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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.
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.
During the last two decades, scientists have grown increasingly aware that viruses are emerging from the human–animal interface. In order to combat this increasingly complex problem, the One Health approach or initiative has been proposed as a way of working across disciplines to incorporate human, animal, and environmental health. Of particular concern are emerging respiratory virus infections; in a recent seminar given by the National Institute of Health on emerging and re-emerging pathogens, nearly 18% were respiratory viruses (1). Among the recently emerged respiratory pathogens contributing to the high burden of respiratory tract infection-related morbidity and mortality, displayed graphically in Figure 1, are influenza viruses, coronaviruses, enteroviruses (EVs), and adenoviruses (Ads). In this report, we summarize the emerging threat characteristics of these four groups of viruses.
Influenza viruses are known to constantly evolve and cross species barriers. The genetic diversity of influenza viruses is ever increasing with more novel influenza subtypes being discovered periodically. The purpose of this review is to provide an up-to-date overview of ecology and evolution of influenza viruses including the novel influenza viruses in bats and cattle. In addition, we discussed the growing complexity of influenza virus–host interactions and highlighted the key research questions that need to be answered for a better understanding of the emergence of pandemic influenza viruses.
Since the identification of the first coronavirus – infectious bronchitis virus (IBV) isolated from birds – many coronaviruses have been discovered from such animals as bats, camels, cats, dogs, pigs, and whales. They may cause respiratory, enteric, hepatic, or neurologic diseases with different levels of severity in a variety of hosts, including humans. Coronaviruses have positive-sense single-stranded RNAs, their genomic size are 26 to 32 kilobases, the largest for an RNA virus. And the viruses themselves appear crown-shaped under electron microscopy. Coronaviruses belong to the subfamily Coronavirinae in the family Coronaviridae in the order Nidovirales. Coronavirinae is further divided into four genera, Alpha-, Beta-, Gamma-, and Deltacoronavirus, based on their phylogenetic relationships and genomic structures.
Coronaviruses occasionally jump across host barriers, often with lethal consequences. The alpha- and betacoronaviruses only infect mammals and usually cause respiratory illness in humans and gastroenteritis in animals. Gamma- and deltacoronaviruses mainly infect birds, and no human infection has been reported. Six coronaviruses known to infect humans are 229E, NL63 (genus Alpha-), OC43, HKU1, SARS-CoV, and MERS-CoV (Beta-), whereas only SARS- and MERS-CoV have caused large worldwide outbreaks with fatality, others usually cause mild upper-respiratory tract illnesses. A novel coronavirus was identified in a pneumonia patient in Wuhan on January 9 of this year represents the seventh human-infecting coronaviruses.
Severe acute respiratory syndrome (SARS, induced by SARS-CoV) first emerged in Guangdong province, China in 2002 and quickly spread around the world, with more than 8000 people infected and nearly 800 died. The MERS-CoV is a new member of Betacoronavirus and caused the first confirmed case of Middle East Respiratory Syndrome (MERS) in Saudi Arabia in 2012. Over 2000 MERS-related infections have been reported as of 2019 with a ∼34% fatality rate (https://www.who.int/).
Influenza is among the major infectious disease problems affecting animal and human health globally. Several human influenza pandemics have been recorded since 1590 AD, with the most significant of those being the “Spanish flu” of 1918, often referred to as the “mother of all pandemics”. Spanish flu pandemic is believed to have affected approximately 25–30 percent of the world’s population and caused more than 50–60 million human deaths globally. Influenza infections in humans occur either as epidemic (seasonal or interpandemic) influenza caused by influenza A and B viruses, or as sporadic pandemic influenza caused by influenza A viruses. Study of influenza pandemics has been of great interest to epidemiologists. Influenza epidemics and pandemics have been repeatedly occurring for centuries, but to date the ability to predict a pandemic has not been achieved.
The majority of emerging infectious diseases that affect humans originate from animal reservoirs, predominantly wild life, including bats, rodents and birds. Norovirus is one of five genera of the family Caliciviridae and the most common non-bacterial cause of foodborne gastroenteritis worldwide. Noroviruses are currently categorized into at least seven genogroups (GI–GVII) that are further divided into more than 40 genotypes. The virus contains three open reading frames (ORFs), ORF1 encoding the polyprotein that includes the viral polymerase, and ORF2 and ORF3 encoding the major- and minor capsid protein (VP1, VP2), respectively. Recombination between ORF1 and ORF2 frequently occurs and therefore a dual nomenclature describing both the polymerase and capsid genotype is used. Viruses from genogroups GI, GII and GIV are known to infect humans. Animal noroviruses including viruses found in pigs, dogs, and cats are closely related to human strains and cluster within GII (porcine norovirus) and GIV (feline and canine norovirus), respectively. Noroviruses belonging to the other genogroups infect a broad range of hosts that includes livestock animals such as cows and sheep but also marine mammals and rodents. In the past years, an increasing number of metagenomic studies have led to the discovery of additional noroviruses in new animal hosts and it seems evident that we lack understanding of the full diversity of noroviruses and their host range. Most human infections and outbreaks are caused by viruses belonging to GI and GII. The GII.4 genotype viruses have been particularly prevalent in the past two decades, and evolve through accumulation of mutations but also by recombination. Such recombinants and other new genotypes emerge regularly but the origin of these new viruses is not well understood. This regular detection of novel strains and the reporting of human-like norovirus genotypes in stool samples of symptomatic and asymptomatic farm animals have sparked interest in the possible role of animals as potential zoonotic reservoir for these emerging strains. Antibodies directed against bovine and canine norovirus have been detected in humans suggesting some level of exposure of humans to animal norovirus. For other viruses of the Caliciviridae family, interspecies transmission has been reported including some case reports of zoonotic events between marine mammals and humans (reviewed in).
This systematic review summarizes the literature on the known animal reservoir for norovirus, the virus diversity, prevalence, and geographic distribution, as well as pathological findings associated with norovirus infections in animals. We will further discuss the existing evidence and probability of interspecies transmission including susceptibility of animals used as models in norovirus research. There are several reviews that focus exclusively on the role of mice in norovirus research; therefore, we will discuss murine norovirus only in context of surveillance of wild animals. Molluscs are an important vehicle of foodborne norovirus transmission, but do not support norovirus replication and have been reviewed elsewhere.
The Paramyxoviridae family within the order of Mononegavirales includes a large number of human and animal viruses that are responsible for a wide spectrum of diseases. Measles virus (MV) is one of the most infectious human viruses known, and has been targeted by the World Health Organization for eradication through the use of vaccines. The paramyxovirus family includes several other viruses with high prevalence and public health impact in humans, like respiratory syncytial virus (RSV), human metapneumovirus (HMPV), mumps virus (MuV), and the parainfluenza viruses (PIV). In addition, newly emerging members of the Paramyxoviridae family – hendra and nipah virus – have caused fatal infections in humans upon zoonoses from animal reservoirs,,. In animals, Newcastle disease virus (NDV) is and Rinderpest virus (RPV) was among the viruses with the most devastating impact on animal husbandry. Members of the Paramyxoviridae family switch hosts at a higher rate than most other virus families and infect a wide range of host species, including humans, non-human primates, horses, dogs, sheep, pigs, cats, mice, rats, dolphins, porpoises, fish, seals, whales, birds, bats, and cattle. Thus, the impact of paramyxoviruses to general human and animal welfare is immense.
The Paramyxoviridae family consists of two subfamilies, the Paramyxovirinae and the Pneumovirinae. The subfamily Paramyxovirinae includes five genera: Rubulavirus, Avulavirus, Respirovirus, Henipavirus and Morbillivirus. The subfamily Pneumovirinae includes two genera: Pneumovirus and Metapneumovirus
. Classification of the Paramyxoviridae family is based on differences in the organization of the virus genome, the sequence relationship of the encoded proteins, the biological activity of the proteins, and morphological characteristics,. Virions from this family are enveloped, pleomorphic, and have a single-stranded, non-segmented, negative-sense RNA genome. Complete genomic RNA sequences for known members of the family range from 13–19 kilobases in length. The RNA consists of six to ten tandemly linked genes, of which three form the minimal polymerase complex; nucleoprotein (N or NP), phosphoprotein (P) and large polymerase protein (L). Paramyxoviruses further uniformly encode the matrix (M) and fusion (F) proteins, and – depending on virus genus – encode additional surface glycoproteins such as the attachment protein (G), hemagglutinin or hemagglutinin-neuraminidase (H, HN), short-hydrophic protein (SH) and regulatory proteins such as non-structural proteins 1 and 2 (NS1, NS2), matrix protein 2 (M2.1, M2.2), and C and V proteins,.
Routine diagnosis of paramyxovirus infections in humans and animals is generally performed by virus isolation in cell culture, molecular diagnostic tests such as reverse transcriptase polymerase chain reaction (RT-PCR) assays, and serological tests. Such tests are generally designed to be highly sensitive and specific for particular paramyxovirus species. However, to detect zoonotic, unknown, and newly emerging pathogens within the Paramyxoviridae family, these tests may be less suitable. Development of virus family-wide PCR assays has greatly facilitated the detection of previously unknown and emerging viruses. Examples of such PCR assays are available for the flaviviruses, coronaviruses, and adenoviruses. For the Paramyxoviridae, Tong et al. described semi-nested or nested PCR assays to detect members of the Paramyxovirinae or Pneumovirinae subfamily or groups of genera within the Paramyxovirinae subfamily. Although these tests are valuable for specific purposes, nesting of PCR assays and requirement for multiple primer-sets are sub-optimal for high-throughput diagnostic approaches, due to the higher risk of cross-contamination, higher cost, and being more laborious.” Here, a PCR assay is described that detects all genera of the Paramyxoviridae with a single set of primers without the requirement of nesting. This assay was shown to detect all known viruses within the Paramyxoviridae family tested. As the assay is implemented in a high-throughput format of fragment analysis, the test will be useful for the rapid identification of zoonotic and newly emerging paramyxoviruses.
Clinical signs of classical swine fever usually appear 5–10 days after infection (occasionally longer). An individual pig may show one of four types of clinical effect; Peracute (sudden death, especially at the beginning of a farm outbreak), Acute (fever, depression, weakness, anorexia, conjunctivitis, diarrhoea or vomiting, purple discoloration of abdominal skin, or necrosis of the tips of extremities, and neurological signs), Chronic (weight loss, hair loss, dermatitis, discoloration of abdomen or ears) and subclinical. Affected pigs may recover or relapse, depending on the severity of the disease. Reproductive effects is also common; abortions, stillbirths, mummifications and also congenital tremor of piglets.
Alkhurma hemorrhagic fever virus (AHFV) in humans was discovered in 1994. The first case reported in a butcher from the city of Alkhurma, a district south of Jeddah in Saudi Arabia, died of hemorrhagic fever after slaughtering a sheep. The viral infection has a reported fatality rate of up to 25%. Interestingly, one of the previous reports regarding this disease showed a misunderstanding of the real name of this infection, called Alkhurma, not Alkhumra. Because subsequent cases were diagnosed in patients from the small town known as Alkhurma in Jeddah from where the virus got its scientific name; the name was accepted by the International Committee on Taxonomy of Viruses. Thus, based on evidence, the first case was confirmed to be the butcher, following the slaughtered sheep. Therefore, a study was conducted among affected patients to address this disease as a public health issue. Blood samples were collected from household contacts of patients with laboratory-confirmed virus for follow-up testing by enzyme-linked immunosorbent serologic assay (ELISA) for AHFV-specific immunoglobulin (Ig) G. Samples from persons seeking medical care were tested by ELISA for AHFV-specific IgM and IgG using AHFV antigen. Viral-specific sequence was performed by reverse transcription PCR (TiBMolbiol, LightMix kit; Roche Applied Science, Basel, Switzerland). A total of 11 cases were identified through persons seeking medical care, whose illnesses met the case definition for AHFV, and another 17 cases were identified through follow-up testing of household contacts.
Subsequently, the virus was isolated from six other butchers of different ages (between 24 and 39 years) from the city of Jeddah, with two deaths. The diagnosis was established from their blood sample tests. The serological tests later confirmed four other patients with the disease. From 2001 to 2003, the study on the virus initial identification in the city of Alkhurma again identified 37 other suspected cases; with laboratory confirmation of the disease in 20 (~55%) of them. Among the 20, 11 (55%) had hemorrhagic manifestations and 5 (25%) died. The virus was later identified in three other locations: from the Western Province of Saudi Arabia (Ornithodoros savignyi and Hyalomma dromedarii were found by reverse transcription in ticks) and from samples collected from camels in Najran. AHFV virus was considered as one of the zoonotic diseases; however, the mode of transmission is not yet clear. Recently, it was suggested that the disease reservoir hosts may include both camels and sheep. The virus might also be transmitted as a result of skin wounds contaminated with the blood or body fluids of an infected sheep; through the bite of an infected tick, and through drinking of unpasteurized or contaminated milk from camels.
In humans, this zoonotic disease may present with clinical features ranging from subclinical or asymptomatic features to severe complications. It is related to Kyasanur Forest disease virus, which is localized in Karnataka, India. However, epidemiologic findings suggest another wider geographic location for the disease in western (including Jeddah and Makkah) and southern (Najran) parts of Saudi Arabia, and the virus infections mostly occur in humans. A study was conducted by Alzahrani et al. in the southern part of Saudi Arabia particularly in the city of Najran (with populations of ~250,000), an agricultural city in Saudi Arabia, where domestic animals are reared at the backyard of owners. After the initial virus identification, from January 2006 through April 2009, 28 persons with positive serologic test results were identified. Infections were suspected if a patient had an acute febrile illness for at least two days; when all other causes of fever have been ruled out. Additionally, data analysis indicated that patients infected with the virus were either in contact with their domestic animals, involved in slaughtering of the animals, handling of meat products, drinking of unpasteurized milk, and/or were bitten by ticks or mosquitoes. Symptoms consistent with AHFV infection—including fever, bleeding, rash, urine, color change of the feces, gum bleeding, or neurologic signs—then develop. Fortunately, infected patients responded to supportive care (including intravenous fluid administration and antimicrobial drugs when indicated), with no fatal cases.
In summary, AHFV is a zoonotic disease with clinical features ranging from subclinical or asymptomatic features to severe complications. Another study highlighted different characteristics of the exposure to the blood or tissue of infected animals in the transmission of AHFV to humans. Of the 233 patients confirmed with infections, 42% were butchers, shepherds, and abattoir workers, or were involved in the livestock industry. More recently, a study on infection using C57BL/6J mice cells showed that the clinical symptoms of the disease were similar to the presentations in humans. However, Alkhurma disease resulted in meningoencephalitis and death in Wistar rats, when high titers to the infection occurred. In addition, exposures to mosquito bites are regarded as potential sources of transmissions of the infection; however, very few available data support this. Although, available data shows that Alkhurma virus has been isolated following mosquito bites. However, another study suggested that mosquitoes may play a role only as a vector in the transmission of the disease.
Occupational medicine professionals are uniquely positioned to provide information on the potential impact of a pandemic influenza. Indeed, infectious disease may disproportionately impact the occupational environment. This is due to factors associated with transmission such as the proximity of co-workers to one another in the workplace, during the daily commute to work, or simply dealing face to face with customers. Of particular concern is the health and safety of those health care professionals caring for infected patients. The recent experience with Severe Acute Respiratory Syndrome (SARS) provides some useful insight into the consequences of a novel infection on a modern society and more specifically on the health care community.
There are many similarities between the SARS epidemic and the anticipated experience with avian influenza. Both have been associated with food and animals. In the early stages of SARS, more than a third of infected humans were food handlers, and it was later inferred that the SARS coronavirus had originated in civet cats, and that the first transmission of infection to humans may have occurred in those workers handling civet cats. However, the greatest impact of SARS was subsequently felt in health care workers where they were estimated to have accounted for over 20% of total SARS cases in Singapore and 40% in Canada. Thus, not only are individuals working closely with infected animal hosts at risk for first line crossover transmission of an emerging virus but they are also at risk of acquiring the virus from coworkers, or in the case of health care professionals, from patients.
Influenza viruses are RNA viruses that are members of the orthomyxovirus family and classified into four types: A, B, C, and D (2). As shown in Table 1, these four types of viruses are characterized by their immunologically distinct nucleoprotein and matrix protein antigens. Influenza A and B viruses consist of hemagglutinin (HA), which binds a sialic acid receptor, allowing the virus to enter the host cell, and neuraminidase (NA), which cleaves the sialic acid to release the virus. Similarly, influenza C and D viruses contain HA-esterase fusion glycoproteins that also allow for the attachment of viral and cellular membranes. Antigenic shifts (influenza A only) in HA, NA, and the HA-esterase proteins contribute to the generation of novel viral strains. The host range of influenza viruses includes humans, birds, pigs, bats, and other livestock animals such as cattle and goats. The network of the influenza viral transmission is complex with both inter- and intraspecies transmission. As the viruses continue to change in their genetic sequences, ongoing research is imperative in investigating the ecology of these viruses at the human–animal interface to control further spread of infections and prevent the risk of future pandemics.
An infectious etiology for cancer was first documented in animals during the early part of the nineteenth century with the diagnosis of pulmonary adenocarcinoma in sheep (later attributable to jaagsiekte sheep retrovirus) (5). Animals are the host species for many oncogenes. Among the most studied are rodent (Abl, Int1/Wnt1, Int2, Notch1, Pim1/2, Runx, Tpl2), fowl (Erb-b, Fos, Myc, Src), feline (Myc), and fish (cyc) (6). For example, reticuloendothesliosis virus readily induces cancer in chickens (avian leucosis/sarcoma). The virus has been found in eggs intended for human consumption and vaccines prepared in eggs (7). A wide variety of viruses, mirroring their human analogs, are ubiquitous among animals in nature and their habitat (e.g., fecal coliform contamination) (8–10). Common types include viruses in the polyoma, adeno, retro, and papilloma family.
Animal viruses potentially express oncoproteins in human cells even though stringent replicate restrictions exist in the latter (11). The “hit and run” hypothesis posits that certain viruses interfere with the hosts immune system to cause cancer, yet do not integrate into the victims DNA (leaving no detectable fingerprints) (12). Newborn hamsters infected with polyoma virus have been shown to develop cancers, even though the cells of this species do not support virus replication (13). Similarly, tumors induced in immunocompetent mammals with Rous sarcoma virus do not present neutralizing antibodies (14). In contrast, some animal viruses [e.g., feline leukemia virus (FeLV)] have been observed to replicate in vitro in human cells (15, 16). Sera collected from 69% of 107 persons among 46 households with at least 1 FeLV gs-a positive cat tested positive for antibodies against FeLV (15). Although it is unclear exactly how antibodies directed toward animal viruses could have oncogenic or mitogenic effects on host cells, these findings support the idea that long-lasting “biological memory” of animal virus exposure can exist within the host in the absence of direct effects on host DNA.
Humans and animals have coexisted since the beginning of time, sharing viruses, bacteria, and perhaps the etiology of cancers. Approximately 75% of viruses and 50% of bacteria known to cause disease in humans are zoonotic and can be transmitted between animals and people (1). While evolution has provided adaptive immunity against microbes and cancer, the ability to defend against infection is sometimes absent or compromised. Excluding ionizing radiation, sunlight, and tobacco, infection represents the main known cause of human cancers throughout the world. The list is long including cancers of the anogenital track (HPV), stomach (H. pylori), liver (HBV, HCV, liver flukes), bladder (schistosoma hematobium), prostate (XMRV), and other specific cancers such as adult T-cell leukemia (HTLV-1), Kaposi sarcoma (HHV-8), Merkel Cell Carcinoma (MCPyV), and Burkitt’s lymphoma (EBV) (2, 3). The prevalence and persistence of tumor viruses varies in different parts of the world. Nearly 30% of cancers in developing and tropical countries are attributable to infectious causes compared with 10% in developed countries (4). However, the connection between viruses, bacteria, and cancer, and the role of animals, remains unclear or paradoxical in nature.
Border disease is an important disease in sheep, caused by infection of the foetus in early pregnancy. Surviving lambs are persistently viremic, and the virus is present in their excretions and secretions, including semen. Ruminants and possibly also pigs can be readily infected by contact with these persistent excretors or with acutely infected sheep. Acute infections in immunocompetent animals usually are transient and subclinical and result in immunity to challenge with homologous but not heterologous strains of virus. The disease is characterised by low birth weight and viability, poor conformation, tremor, and an excessively hairy birth coat in normally smooth-coated breeds. Kids may also be affected, and a similar condition occasionally occurs in calves. The disease has been recognized in most sheep-rearing areas of the world.
Infectious diseases have been emerging and reemerging over millennia. Human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus (SARS-CoV), and the most recent 2009 pandemic H1N1 influenza virus are only a few of many examples of emerging infectious pathogens in the modern world. Each of these diseases has global societal and economic impact related to unexpected illnesses and deaths, as well as interference with travel, business, and daily activities. To overcome emerging, reemerging, as well as stable infectious diseases, the demand for development of efficient vaccines has greatly increased. Historically, live attenuated vaccines have provided the most effective protection against viral infection and disease. However, there have been safety concerns with the risk of reversion to the wild-type pathogen phenotype as shown with some traditional live attenuated vaccines such as the polio vaccine. Furthermore, development of live attenuated vaccines has not been successful for many important pathogens. On the other hand, inactivated vaccines are generally not very effective and require a high containment laboratory for cultivation of highly virulent pathogens. Also, there is a risk of incomplete inactivation for inactivated vaccines. Therefore, there is a need for an alternative approach for development of vaccines.
Replicating viral vector vaccines offer a live vaccine approach without requiring involvement of the complete pathogen or cultivation of the pathogen. Replicating viral vectors have the ability to synthesize the foreign antigen intracellularly and induce humoral, cellular, and mucosal immune responses. Specifically, vectored vaccines can have advantages for (i) viruses for which a live attenuated vaccine might not be feasible (i.e., HIV); (ii) viruses that do not grow well in vitro (i.e., human papillomavirus, hepatitis C virus, and norovirus); (iii) highly pathogenic viruses that present safety challenges during vaccine development (i.e., SARS-CoV and Ebola virus); (iv) viruses that lose infectivity due to physical instability (i.e., respiratory syncytial virus (RSV)); and (v) viruses that can exchange genes with circulating viruses (i.e., coronaviruses, influenza viruses, and enteroviruses). A vectored vaccine can be rapidly engineered against a newly emerging pathogenic virus by inserting the gene of the protective antigen of the virus into the genome of the viral vector. In general, the magnitude of the immune response to live viral vector vaccines is substantially greater and broader than that induced by vaccines based on subunit proteins or inactivated viruses. Furthermore, manufacturing of vectored vaccines against highly pathogenic viruses do not require a high level of biosafety containment laboratories.
Newcastle disease virus (NDV) is a fast-replicating avian virus that is prevalent in all species of birds. In most avian species, NDV infections do not result in disease. In chickens, NDV causes a highly contagious respiratory and neurologic disease, leading to severe economic losses in the poultry industry worldwide. NDV strains vary widely in virulence. Based on the severity of the disease in chickens, NDV strains are classified into three pathotypes: lentogenic strains which cause mild or asymptomatic infections that are restricted to the respiratory tract; mesogenic strains which are of intermediate virulence; and velogenic strains which cause systemic infections with high mortality. Naturally occurring low-virulent NDV strains, such as LaSota and B1, are widely used as live attenuated vaccines to control Newcastle disease in poultry. Although NDV primarily infects avian species, many non-avian species have also been shown to be naturally or experimentally susceptible to infection. The advent of a reverse genetics system to manipulate the genome of NDV not only allowed us to study the molecular biology and pathogenesis of NDV but also to develop NDV as a vaccine vector against diseases of humans and animals. NDV vector has several advantages over other replicating viral vectors.
Avirulent NDV strains are highly safe in avian and non-avian species. NDV replicates well in vivo and induces a robust immune response. In contrast to adeno, herpes, and pox virus vectors whose genome encodes a large number of proteins, NDV encodes only seven proteins and is thus less competition for immune responses between vector proteins and the expressed foreign antigen. NDV replicates in the cytoplasm, does not integrate into the host cell DNA, and does not establish persistent infection. Recombination involving NDV is extremely rare. NDV has a modular genome that facilitates genetic manipulation. NDV infects via the intranasal route and therefore induces both mucosal and systemic immune responses. A wide range of NDV strains exists that can be used as vaccine vectors. NDV-vectored vaccine can also be used as a “differentiating infected from vaccinated animals” (DIVA) vaccine. In this review article, we have reviewed the biology of NDV, development of reverse genetic systems for generation of NDV-vectored vaccines, and use of NDV vector for development of human and veterinary vaccines.
More than 70% of the emerging infectious disease agents are caused by microbes jumping from animals into human. This has been well exemplified by the highly fatal human infection due to avian influenza A H5N1 in 1997. The outbreak of severe acute respiratory syndrome (SARS) caused by a novel coronavirus in 2003, confirmed again that microbes can jump species from animals to humans with unpredictable consequence. The human SARS coronavirus was traced to caged civets in the market, and later Chinese horseshoe bat, Rhinolophus sinicus, was suggested to be a likely reservoir of SARS coronavirus. Bats are ideal incubators for new emerging infectious agents as they are mammals which roosted together and can fly over vast geographical distance. This has reignited the interest in seeking for new bat viruses including many bat coronaviruses and the recent discovery of bat influenza virus. Besides the SARS coronavirus, viruses in bats often infect human through intermediate hosts such as horses for Hendra virus, pigs for Nipah virus, and chimpanzees for Ebola virus. It is therefore important to catalogue as comprehensively as possible the animal viruses present in wild life especially the bats and birds, the food animals such as pigs and cattles, the pet animals such as cats and dogs, and monkeys which are phylogenetically close to humans. Using consensus primer polymerase chain reaction (PCR) screening, we have been able to discover relatively closely related species of virus in many different animals,–. However more distant or novel families of virus can only be found by metagnenomics using deep sequencing with the newer generation sequencers,. We report in this paper the discovery and characterization of a novel bat papillomavirus (PV) from rectal swab samples randomly collected from asymptomatic wild, food and pet animals using a metagenomic approach.
The MAstV-1 species is comprised of HAstV-1–8, and surveillance has revealed that HAstV-1 is the most commonly detected type in children, followed by HAstV-2–5, whereas HAstV-6–8 have been rarely detected. HAstV-4 and HAstV-8 have been associated with infection of older children and longer duration of diarrhea (>7 days). A HAstV-4 strain was also isolated from an infant with fatal meningoencephalitis. Based upon the phylogenetic analysis of the ORF2 region, different lineages within each HAstV type have been proposed; HAstV-1 (HAstV-1a–d) and HAstV-2 (HAstV-2a–d) have been divided into four lineages, whereas HAstV-3 (HAstV-3a–b) and HAstV-4 (HAstV-4a–c) have been classified into two and three lineages, respectively.
Hendra virus (HeV) and Nipah virus (NiV) are closely related highly pathogenic paramyxoviruses that have emerged independently in the past 15 years and continue to emerge in new locations. Flying foxes in the genus Pteropus are considered to be the natural reservoir for both viruses as demonstrated by seroconversion and isolation of HeV- and NiV-like viruses from bat tissues and secretions [1, 2]. Additionally, extensive serological surveys have not demonstrated the presence of HeV- or NiV-specific antibodies in other species. Indeed the flying fox geographic range encompasses all locations where HeV and NiV have been found. Paramyxoviruses are large, enveloped, negative-sense ssRNA viruses, and include such well-known members as measles virus (MeV), simian virus 5 (SV5), and respiratory syncytial virus (RSV). It is a diverse virus family, with various members causing common upper and lower respiratory tract infections to less common manifestations of neurological disease. In contrast, NiV and HeV are distinguished from all other paramyxoviruses most notably by their broad species tropism and high case fatality, and they have been classified into the new Henipavirus genus within the family Paramyxoviridae. HeV has appeared sporadically in Australia since 1994 where infection has been transmitted from horses to humans (reviewed in). Presumably horses become infected through spillover events from flying foxes, although no virus has been isolated from flying foxes during outbreaks. In horses, the disease presented as a severe respiratory infection, while one of the two reported human mortalities had severe respiratory disease, and the other succumbed to encephalitis 13 months following the presumed time of exposure. Recent outbreaks where horse fatalities were documented include 1999, 2004 and 2006 and although no human mortalities have occurred, one mildly ill, seroconverting, human case has been reported. NiV first appeared in peninsular Malaysia and Singapore in 1998-9 and the majority of infections occurred in pigs with subsequent transmission to humans (reviewed in [9, 10]). In pigs, infection was largely subclinical; however, where clinical disease was observed, it manifested as respiratory and encephalitic disease with low fatality ratios for respiratory cases. In contrast, humans developed severe febrile encephalitis with high case fatality and up to 25% of NiV cases also exhibited respiratory signs including non-productive cough. Interestingly, both relapsing and late-onset encephalitis syndromes with significant fatality (∼18%) have been recognized following either acute NiV encephalitic episodes or non-encephalitic/ asymptomatic infection. NiV has re-emerged numerous times since 1998: twice in 2001 in Bangladesh and West Bengal India, again in 2003 in Bangladesh, three times in Bangladesh in 2004 and 2005, and most recently in 2007 in Nadia, India. Significant observations in all of the Bangladesh and Indian NiV outbreaks have included a higher incidence of acute respiratory distress syndrome in conjunction with encephalitis, epidemiological findings consistent with person-to-person transmission, and higher case fatality ratios (∼75%). Furthermore, no intermediate or amplification host has been identified and direct transmission of NiV from the reservoir host to humans has been suggested. In West Bengal in 2001 there was no concurrent illness in animals and in Bangladesh in 2004 the common epidemiological link among cases was drinking fresh date palm sap [12, 17]. In general, it is believed that date palm sap is regularly contaminated by flying foxes and their excretions.
NiV and HeV are classified as zoonotic biosafety level 4 (BSL-4) viruses and infectious virus can only be studied at a handful of laboratories worldwide. Both viruses have also been included among the various pathogenic agents of biodefense concern and each are classified as priority pathogens in category C by the Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious Diseases (NIAID). The category C agents include high emerging pathogens with the potential for causing morbidity and mortality with major economic and health impacts. Henipaviruses in particular, could be engineered for mass dissemination because of their availability from natural sources and their relative ease of propagation and dissemination. Currently there are no specific antiviral therapies or vaccines available for treating or preventing NiV or HeV infection resulting from a natural outbreak, laboratory accident or deliberate misuse.
Astroviruses are classified within the unassigned Astroviridae family and are non-enveloped viruses characterized by a positive sense, single-stranded RNA (ssRNA) genome 6.4–7.9 kb long comprised of a 5′-untranslated region (UTR), three open reading frames (ORFs)—ORF1a, ORF1b, and ORF2, a 3′-UTR, and a poly A tail. The ORF1a region encodes a non-structural polyprotein (serine protease), ORF1b encodes a polyprotein including the RNA-dependent RNA polymerase (RdRp), and ORF2 encodes the viral capsid protein. A further ORF, termed ORFX, has been observed in classic HAstVs and some mammalian astroviurses, overlapping the 5′ end of ORF2 which may be translated through a leaking scanning mechanism. Astroviruses exhibit several distinctive features in addition to a distinctive morphology. The viruses lack a RNA-helicase domain encoded within the genome and utilize a ribosomal frameshifting mechanism to translate the RdRp, which distinguishes the Astroviridae family from other non-enveloped ssRNA virus families such as Picornaviridae and Caliciviridae. The greatest diversity in the genome is within the ORF2 region, which is characterized by a highly-conserved N-terminal domain (amino acids (aa) 1–424), a hypervariable domain (aa 425–688) which is believed to form the capsid spike and contribute to receptor binding, and a highly acidic C-terminal domain.
Veterinary medicine considers prophylactic vaccines, in combination with strict bio-security, to be the most cost-effective tools for preventing viral infections. In general, veterinary viral vaccines aim to protect susceptible host animals from fatal infectious diseases by inducing a rapid and long-lasting immune response and by preventing the spread of such diseases among populations by reducing viral shedding from infected animals. Such vaccines must be cost-effective, stable, and easy to administer. Live attenuated virus and/or inactivated virus vaccines have been used for decades to prevent viral infectious diseases; however, many vaccines do not satisfy the requirements for an “ideal vaccine” in the field due to limited effectiveness and/or side effects. In addition, no vaccines are available for some infectious diseases.
Advances in recombinant DNA technology have made it possible to design new innovative genetically engineered vaccines with improved safety profiles and greater protective efficacy. These “next generation” vaccines include DNA vaccines, subunit or virus-like particle vaccines, genetically modified marker vaccines, and virus vectored vaccines. Of these, the latter are thought to be a promising tool for developing polyvalent or antigen delivery vaccines that express foreign antigen(s) derived from pathogens of economic importance from a veterinary and human perspective.
Many viruses have been used to develop virus vectored vaccines, which provide effective protective immunity against foreign antigens. The number of vectored vaccines licensed for veterinary and human use has increased over time. Initially, vectored vaccines were based on DNA viruses such as herpesviruses, animal poxviruses, and adenoviruses. Currently, with advances in reverse genetics approaches, many RNA viruses have been adapted for use as vectored vaccines. Such vaccine vectors include both positive-sense RNA viruses (picornaviruses, coronaviruses, and flaviviruses) and negative-sense RNA viruses (paramyxoviruses and orthomyxoviruses). In particular, Newcastle disease virus (NDV), a paramyxovirus that infects birds, is used as an important vaccine vector for development of bivalent vaccines against pathogens of economic importance to the poultry industry. Numerous studies demonstrate that NDV is a promising vector for delivery of protective antigens derived from pathogens infecting mammals and humans; indeed, NDV vectors are safer and more efficient than conventional whole virus vaccines. This article reviews recent developments in the field of NDV-vectored vaccines and the potential use of such vaccines in veterinary and human medicine.
Infectious bronchitis (IB) is primarily a respiratory disease of chickens but with potential to cause more widespread infection in the urinary and reproductive tracts in chicken leading to significant production losses in commercial broiler and layer flocks worldwide. The causative infectious bronchitis virus (IBV) belongs to the family Coronaviridae. The disease is usually characterized by high morbidity and low mortality in mature birds, whereas in naive young birds (2–3 weeks of age), mortality up to 100% can be observed. Being an RNA virus with the ability to mutate and recombine, IBV persist as numerous serotypes and strains. The control of IB relies on vaccination. Vaccines are available for commonly occurring serotypes and strains but they are not necessarily antigenically similar to the wild-type viral strains circulating in poultry barns. Although, these vaccine strains may provide some degree of protection for some related strains known as protectotypes, the commonly available vaccines may not elicit protective immune responses in a flock if the field strains are antigenically very different from the vaccine strains. Owing to this reason, vaccination against IBV is not currently considered to be a very effective control method and other biosecurity measures are necessary to prevent the introduction of IBV into poultry production facilities.
IBV is known to replicate in the respiratory tract leading to changes in the muco-cilliary clearance mechanism, as such, expose the IBV infected birds to secondary bacterial infections. Additionally, IBV has tropisms for a variety of tissues. However, the mode of dissemination from the common route of entry, i.e. the respiratory route, to the rest of the body systems could potentially be due to the initial viremia. Once disseminated, IBV infects epithelial cells of the reproductive and urinary systems, particularly the oviduct and kidney depending on the infecting strain. Recently, it has been shown that a nephro-pathogenic strain of IBV (B1648) could replicate in peripheral blood monocytes leading to viremia. The infection of circulating monocytes could potentially disseminate IBV to the urinary tract, liver and spleen.
Macrophages play roles in innate immune responses, as well as in mounting adaptive immune responses by functioning as antigen presenting cells, as such they are critical in protecting animals from microbial infections. Although it is known that macrophage numbers are elevated in the respiratory tract in response to IBV infection, the role played by macrophages in IBV infection, particularly if they serve as a target cell for viral replication is not known. Macrophages have been implicated to play in an important role in the pathogenesis of some animal and human viruses including Marek’s disease virus in birds, feline corona virus in cats, and human immunodeficiency virus (HIV). It was also shown that coronaviruses such as severe acute respiratory syndrome (SARS)-coronavirus (CoV) can replicate within human macrophages thereby interfering with macrophage functions leading to severe pathology. However, a single report based on in vitro studies indicated that IBV, particularly nonpathogenic Beaudette and Massachusetts type 82822 strains do not replicate in avian macrophages.
Therefore, in this study we investigated the interaction of IBV with macrophages in lungs and trachea in vivo and macrophage cell cultures in vitro using two IBV strains, Connecticut A5968 (Conn A5968) and Massachusetts-type 41 (M41) which are known to induce clinical disease and pathological lesions in chickens. As implicated in some other viruses, we hypothesized that these two strains of IBV replicate within avian macrophages leading to productive replication and interfering with selected macrophage functions in the process.
Coronaviruses (CoVs) are enveloped, single-stranded, positive-sense RNA viruses in the family Coronaviridae that is within the order Nidovirales. The Coronaviridae contain at least four major genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Porcine CoVs are significant enteric and respiratory pathogens of swine. In 1946, porcine transmissible gastroenteritis virus (TGEV), an alphacoronavirus (α-CoV), was identified as the cause of a devastating enteric disease of pigs in the United States (1). A second U.S. porcine α-CoV, porcine respiratory coronavirus (PRCV), was officially identified in 1984 (2). PRCV is a deletion mutant of TGEV that alters viral tropism from intestinal to respiratory epithelia (3, 4). In swine, PRCV replicates almost exclusively in the respiratory tract and closely resembles other porcine viral pneumonias (2–4). In 1971, a new α-CoV, porcine epidemic diarrhea virus (PEDV), was identified in the United Kingdom (5). Both TGEV and PEDV replicate in small-intestinal enterocytes, causing life-threatening acute enteric disease in suckling piglets that is characterized by profuse watery diarrhea, emesis, and resultant dehydration (1, 6, 7). Morbidity rates are high (80 to 100%), as are mortality rates (50 to 90%) (1, 8). Since 2010, variant strains of PEDV differing in sequences from the classic European strain (CV777) have appeared in China, South Korea, Japan, and many Asian countries, causing up to 100% mortality in suckling piglets (8, 9). In May 2013, PEDV was identified as a new cause of neonatal diarrhea in Iowa (10, 11). Infection rapidly spread to more than 30 states, Canada, and Mexico and caused significant economic losses in the swine industry (12–14). Sequence analyses suggest that U.S. PEDV strains originated from China (12).
The Deltacoronavirus genus has been only recently defined by genomic sequence analysis of both pig and avian isolates (15). Since 2009, avian deltacoronaviruses have been detected in a wide range of domestic and wild birds (15–17). The porcine deltacoronaviruses (PdCV) Hong Kong (HK) strains HKU15-155 and HKU15-44 were recently detected in rectal swabs from pigs (15). The potential of the HKU15-155 and HKU15-44 PdCVs to cause significant clinical disease in swine is not known. In mid-January 2014, PdCV was identified in fatal cases of PEDV-negative diarrhea in Ohio piglets (18). Field reports document a history and clinical presentation (vomiting, diarrhea, and dehydration) typical of TGEV and PEDV; like for the other swine enteric CoVs, morbidity and mortality rates at PdCV-infected farms are high (18–21). In some instances, PdCV is the only virus recovered from these diarrhea outbreaks; in others, it may be present as a coinfection with PEDV. To date, outbreaks have been documented in more than 20 states in the United States. In April 2014, a PdCV strain (KOR/KNU14-04/2014) was also identified in feces from diarrheic piglets in South Korea (22).
Aside from genomic sequence data, nothing is known about the U.S. PdCV. Although the virus is identified in diarrhea outbreaks, experimental studies that directly demonstrate its disease-causing potential remain to be shown. The objective of this study is to characterize the U.S. PdCV isolate in terms of genetic characteristics, phylogeny, and virulence in gnotobiotic (Gn) and conventional piglets. Genomic sequencing found that U.S. PdCV strains share 99.6 to 99.7% homology with each other and 99.0 to 99.1% homology with Hong Kong isolates (HKU15-155 and HKU15-44). We found that the U.S. PdCV strains caused severe diarrhea, vomiting, and dehydration clinically indistinguishable from those caused by PEDV and TGEV. Histologically, the PdCV strains caused severe lesions in the stomach and small intestine and mild interstitial pneumonia in lungs. Collectively, our study provides the first proof that PdCV causes significant enteric disease in swine.
We are constantly exposed to animal viruses through the food that we eat, the pets that we keep, and our interactions with nature. The vast majority of viruses that enter our bodies pass harmlessly through our gastrointestinal tracts or are destroyed by our immune systems. However, on rare occasions, an animal virus encounters a human host and begins to replicate itself, executing its entire lifecycle within human cells and expanding one virion into a population of many. Replication of an animal virus within the body of this first human subject is the key moment in the zoonotic process because it renders possible two things. First, the virus will now mutate and evolve under the selective constraints of the human body for the first time, adapting and improving itself for replication in this new host. Second, high virus titers produced by viral replication mean that spread to a second human is now possible, initiating selection for variants with increased capacity to spread in the human population.
Significant effort has been put into understanding the factors that contribute to the spread of zoonotic viruses through the human population once an animal virus has begun the process described above. Factors that facilitate spread of viruses through populations can include high population density, the presence of viral vectors, and many others. However, less investment has been made in finding the animal viruses that have the greatest potential to begin these zoonotic events in the first place. In the following essay we will argue that, while humans are constantly exposed to animal viruses, those animal viruses with real potential to replicate themselves in a human cell are exceedingly rare. We assert that host genetics plays a major role in determining which animal viruses will be able to make copies of themselves in the human body. This is because animal viruses that pose the greatest risk to humans will have few (or no) genetic barriers to replicating themselves in human cells, thus requiring minimal mutations to make this jump.
Over the past two decades, there has been mounting interest in the increasing number of viruses causing unexpected illness and epidemics among humans, wildlife and livestock. All too often outbreaks have seriously stretched both local and national resources at a time when health-care spending in the economically developed world has been constrained. Importantly, capacity to identify and control emerging diseases remains limited in poorer regions where many of these diseases have their origin.
Emerging disease is a term used with increasing frequency to describe the appearance of an as yet unrecognized infection, or a previously recognized infection that has expanded into a new ecological niche or geographical zone and often accompanied by a significant change in pathogenicity.1 The key message is that these are representative of constantly evolving infections responding to rapid changes in the relationship between pathogen and host.
Among 1400 pathogens of humans over 50% of these have their origins in animal species, that is, “are diseases or infections naturally transmitted between vertebrates and humans” (World Health Organization). According to Woolhouse and colleague2 emerging or re-emerging pathogens are far more likely to be zoonotic. Viruses are over-represented in this group. Moreover, viruses with RNA genomes account for a third of all emerging and re-emerging infections. Emerging pathogens are typically those with a broad host range, often spanning several mammalian orders. Almost certainly many of these infections have been the result of the development of agricultural practices and urbanization (Figure 1).
Recent interest in emerging infections has focused on three key areas. First, how the interplay of climate, environment and human societal pressures can trigger unexpected outbreaks of emerging disease. Second, the understanding of how viruses can transmit between a reservoir and new host species, Third, identifying those aspects of the disease process that offer opportunities for therapy and prevention. To these must be added a broader understanding of how viruses evolve over time, clues to which are now being uncovered through looking closely at genetic elements of the host genome responsible for resisting virus invasion. Meeting these objectives will provide a more rigorous basis for predicting virus emergence.