfortunately, performing most of these assays requires highly trained staff, a sophisticated infrastructure, or considerable monetary funds, and are therefore not necessarily viable options for developing countries such as Morocco. SYBR green I-based RT-PCR assays have proven to be among the most effective tools in the rapid and differential detection of a variety of viral diseases such as avian influenza, Newcastle disease, and IB. These inexpensive and easily performed assays are important to rapidly identify the causative agent of any upper respiratory disease or changes in egg shell quality and egg production in chickens [17, 18].
However, an assay employing real-time RT-PCR with SYBR green I dye to target the N gene of IBV is lacking. Here we report the development of a real-time RT-PCR assay with SYBR green I dye for rapid detection of IBV viral RNA directly from Moroccan clinical samples. We also compared the assay with conventional RT-PCR and agarose gel electrophoresis to detect IBV PCR-amplified products.
The World Health Organization constantly monitors global influenza activity. It has noted global circulation of H1N1, H3N2, and two lineages of type B (Victoria- and Yamagata-) viruses that cause 670,000 annual deaths worldwide. In the past few years, human infections with several subtypes of avian influenza virus (AIV) (e.g., H5 and H7) occurred sporadically. Highly pathogenic avian influenza (HPAI) H5N1 and H5N6 viruses have infected 878 humans with 53% mortality since 1997. Since the first case of human infection with low pathogenic avian influenza (LPAI) H7N9 virus reported in China in 2013, the number of humans infected with this virus has dramatically increased to more than 1,567 as of April 2019. Recognizing this public concern, it is important to distinguish seasonal influenza and avian influenza viruses such as H5 and H7N9 that occur simultaneously in humans, especially in China.
Vaccination and treatment with antiviral drugs (e.g., neuraminidase inhibitors (NAIs)) are primary interventions to prevent viral infections and their spread. However, vaccine production usually takes 6–12 months to prepare for newly emerging viruses. NAIs also should be taken within the first 48 h following an infection. Thus, rapid and accurate diagnosis of viral infections is important for mitigating the spread of virus within a community, facilitating immediate treatment with NAIs, and controlling carriers of these pathogens. Methods to detect and identify influenza viruses have improved over the past decades, ranging from traditional virus culture to introduction of serological and molecular diagnostic technology (e.g., real-time RT-PCR and PCR) and more recently, rapid influenza detection tests (RIDT) [9–11]. With various influenza-specific diagnostic tools, selecting the most appropriate approach is based on a number of factors, including sensitivity, specificity, throughput, cost, and availability.
Virus isolation and serology method has traditionally been used to detect influenza virus. However, it may take several days to obtain results. RIDT is a rapid method of performing point-of-care testing (POCT) in the field. Most RIDT diagnostic kits can detect influenza nucleoprotein antigen. However, RIDT has two potential limitations: i) relatively large numbers of influenza viruses must be present for accurate detection in the collected sample, and ii) inability to distinguish between influenza subtypes. Overall, sensitivity and accuracy of RIDT are lower than those of qRT-PCR-based methods that not only can amplify small amounts of target viral RNA, but also can allow for determination of influenza A virus subtype using specifically designed primers. Despite qRT-PCR-based approaches have these advantages, they typically take at least a few hours up to 2 days to obtain results. In addition, qRT-PCR needs trained personnel and sophisticated facilities for sample processing. These disadvantages limit its function in ensuring rapid prescription and administration of antiviral agents to patients. Recently, many Clinical Laboratory Improvement Amendments (CLIA)-waived molecular tests have been approved for point-of-care use (https://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm). Although the detection time (similar to RIDT) and sensitivity (better than RIDT) of CLIA-waived molecular tests have been improved, they are mostly limited to seasonal flu detection. They are incapable of discriminating seasonal influenza of avian subtypes that can cause human infection.
Loop-mediated isothermal amplification (LAMP) assays can amplify specific nucleic acids at a consistent temperature. They have been used for rapid detection of specific genes [17–20]. In particular, LAMP method combined with reverse transcription (called RT-LAMP) is a method for simultaneously synthesizing cDNA from template RNA and amplifying DNA. Thus, RT-LAMP is useful for detecting RNA viruses. In addition, polymerase enzyme produces protons and subsequently leads to decreased pH in the presence of extensive DNA polymerase activity during LAMP reaction, thus facilitating real-time and simple detection of amplicons as observed by a change from pink to yellow color in the reaction solution. The specificity and sensitivity of RT-LAMP are potentially comparable to those of existing PCR-based diagnostics with much shorter reaction time. Recently, influenza diagnostics tools leveraging RT-LAMP technology have been reported [23–30]. However, most of these tools can only diagnose a single or a small number of human influenza viruses. Their ability to diagnose newly emerging viruses is limited. None of these methods can simultaneously differentiate infection of seasonal influenza from multiple avian influenza virus infection including recently emerging H5Nx and H7N9, although this is critical when infection by those viruses to humans simultaneously occurs.
Thus, the objective of this study was to develop a multiplex RT-LAMP diagnostic method capable of simultaneously detecting human influenza viruses (two lineages of type B, H1N1 and H3N2) currently circulating in humans and avian influenza viruses (H5N1, H5N6 and H7N9) in rapidly emerging human infections. This assay also involves a one-pot colorimetric visualization approach that allows for direct observation by the naked eye. Overall, this diagnostic assay may be useful as a rapid and highly sensitive POCT that requires no laboratory equipment for field-based applications.
The influenza virus has been in existence for centuries and has been constantly infecting both humans and animals (including birds). The avian influenza (AI) virus (also called avian flu or bird flu virus) is a subtype that causes contagious respiratory disease mainly in birds. Wild waterfowls, especially ducks, are natural reservoirs and can carry the virus without manifesting symptoms of the disease and spread the virus over great distances. Domesticated poultry are also susceptible to avian flu and can cause varying symptoms ranging from reduced egg production to rapid death. The severe form of the disease is called "highly pathogenic avian influenza" (sometimes abbreviated as HPAI) and is associated with near 100% mortality rates among domesticated birds. AI has become endemic in several parts of Asia and it is believed that this is a result of unregulated poultry rearing practices in rural areas of developing countries. This is of concern because such birds often live in close proximity to humans and this increases the chance of genetic re-assortment between avian and human influenza viruses which may produce a mutant strain that is easily transmitted between humans.
In the past, avian influenza viruses have rarely caused severe disease in humans. However, in Hong Kong during 1997, a highly pathogenic strain of avian influenza of H5N1 subtype crossed from birds to humans who were in direct contact with diseased birds during an avian influenza outbreak among poultry. The cross-infection was confirmed by molecular studies which showed that the genetic makeup of the virus in humans were identical to those found in poultry. The H5N1 virus caused severe illness and high mortality among humans: among 18 persons who were infected, 6 died. The outbreak ended after authorities slaughtered Hong Kong's entire stock of 1.5 million poultry. Since then, AI among birds has been reported all over the world and one of the factors responsible for the spread is the trans-oceanic and trans-continental migration of wild birds. Most deaths from AI have occurred in Indonesia to date and nearly all of the human cases resulted from close contact with infected birds. However, there has been a reported cluster of plausible human-to-human transmission of the H5N1 virus within an extended family in the village of Kubu Sembelang in north Sumatra, Indonesia, in May 2006.
Strains of influenza virus are classified into subtypes by their protein coat antigens, namely haemagglutin (HA) and neuramidase (NA). Of the 15 HA subtypes known, H1, H2 and H3 are known to have circulated among humans in the past century and hence, most people have gained immunity to interrupt the transmission of the virus. However, the H5N1 strain is unfamiliar to most humans and our low herd immunity to it poses a pandemic threat. There are thought to be three pre-requisites for a viral pandemic to occur: (1) the infectious strain is a new virus subtype which the population has little or no herd immunity; (2) the virus is able to replicate and cause serious illness and (3) the virus has the ability to be transmitted efficiently from human to human. The H5N1 virus satisfies the first two pre-requisites of a pandemic but has not developed the ability to be transmitted easily from human to human, yet.
Influenza A viruses (IAV) are negative-sense and single-stranded RNA, enveloped viruses, belonging to the family Ortomixoviridae. Their genome is organized in eight RNA segments, encoding up to 13 proteins. The hemagglutinin (HA) and neuraminidase (NA) are the most abundant glycoproteins in the virion. To date, 17 HA and 9 NA subtypes have been described (reviewed by) and the combination of those proteins results in diverse subtypes of IAV.
Different subtype combinations of IAV circulated in humans during the last century. The variation in circulating subtypes is usually a consequence of reassortment (antigenic shift) that occurs in animal reservoirs, resulting in a new subtype that is able to transmit to the human population (reviewed in). The circulating subtypes as of 2012 are H1N1 viruses which caused a pandemic in 2009, and H3N2 viruses. Aquatic wild birds are the natural hosts of IAV. Sixteen HA subtypes (1–16) and nine NA subtypes have been detected in different combinations in aquatic wild birds, mostly establishing short-lived subclinical enteric infections (reviewed in). Sporadically, viruses transmit from aquatic wild birds to poultry or mammals, and new genotypes of influenza virus may become established in these new “non-natural” hosts. The most important of those influenza viruses are the H5 and H7 subtypes. Some of them evolve to become genetic variants that are able to cause severe disease in poultry and mammals.
Since 1997 there have been several outbreaks of H5N1 influenza viruses transmitted to the human population directly from poultry, showing great virulence and low rates of survival. These viruses are known as High Pathogenic Avian Influenza Viruses (HPAIV). Common symptoms at early stages of the infection are fever, cough and dyspnea, and in the most severe cases, development of acute respiratory distress syndrome and respiratory failure. As of August 2012, more than 600 confirmed cases of infection by H5N1 viruses have been reported to the World Health Organization (WHO), with a lethal outcome in 59% of those documented cases. However, there is evidence that indicates that this lethality rate might be overestimated due to reduced sensitivity of the WHO confirmation criteria, no formal H5N1 confirmation by health providers in rural areas, and subclinical or mild infections. Fortunately, avian strains of IAV are not efficient at infecting humans, and direct transmission from human to human has been reported only in close family clusters, with very limited spread of the virus.
In this review we discuss the findings that researchers in the virology and immunology fields have reported to date regarding the induction and evasion of the innate immune response to HPAIV in humans, which is believed to contribute to the severe pathogenesis that these IAV cause in the human host. Also, we focus on the virulence factors of HPAIV that might contribute to the hyper-induction of cytokines or hypercytokinemia and/or evasion of the antiviral response.
The acute phase responses were included as an objective measurement of infection severity. Results from measurements of the acute phase protein C - Reactive Protein (CRP), Serum Amyloid A (SAA) and haptoglobin are shown in Figure 5. Both groups of pigs (group 1: H1N1 followed by H1N2, group 2: H1N2 followed by H1N1) showed haptoglobin and CRP responses following each of the inoculations, peaking on PID 4 and 35 (group 1) or 4 and 39 (group 2). No SAA response was seen for group 2 after the H1N2 infection, however, these pigs did show an SAA response after the subsequent H1N1 inoculation. In contrast, an SAA response was seen both at the first infection (H1N1) and the second infection (H1N2) for group 1. The difference between groups for all three acute phase proteins were not statistically significant when using an unpaired t-test with 95% confidence interval (CRP, p = 0,4; haptoglobin, p = 0,8; SAA, p = 0,5).
Since February 2013, confirmed cases of human infection by a novel avian influenza A H7N9-subtype virus have been continuously identified in China. As of November 16, 2014, a total of 457 confirmed cases had been reported, including 177 deaths. This is the first time that avian influenza A H7N9-subtype virus infection has been reported in humans. The virus has been identified as a novel reassortant influenza virus that differs genetically from the other previously identified avian influenza A H7N9-subtype viruses. It carries six internal genes originating from the avian H9N2 influenza viruses but has the hemagglutinin (HA) and neuraminidase (NA) genes from the avian H7 and N9 influenza viruses, respectively. Investigations of viral sequences revealed that this virus contains several mammalian-adaptive mutations that are known to be associated with improved invasion and replication of avian influenza viruses in mammals [2, 3]. Subsequent experimental studies demonstrated that this virus could replicate in the respiratory tracts of various animals, including non-human primates, and could be transmitted by direct contact and aerosolization in the ferret [4–6]. In addition, it was demonstrated that infected chickens could survive and shed virus for up to 14 days without any obvious clinical signs of the disease. The observed low pathogenicity of avian influenza A (H7N9) virus in poultry weakens the warning effects of symptom-based screening for infected poultry, thus facilitating the spread of this virus among poultry and increasing the risk of human exposure. Although no sustained human-to-human transmission has been determined, several cases of family clusters have been identified in some provinces of China that experienced the outbreak, suggesting that limited non-sustained human-to-human transmission may occur under some circumstances, such as long-term, unprotected close contact [7, 8]. Considering the probable lack of pre-existing immunity among humans to this newly emerged H7N9 virus, this virus poses a great threat to national and global public health.
Laboratory-designed, in-house nucleotide detection assays have been developed and used in the public health laboratories of the Chinese National Influenza-Like Illness Surveillance Network (CNISN). These assays are currently the main tools employed for the rapid identification of avian influenza A (H7N9) virus and have played a critical role in early responses to the outbreak of H7N9 avian virus infection [9–15]. However, because the possibility of sustained human-to-human transmission cannot be completely excluded and because new cases have continuously accumulated, appearing as a second epidemic wave in winter 2013 and spring 2014 in China [1, 16], careful and persistent monitoring of avian influenza A (H7N9) virus is necessary for urgent and long-term responses to threats from the virus. Thus, enhanced detection capacities with sustained quality-control measures are urgently needed to allow a better response to the current outbreak of this novel influenza virus and to improve preparedness for its re-emergence or even a potential pandemic in the future. Compared with in-house assays, commercial diagnostic kits typically provide a more sustainable alternative source of accurate detection tests, as they support larger-scale production, certified manufacturing practices, well-studied product performance and stable quality control; hence, they can be used in a broad range of clinical laboratories.
Therefore, to meet the increasing need for detection, the China Food and Drug Administration (CFDA) has approved three commercial diagnostic products for specifically detecting avian influenza A (H7N9) virus RNA, which can be used in the laboratories that are not a part of CNISN under the Emergency Use Authorization (EUA). Here, to ensure the safety and effectiveness of these commercial molecular diagnostic assays, we conducted analytical and clinical evaluations using a well-characterized quality-control panel of viral cultures and a sufficient number of clinical specimens collected throughout the major epidemic regions of China.
Intensive poultry farming leads to higher risk of infectious disease emergence causing great economical losses. Boundary spanning between clinical manifestations of different agents is peculiar to the course of many infections nowadays. More and more infectious diseases progress in association with different microorganisms and it effects significantly the clinical manifestation and differential diagnosis of the disease.
Currently, the viral infections such as avian influenza, Newcastle disease, infectious bronchitis, and infectious bursal disease, etc., are a potential threat to poultry farming in the Republic of Kazakhstan. Monitoring these economically significant avian diseases is the question of the day for poultry industry.
Avian influenza virus belongs to the Orthomyxoviridae family, Influenza A virus genus. From the beginning of year 2016 the disease outbreaks were recorded in 30 countries. Different AIV strains can cause 10 to 100% mortality among poultry.
The agent of the Newcastle disease is an RNA-containing virus, a member of the Paramyxoviridae family, Rubulavirus genus. In 2016 13 countries reported Newcastle disease cases to the OIE. In poultry industrial farms, all infected birds need to be sacrificed due to threat of dissemination of the infection across countries.
The agent of the infectious bursal disease is RNA-containing virus of Avibirnavirus genus in Birnaviridae family. In outbreaks of the infectious bursal disease practically the entire population is affected and the lethality rate can approach 90%, the reconvalescent birds become susceptible to the majority of infectious diseases of viral and bacterial etiology.
The causative agent of infectious bronchitis is an RNA-containing Coronavirus avia of Coronavirus genus in Coronaviridae family. Economical losses due to infectious bronchitis is composed of reduced egg and meat productivity, compulsory slaughter of sick birds, high death rate in young population. When the infection circulates in the farm for the first time the lethality rate can reach 70%.
Currently, standard immunological methods or methods based on polymerase chain reaction (PCR) [8, 9] are widely used to identify the above mentioned viruses. Unfortunately, they can detect only one agent in a specimen.
There are also multiplex RT-PCR assays that make possible simultaneous detection of more than one infectious agent by using multiple primer pairs. Advantage of the multiplex RT-PCR is in combination of sensitivity and quickness of PCR alongside with elimination of need to test clinical specimens for each agent separately [10, 11].
Avian viruses can cause diseases independently, in alliance with each other or in association with bacterial agents. Thereby, rapid and sensitive methods of detection are required that are able to differentiate viral infections for surveillance of newly emerging avian viruses as well as for disease control.
Application of DNA microarray technology that makes possible multivariate analysis of genetic material is a highly promising way for simultaneous detection of several agents (AIV, NDV, IBV and IBDV) in one specimen.
The paper describes the technique for rapid and simultaneous diagnosis of avian diseases such as avian influenza, Newcastle disease, infectious bronchitis and infectious bursal disease with use of oligonucleotide microarray, conditions for hybridization of fluorescent-labelled viral cDNA on the microarray and its specificity tested with use of AIV, NDV, IBV, IBDV strains as well as biomaterials from poultry.
The objective of this study is to develop an oligonucleotide microarray for rapid diagnosis of avian influenza, Newcastle disease, infectious bronchitis, and infectious bursal disease that will be used in the course of mass analysis for routine epidemiological surveillance owing to its ability to test one specimen for several infections.
The most pest-prone species of poultry are primarily hens, quail and turkeys. The condition is caused by a virus belonging to the Herpesvirus genus. The way they penetrate the organism is through the respiratory system or gastrointestinal tract. Infection usually occurs immediately after hatching. The virus contained in the exfoliated warts of the pen still retains its virulence for more than 12 months after initiation. Infected birds show weight loss and paroxysmal symptoms. However, it often occurs that the course of this disease is very violent and no clinical symptoms were observed in humans (Ryan and Ray 2004; Koelle and Corey 2008; Johnston et al. 2011; Schiffer et al. 2014).
Bats are well-known reservoirs for viruses with zoonotic potential. Spillover of virus from bats to humans is thought to have caused acute infections by the paramyxoviruses Hendra and Nipah, severe acute respiratory syndrome (SARS)-coronavirus, Australian bat lyssavirus, and the filoviruses Marburg and Ravn. Bats may have also been the ancestral source of hepatitis C, hepatitis B, mumps, and GB viruses that are endemic in humans. Influenza A virus can now be added to this growing list; two new lineages of influenza A viruses were recently detected in the little yellow‑shouldered bat (Sturnira lilium, family Phyllostomidae), in Guatemala, and the flat-faced fruit‑eating bat (Artibeus jamaicensis planirostris, family Phyllostomidae), in Peru.
Influenza A virus is a remarkably promiscuous virus. Viruses circulating in birds, pigs and people garner the most attention, given their impact on public health, yet influenza virus naturally infects a diverse array of animals. These hosts include dogs, horses, cats, non-human primates, cattle, seals, whales, guinea pigs, ferrets, mink, giant pandas, pikas, raccoon dogs, anteaters, camels, and penguins (reviewed in). The detection of influenza A virus in bats, which represent ~20% of all known mammals, dramatically expands the host range of this virus.
Influenza A virus is a member of the Orthomyxoviridae family with a segmented genome composed of eight single-stranded negative-sense RNAs. The viral genome exploits splicing, frame-shifting and leaky scanning to code for at least 14 different proteins. Influenza viruses are classified into subtypes based on their two major surface proteins, hemagglutinin (HA) and neuraminidase (NA). Prior to the identification of influenza virus in bats, 16 HAs and nine NAs had been identified, circulating primarily in avian reservoirs. Of these, only H1N1, H2N2, and H3N2 are known to have caused pandemics in humans.
The viruses in bats, H17N10 in the little yellow-shouldered bat and H18N11 in the flat-faced fruit-eating bat, are completely new subtypes that are evolutionarily distinct from all other circulating strains. Three H17N10 genomes (A/little yellow-shouldered bat/Guatemala/164/2009, A/little yellow-shouldered bat/Guatemala/153/2009, A/little yellow-shouldered bat/Guatemala/060/2010), and one H18N11 genome (A/flat-faced bat/Peru/033/2010) were reconstructed by RT-PCR. Each of the bat genomes maintains the same genomic architecture and coding potential of other influenza A viruses. H17N10 was initially detected in rectal swabs, and subsequently in liver, kidney, intestine, and lung tissue. H18N11 RNA was also first detected in a rectal swab, and then exclusively in intestinal tissue. Infectious isolates were not recovered from these animals, but the abundance of genomic RNA in the intestine suggests that tissue tropism in bats is more akin to birds, in which influenza virus replicates in the intestinal tract, than to most mammals, in which infections occur primarily in the respiratory tract. Reports from 1979–1982 also claimed isolation of influenza A virus from bats (A/bat/Alma-Ata/73/1976), as well as the detection of antibodies against influenza virus in bats. However, this earlier bat virus showed immuno-reactivity to sera raised against human H3N2 viruses, and the bat sera recognized human H2N2 and H3N2 viruses, indicating that if these were bona fide influenza virus infections in bats, they were distinct from the newly described viruses from South American bats.
H17N10 and H18N11 viruses were identified in bats of different species located over 3000 km apart and over multiple years. The two subtypes are more closely related to each other than to any other influenza A virus, yet they display a high degree of divergence. This suggests that replication and diversification of these viruses occurred over a significant period of time. The seroprevalence was high in South American bat populations (up to 50%), indicating that infections can be common. Although, surveillance in Central European bats failed to detect any influenza virus in over 1300 animals, suggesting that not all bat populations are infected. Thus, bats might represent a vast migratory reservoir of novel influenza viruses. A major concern with the discovery of these viruses, and many other unique influenza strains, is their potential to cause disease in humans. Even though infectious isolates or recombinant versions of H17N10 and H18N11 have not yet been reported, significant progress has been made in understanding the biology and replicative capacity of these viruses.
Recently in China, an outbreak of influenza occurred that was caused by a novel influenza A (H7N9) viral infection of avian origin. According to published reports, patients with H7N9 virus infection present with rapid, progressive pneumonia commonly leading to the development of acute respiratory distress syndrome (ARDS), respiratory failure and even multiorgan dysfunction syndrome. More importantly, patients with H7N9 virus–mediated influenza have a high mortality rate. Previous studies have revealed the clinical characteristics, epidemiology and virology, laboratory diagnosis, and treatment of patients with H7N9 virus infection. However, little is known about the impact of H7N9 virus infection on the immune system.
In this paper, we describe the cytokine profiles and functional phenotypes of immunocompetent cells in 27 patients with H7N9 virus–mediated influenza and 30 healthy controls (HCs). We determined the functional phenotypes of immunocompetent cells and serum cytokine profiles of the participants. We describe the cytokine profiles and functional phenotypes of immunocompetent cells in 27 patients.