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Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
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To asses the sensitivity of the PMX-1-PMX-2-based assay as compared to standard diagnostic tests, we obtained anonymized human clinical samples that had tested positive for different paramyxoviruses using specific Taqman assays in the clinical virus diagnostic unit of Erasmus MC. Clinical samples were selected for diversity in virus species, type of clinical specimen, and virus load. The sample collection included clinical specimens positive for MuV, HMPV, MV, PIV-1, PIV-2, PIV-3, PIV-4, RSV-A, and RSV-B. Four different types of clinical specimens were used: oral, (sputum, saliva, throat swab and mouth swab), nose (nose wash and nose swab), lung (broncho-alveolar lavage), and other (plasma and urine). Virus load, as measured by the cycle threshold (Ct) value in real-time Taqman assays, ranged from Ct 15 to Ct 38. Thirty-five samples were selected, RNA was extracted using the MagnaPure LC system, and the RT-PCR assay for detection of paramyxoviruses and fragment analysis was performed (Figure 4). Out of the 35 samples, the pan-paramyxovirus RT-PCR assay detected 27 human paramyxoviruses. The sample with the lowest Ct value (highest concentration target nucleic acid) that remained negative in the pan-paramyxovirus RT-PCR assay was a nose wash containing PIV-2 with a CT value of 30. The virus load in the 8 samples that remained negative in the pan-paramyxovirus RT-PCR assay (mean Ct 34.7, standard deviation 2.5) was lower than the load in the 27 samples yielding a positive reaction (mean Ct 24.5, standard deviation 5.2). Out of the virus specimens tested, 2/3 of the MuV specimens were positive, 4/4 for HMPV, 2/3 for MV, 3/5 for PIV-1, 4/5 for PIV-2, 3/3 for PIV-3, 3/5 for PIV-4, 4/5 for RSV-A, and 4/5 for RSV-B.
Fifty-four additional human throat samples were obtained from the clinical virus diagnostic unit of Erasmus MC. These samples were collected in 2000 and 2001 from patients with respiratory illnesses. The samples tested negative for the presence of RSV, influenza A, B and C, PIV-1 and -4, adenoviruses and rotaviruses by direct immunofluorescence on throat swabs and by immunofluorescence upon tissue culture. Of these 54 samples, one tested positive for PIV-1, two for PIV-4 and three for RSV with the pan-paramyxovirus RT-PCR assay followed by nucleotide sequencing of the PCR fragments (data not shown).
High-titre virus stocks of HMPV, HRSV, HPIV-1, HPIV-2, HPIV-3, HPIV-4, and MV were serially diluted to 10−10. Dilutions were tested using agent-specific real-time PCR assays in our diagnostics department. The same RNA was used for the pan-paramyxovirus RT-PCR assay with subsequent fragment analysis. For HMPV, agent-specific real-time PCR assays detected positive samples up to a dilution of 10−6, while fragment analysis detected positive samples up to a dilution of 10−5. For the other viruses, these comparative dilutions were: RSV 10−7 and 10−5, PIV-1 10−7 and 10−5, PIV-2 10−5 and 10−4, PIV-3 10−8 and 10−5, PIV-4 10−6 and 10−5, MV 10−8 and 10−5. Thus, on average, the pan-paramyxovirus RT-PCR assay was 2-log less sensitive than agent-specific RT-PCR assays.
Fragment analysis using a 3130xl Genetic Analyzer was used to facilitate screening of larger numbers of samples without the requirement of running agarose gels (Figure 3). To this end, the forward primer PMX1 was labelled with the fluorescent dye 6-FAM. Samples were analyzed in a 96-well format. Seven tenfold serial dilutions of an APMV-3 virus stock were made and amplified using the pan-paramyxovirus RT-PCR assay. Upon agarose gel electrophoresis, 10−5 was the last dilution of virus still yielding a visible band. Upon fragment analysis, positive samples could be detected up to a dilution of 10−7. When both forward and reverse primers were labelled, no significant increase in detection was observed (data not shown). Therefore, only the forward primer PMX1 was labelled.
First discovered in 1953 by Rowe et al., Ads are non-enveloped, double-stranded DNA viruses with 57 unique serotypes, some of which are specific for attacking the respiratory track, conjunctiva, or gastrointestinal track (40). Key features of Ad infections include various symptoms of disease, including rhinorrhea, nasal congestion, cough, sneezing, pharyngitis, keratoconjunctivitis, pneumonia, meningitis, gastroenteritis, cystitis, and encephalitis. Illnesses may be asymptomatic, mild, or severe; however, immunocompromised patients and infants are at increased risk of severe morbidity and death.
Frequent human-animal contact is the major cause for viral cross-species transmission. Next-generation sequencing is a highly efficient method for rapid identification of microorganisms and for surveillance of pathogens for infectious diseases. Animal models and other laboratory tests would be needed to pinpoint the causative agents. The novel coronaviruses in Wuhan likely had a bat origin, but how the human-infecting viruses evolved from bats requires further study. The human-infecting virus may become more infectious but less virulent as it continues to (co-)evolve and adapt to human hosts. Since Wuhan is one of the largest inland transportation hubs in China and the city has been closed off, it is urgently necessary to step up molecular surveillance and restrict the movement of people in and out of the affected areas promptly, in addition to closing the seafood markets. To prevent human-to-human transmission events, close monitoring of at-risk humans, including medical professionals in contact with infected patients, should also be enforced. Finally, virome projects should be encouraged to help identify animal viral threats before viral spillover or becoming pandemics.
Outbreaks of Ad in the general population have been characterized by infection due to novel viruses such as Ad7h, Ad7d2, Ad14a, and Ad3 variants. These novel viruses are sometimes associated with high attack rates and a high prevalence of pneumonia. Severe mortality is also prevalent among patients with chronic disease and in the elderly.
One of the most important novel serotypes, Ad14, previously rarely reported, is now considered as an emerging Ad type causing severe and sometimes fatal respiratory illness in patients of all ages (45). Beginning in 2005, Ad14 cases were suddenly identified in four locations across USA (46); the strain associated with this outbreak was different than the original Ad14 strain isolated in 1950s. The novel strain, Ad14a, has now spread to numerous US states and is associated with a higher rate of severe illness when compared to other Ad strains.
Novel Ad species have also been recently detected in cross-species infections from non-human primates to man in USA and between psittacine birds and man in China (47). These cross-species infections indicate that Ads should be monitored for their potential to cause cross-species outbreaks. In a recent review of the risks of potential outbreaks associated with zoonotic Ad (48), it was noted that intense human–animal interaction is likely to increase the probability of emergent cross-species Ad infection. Additionally, the recombination of AdVs with latent “host-specific” AdVs is the most likely scenario for adaptation to a new host, either human or animal.
Currently, there are no FDA approved antivirals for Ad infection; however, the best antiviral success has been seen with ribavirin, cidofovir, and most recently brincidofovir an analog of cidofovir (49).
A total of 390 sera were collected from two different veterinary clinic laboratories located in Apulia region, Southern Italy and tested upon request of the veterinarian practitioners after anamnesis, medical history and clinical examination. One-hundred seventy-four sera (collection A) had been collected for diagnosis of infectious diseases (FIV, FeLV, feline coronavirus (FCoV), toxoplasmosis, hemoplasmosis, bacterial and fungal infections). A total of 147/174 (84.5%) sera were submitted with a suspect/request of diagnosis for FIV/FeLV, with 42 sera being positive for retrovirus. Fisher’s exact test was performed to the collection A to evaluate the correlation between DCH positive cats and retrovirus positive cats. The significance level of the test was set at 0.05. Of the other 27 sera (15.5%), 14 were sent for a suspect/request of diagnosis for coronavirus (with 7/14 being positive), 5 for toxoplasmosis (with 2/5 being positive), 2 for giardia (with 1/2 being positive). Five sera were collected from animals with suspected bacterial/fungal infections and 1 serum (negative) was from a cat with suspected hemoplasmosis. A total of 216 sera (collection B) submitted to the laboratory for pre-surgical evaluation (n = 85) or for suspected metabolic (n = 127) or neoplastic (n = 4) disease was used for comparison to generate a baseline. Information on the sera analyzed in the study is included in Fig. 1. The study was approved by the Ethics Committee of the Department of Veterinary Medicine, University of Bari (authorization 23/2018). All experiments were performed in accordance with relevant guidelines and regulations.
Total DNA was extracted from collected sera by using QIAamp cador Pathogen Mini Kit (QIAGEN, Hilden, Germany), according to the manufacturer’s instructions. We performed sample screening using a PCR with consensus pan-hepadnavirus primers2 and a PCR with primers specific for DCH3. Also, we screened sera using a quantitative PCR (qPCR) designed based on the sequence of the Australian reference strain AUS/2016/Sydney (GenBank accession nr. MH307930) (Table 2). For qPCR, we calculated DCH DNA copy numbers on the basis of standard curves generated by 10-fold dilutions of a plasmid standard TOPO XL PCR containing a 1.4 kb long fragment of the polymerase region of the Australian reference strain AUS/2016/Sydney (IQ Supermix; Bio-Rad Laboratories SRL, Segrate, Italy). We added 10 μL of sample DNA or plasmid standard to the 15-μL reaction master mix (IQ Supermix; Bio-Rad Laboratories SRL, Segrate, Italy) containing 0.6 μmol/L of each primer and 0.1 μmol/L of probe. Thermal cycling consisted of activation of iTaq DNA polymerase at 95 °C for 3 min and 42 cycles of denaturation at 95 °C for 10 s and annealing-extension at 60 °C for 30 s. We evaluated the specificity of the assay using a panel of feline DNA viruses (parvovirus, herpesvirus and poxvirus). The qPCR assay was able to detect as few as 101 DNA copies per mL of standard DNA and 3.3 × 100 DNA copies per mL of DNA template extracted from clinical samples. DCH quantification displayed acceptable levels of repeatability over a range of target DNA concentrations, when calculating the intra- and inter-assay coefficients of variation within and between runs, respectively15,16.
We carried out inferential statistical analyses using the Chi-Squared test with Yates’ Correction, the evaluation of the odds ratio (OR) and 95% confidence interval (CI95%) with the online software MedCalc easy-to-use Statistical software (https://www.medcalc.org/calc/odds_ratio.php). The significance level of the test was set at 0.05.
Full genome sequences of hepadnaviruses were retrieved from the GenBank database and aligned using Geneious version 9.1.8 (Biomatters LTD, Auckland, New Zealand) and the MAFFT algorithm17. A set of genome sequences used in a previous study2 was integrated with additional genome sequences of hepadnaviruses of recent identification in mammalian, avian, amphibian species and in fish. The final dataset included 53 hepadnavirus genomes. Phylogenetic analysis was performed using JModel test (http://evomics.org/resources/software/molecular-evolution-software/modeltest/) to evaluate the correct best-fit model of evolution for the entire dataset. Bayesian analysis18,19 was therefore applied using four MCMC chains well-sampled and converging over one million generations (with the first 2000 trees discarded as “burn-in”) and supplying statistical support with subsampling over 1000 replicates. The identified program settings for all partitions, under the Akaike information criteria, included six-character states (general time-reversible model), a proportion of invariable sites and a gamma distribution of rate variation across sites (GTR + I + G). We also tried to perform phylogenetic analyses using other evolutionary models (Maximum likelihood, Neighbor joining) to compare the topology of phylogenetic trees. We could observe similar topologies with slight difference in bootstrap values at the nodes of the tree. Accordingly, we did prefer to retain the Bayesian tree. We deposited the nucleotide genome sequence of strain ITA/2018/165-83 (MK117078) in GenBank.
The MERS-CoV infection is considered to be a new respiratory disease with a dire global concern. MERS-CoV infections are caused by a newly emerging coronavirus (CoV), belonging to the designated lineage C of Betacoronavirus of the RNA family Coronaviridae. With respect to viral origin and transmission, bats are thought to be the reservoir host of Betacoronaviruses, and the African Neoromicia bats in particular are the natural reservoir of MERS-CoV.
Since its emergence in 2012 in Saudi Arabia, when an elderly patient (60 years old) with respiratory illness died after admission to a hospital in Jeddah, the disease was subsequently reported to have been transmitted to several countries worldwide, and has affected more than 1000 patients with over 35% fatality.
Moreover, a 60-year-old Saudi man was admitted to a private hospital in Jeddah, Saudi Arabia in June 2012 with a history of fever, severe acute respiratory syndrome with cough, expectoration, and shortness of breath. He did not smoke; and for the disease, which was suggested to be due to an animal transmission of coronaviruses, he was treated with oseltamivir, levofloxacin, and piperacillin-tazobactam. On day 11, he died. After this, a 61-year-old Saudi male with hypertension and diabetes with no history of smoking, reported for surgery. At the time of admission, he was asymptomatic. He was initially screened using nasopharyngeal swab, endotracheal aspirate, and serum sample for MERS-CoV per protocol with the MERS RRT-PCR assay. The results confirmed MERS-CoV infection. He died three days after admission. It was discovered that the patient owned a dromedary camel barn in Saudi Arabia, and had a history of close contact with camels, as well as a habit of raw milk consumption of an unknown duration.
Two studies have suggested a relationship between the infection and contact with dromedary camels. In addition to this, serological diagnostic methods have been used to confirm MERS-CoV infections in dromedary camels for at least 2–3 decades and has thus confirmed camels as an intermediate host for this virus. Thus, in 2012, a novel coronavirus (MERS-CoV) was isolated from two fatal human cases in Saudi Arabia and Qatar; and since then, more than 1400 clinical cases of MERS-CoV have been identified, and the great majority of the cases were from Saudi Arabia. This previous report author raised a thoughtful comment related to the emerging viral diseases “Why We Need to Worry about Bats, Camels, and Airplanes”. Moreover, another study suggested that MERS-CoV infection is usually transmitted from human’s direct contact with dromedary camels, especially when people drink the milk or use camel’s urine for medicinal purposes. More recently, a metagenomics sequencing analysis of nasopharyngeal swab samples from 108 MERS-CoV-positive live dromedary camels marketed in Abu Dhabi, United Arab Emirates, showed at least two recently identified camel coronaviruses, which were detected in 92.6% of the camels in that study. However, limited human-to-human infections have been reported.
The prevalence of MERS-CoV infections worldwide still remains unclear. In addition to this, the WHO reported about 1797 cases of these infections since June 2012, with about 687 deaths in 27 different countries, worldwide. Recently, a study was conducted from June 2012 to July 2016, during which samples were collected from MERS-CoV infected individuals, from the National Guard Hospital in Riyadh (the Saudi Arabian capital city), the MOH in Saudi Arabia, and other Gulf Corporation Council countries, to determine the prevalence of MERS-CoV. The epidemiologic data that were collected, showed that the highest number of cases (about 1441 of 1797 patients) were reported from Saudi Arabia (~93%). Among the 1441 MERS-CoV cases from Saudi Arabia, Riyadh was the worst-hit area with 756 infected cases (52.4%), followed by the western region of Makkah where 298 cases (20.6%) were reported.
Furthermore, this study also showed that the incidence of MERS-CoV infections was highest among elderly people aged ≥60 years; with speculation that there might be certain conditions or factors involved. It is considered that MERS-CoV infection might have a peculiar gender predisposition. Recent data examined the mortality in patients with MERS-CoV and the gender relationships, looking at the survival of cases among females and males. It was suggested that males have a higher risk of death; however, this was contradicted by the findings from two other studies which suggested that males have a low risk of death; while another survey which examined the influence of gender on 3-day and 30-day survival, found a low risk of death especially in the older age group. On the other hand, Badawi et al., suggested that MERS-CoV infections could be mild and may only result in death among patients suffering from any kind of immune system disorder and/or any chronic disease.
More recently, data regarding the mortality in patients with MERS-CoV have been published. According to Saudi Arabia’s MOH daily statements, dated from February 26 through March 3, laboratory-confirmed new cases of MERS-CoV and 2 deaths occurred. Recently, on February 26, patients infected while hospitalized at Riyadh included two men (23 and 59 years old) in stable condition, who were not healthcare workers. According to a February 27 update, a new case involved a 71-year-old man from the city of Buraydah who later died. Meanwhile, on March 1, another MERS-CoV infection in a Riyadh hospital patient, a 64-year-old man who was listed in critical condition and who likewise had contact with camels, as the other two patients, was reported. Thus, the MOH stated that the spillover from camels is thought to be the main source of MERS-CoV in Saudi Arabia, since all these patients were exposed to the animals before reporting ill.
Furthermore, an 83-year-old patient from Riyadh, and other two patients who had camel contacts from Hail city in the north central part of Saudi Arabia were listed in critical condition. The illness in these patients was reported on March 1. According to a March 3 statement, another patient, a 74-year-old man from Najran located in southern Saudi Arabia, was reported. The man was listed in a stable condition. Of these new cases, only one death, involving the 83-year-old man from Riyadh, according to the March 3 MOH statement, was reported. Still, much work is needed to detect the MERS-CoV infection risk in Saudi Arabia, because data showed increasing number of cases exist among the eight countries including Saudi Arabia. Thus, the emergence of MERS-CoV in the region and its continuing transmission from 2012–2017, currently poses one of the biggest threats to global health security. Most cases (over 85%) reported to date have been from countries in the region (e.g., Egypt) notably from Saudi Arabia, with 1527 cases including 624 deaths.
Rabies is an almost invariably fatal zoonotic disease, which belongs to the genus Lyssavirus of the RNA family Rhabdoviridae. Rabies virus is considered an endemic viral infectious disease in animals in Saudi Arabia. Recent scientific data on rabies cases reported in camels at Al-Qassim region (one of the thirteen administrative regions of Saudi Arabia) showed that there is an increasing number of this fatal virus disease. However, the most significant animal bites which have been recorded in Saudi Arabia were caused by different species of animals including dogs, cats, rodents, and foxes. Later, Al-Dubaib reported rabies in dromedaries in Saudi Arabia in 2007 and suggested an incidence of about 0.2% for rabies that was reported among 48 camel herdsmen looking after more than 4000 animals.
Interestingly, another survey was conducted between 1997 and 2006 in the Al-Qassim region of central Saudi Arabia among 4124 camels and showed that about 0.2% of clinical rabies incidence is caused by dogs (may be cause it highly used as a perfect guard for camels), followed by foxes; furthermore, the diagnosis of viral rabies in that region was confirmed among 26 dogs, 10 foxes, 8 camels, and 7 cats. Lately, the relevant government authorities (the MOH and Ministry of Agriculture in Saudi Arabia) in an updated report between 2007 and 2009 showed that there were a total of 11,069 animal bites to humans in Saudi Arabia. Furthermore, most cases of animal bites were caused by dogs (49.5%) and cats (26.6%), followed by mice and rats, camels, foxes, monkeys, and wolves. Moreover, dogs, particularly feral dogs and foxes, are considered the most important host for rabies virus; however, bats are also considered as reservoirs of this disease. Humans can become rabid by direct contact with animal mucosal surfaces via bites.
According to the MOH and Ministry of Agriculture data in Saudi Arabia, pets are responsible for most animal bites in humans, and it is well-known that insufficient vaccination coverage of pets are among the most common hallmarks of the endemic status of rabies worldwide. More recently, many Saudi and expatriate families are keeping pets; however, there are limited number of specialized veterinary clinics (~5) within the Kingdom of Saudi Arabia that have fully licensed veterinary laboratories with state of the art technologies and veterinary staff.
Globally, almost 95% of all human deaths caused by rabies occur in Africa and Asia. However, Saudi Arabia, as one of the Asian countries, has scarce publications and epidemic data on rabies status. Moreover, Memish et al., between 2005 and 2010 in Saudi Arabia, reported the histologic detection of the virus by identifying Negri bodies in the brain samples of 40 animal rabies cases. The study showed that among the 40 suspected rabies cases, 37 (~92.5% of all cases) were found to be positive; thus confirming rabies cases among 11 dogs, 6 foxes, 6 sheep, 5 camels, 4 goats, 3 wolves, and 2 cows.
Furthermore, more recent data confirmed the transmission of rabies virus in Saudi Arabia by feral dogs. In spite of these facts, there are very few studies available, and no case of human rabies has been reported in recent decades from Saudi Arabia. However, in March 2018, a scientific work was reported as the first confirmed case of human rabies in Saudi Arabia from Makkah City, which has now been published. Indeed, several previous global epidemiological data confirmed that rabies accounted for 24,000 to 60,000 human deaths per year, and more than 40% of these cases occur in children < 15 years of age.
In September 2016, a 60-year-old Saudi man, presented with different clinical features—such as nausea, vomiting, and epigastric pain, with significant features suggestive of gastritis—at Makkah hospital. His past medical history was significant for hypertension and diabetes type 2. During the clinical diagnostic procedure of this case, he developed respiratory distress and tachycardia, for which he was transferred to the intensive care unit. Because, his case worsened with chest pain and ventricular tachycardia he was referred to the King Abdullah Medical City in Makkah for further management. The written diagnostic report indicated that he had acute anteroseptal myocardial infarction, had coronary angiogram which suggested that two-vessels were diseased with left main involvement, and surgical intervention was planned. After the decision for surgery, he was found to have leukocytosis and severe retching while attempting to drink water (hydrophobic behavior), which necessitated further review by the infectious disease consultants based on the patient’s clinical symptoms. The consultant team discovered the history of an unprovoked scratch on the patient’s face by a dog in Morocco a month prior to the admission at the hospital. Also, the patient stated that he only received tetanus vaccine. All diagnostic tests including neurologic examination were unremarkable and his saliva polymerase chain reaction (PCR) test confirmed rabies virus. He was administered Verorab rabies vaccine and human hyperimmune rabies immunoglobulin (20 IU/kg) intramuscularly (IM). In addition, he had troponin I (4.65 ng/mL), creatine kinase isoenzyme MB (CKMB) was found (30.08 ng/mL), and serum glucose (200 mg/dL). On the fifth day of hospital, he had recurrent episodes of ventricular tachycardia, progressively worsening of hemodynamic parameters, and he succumbed to his infection on that day. There is no vaccine against rabies recommended for travelers from/to Saudi Arabia, and no rabies treatment is offered to pet dogs. However, vaccination is given to dogs before they are infected; otherwise they are euthanized if infected.
According to a previous study, most patient injuries from animal bites in Saudi Arabia showed some variations due to the monthly incidence and/or, according to the animal species. Bites by dogs and cats were reported frequently throughout the year, with a decrease in April and between August and October. However, bites by foxes increase between August and September while camel bites were more frequent between December and March of the subsequent year. The same previous study suggest that these seasonal variations of injuries might be due to the Saudi population habits, with people going to the desert for leisure activities during good weather periods. Laboratory diagnosis of rabies viral disease occur with the use of the rabies virus direct fluorescent antibody test (DFAT) on brain samples and hippocampal tissue.
While rabies is considered nearly 100% fatal, it is also 100% preventable, and thus vaccination to pets is the key element to prevent the risk of rabies zoonotic infection. Reports of the epidemiology of rabies virus worldwide, and particularly in Saudi Arabia, suggest that it is on the increase, thus the implication of this virus’ potential to spread across borders from high to low prevalence countries was highlighted.
To date, no animal norovirus have been detected in human stool, but some serological evidence hints to possible transmission from animals to humans. This includes a handful of studies that reported seroprevalence against bovine and canine norovirus in humans. A Dutch study compared antibody titres against GIII.2 VLPs from 210 bovine or porcine veterinary specialists against age, sex, and residence matched controls with the aim to evaluate whether higher exposure to animals is reflected in increased titers against animal noroviruses. More veterinarians had anti-GIII.2 IgG antibodies compared to the control group (28% versus 20%). Similarly, the seroprevalence of antibodies to canine GVI.2 VLPs was tested in a cohort of 373 veterinarians versus age, sex, and district matched controls. Of the veterinarians, 22.3% were seropositive for GVI.2 in comparison to 5.8% in the control group. Anti-GIII antibodies were also detected in 26.7% of adult blood donors in Sweden and in a birth cohort in India, which compared seroprevalence of mothers and their children. However, the possible presence of cross-reactive antibodies needs to be considered in these studies: the GIII.2 response was in part correlated with GI.1 response, but not with the GII.4 response. The finding that some sera contained higher antibody titers against GIII.2 than human norovirus indicates that not all anti-GIII.2 response can be explained by cross-reactivity. Importantly, no cross-reactivity between bovine GIII.2 and human GI.3, GII.1, GII.3, GII.4, GII.6 was detected when convalescent anti-GIII.2 sera of a gnotobiotic calf or specific anti-GIII.2 or GII.3 antibodies were used. Cross-reactivity between GVI.2 and GII.4 was assessed by pre-incubating GVI.2 positive sera with GVI.2 VLPs before assessing their binding to GII.4 or GVI.2. Preincubation with GVI.2 blocked binding to GVI.2 VLPs but had no effect on sera binding to GII.4, suggesting that these two genotypes share no conserved epitopes. In contrast, cross-reactivity was observed between more closely related human GIV.1 and canine GIV.2 noroviruses in an age stratified cohort of 535 people in Italy, where 28.2% of the sera reacted to both GIV.1 and GIV.2 VLPs and only 0.9% detected exclusively GIV.2 VLPs.
Viral vectors have potential as novel vaccine candidates in times of pressing need for game-changing vaccines that induce broadly protective immunity against a wide variety of influenza viruses. The major advantage of viral vectors is the possibility of expressing any foreign antigen with or without modification in vivo. Since the proteins are expressed in their native confirmation, antibody responses of the desired specificities are induced. In addition, viral vectors allow de novo protein synthesis in the cytoplasm of infected cells facilitating endogenous antigen processing and MHC class I presentation of immunogenic peptides, which is a requirement for the efficient induction of virus-specific CD8+ T-cell responses. Although all vectors discussed have their own respective advantages and disadvantages, most are replication-deficient in mammalian host cells and are therefore safe for human use, even in immunocompromised individuals. Pre-existing immunity to the vector may pose a problem for some vectors, however there are viral vectors available (like VSV) for which the human population is immunologically naïve. Other vectors (like MVA) proved to be immunogenic even in the presence of pre-existing immunity. For some vector technologies there are some safety concerns, like the use of herpes viruses that persistently infect their hosts and DNA vaccines that might integrate into the host genome. These properties might restrict their applicability as prophylactic vaccines.
As discussed in this review, viral vectors as potential influenza vaccine candidates were not only evaluated in animal models and humans, they were also extensively tested in influenza A virus reservoir species. Vaccination of reservoir species could potentially limit transmission of avian and swine influenza A virus transmission, and therefore limit the zoonotic transmission of these potential (pre-)pandemic viruses to the human host.
In the future, more novel vector-based influenza candidate vaccines will be developed and tested in clinical trials. There is potential for improvement by the modification of viral antigens, like the ‘headless’ or ‘shielded’ HA constructs, to broaden the reactivity of vaccine induced antibodies. In addition to modifying influenza virus antigens, post-translational modifications and modifications to promoter sequences could also alter and improve the immunogenicity.226,227 The biggest challenge of taking vector-based vaccines to the market may be obtaining approval from the regulatory authorities. Only when their safety and superiority over existing vaccine formulations have been demonstrated, implementation of these novel vector-based vaccines may be considered.
Bivalent NDV-vectored vaccines, which have been developed to prevent diseases of economic importance to the poultry industry, have advantages over traditional vaccines (Table 3). Examples include infectious bursal disease virus (IBDV), infectious bronchitis virus (IBV), infectious laryngotrachitis virus (ILTV), and avian metapneumovirus (aMPV).
IBDV, a birnavirus that infects chickens, is an important pathogen that causes severe immunosuppression and high mortality in young chickens. Live attenuated vaccines of moderate virulence (especially widely used intermediate plus vaccines) are used widely to prevent infectious bursal disease (IBD); however, they can cause severe side effects (symptoms consistent with IBD) in young chickens. Huang et al. developed a NDV-vectored IBDV vaccine (rLaSota/VP2) expressing the VP2 gene of IBDV, which is responsible for protective immunity against IBDV. The VP2 gene is inserted into the 3'-end non-coding region of the NDV genome. The live IBV vaccine is very safe in young chickens and protects SPF chickens against virulent NDV and virulent IBDV.
IBV, a coronavirus that infects birds, causes respiratory disease and renal disorders (the nephropathogenic strain) in poultry and poor egg production in laying hens worldwide. Currently available live attenuated IBV vaccines risk giving rise to new variants through recombination with field IBVs. This often reduces the efficacy of IBV vaccines. Importantly, live IBV vaccines interfere with the live attenuated NDV vaccine. To overcome the limitations of currently available live vaccines, Toro et al. developed a NDV-vectored IBV vaccine (rLS/IBV.S2) expressing the S2 subunit of the IBV S glycoprotein. Oculo-nasal immunization of chickens (1.0×107 EID50/dose) provided complete protection from clinical disease (mortality) after challenge with a lethal dose of virulent NDV (CA02). The protective efficacy of the rLS/IBV.S2 vaccine was also assessed using a heterotypic protection approach based on priming with a live attenuated IBV Mass-type vaccine followed by boosting with rLS/IBV.S2. The vaccine protected chickens against clinical disease after lethal challenge with a virulent Ark-type IBV strain, leading to a significant reduction in virus shedding when compared with that in unvaccinated/challenged chickens.
ILTV, a herpesvirus that infects birds, causes respiratory disease in chickens. Currently available live attenuated ILTV vaccines are effective, but there are concerns about safety in chickens because of the risks of virulence acquirement and latent infections during bird to bird transmission. Bivalent NDV-vectored vaccines against ILTV have been developed to overcome side effects associated with the live ILTV vaccine. Kanabagatte Basavarajappa et al. developed a NDV-vectored ILTV vaccine (rNDV gD) expressing glycoprotein D (gD) of ILTV. The protective efficacy of the rNDV gD vaccine against challenge with virulent ILTV and virulent NDV was then evaluated in SPF chickens. Immunizing chickens with rNDV gD (106 TCID50/dose) via the oro-nasal route induced a strong antibody response and provided a high level of protection against subsequent challenge with virulent ILTV and NDV, indicating that rNDV gD has potential as a bivalent vaccine.
Adeno-associated virus (AAV) is a parvovirus that is replication-deficient in humans. Like adenovirus, AAV has a broad cell, tissue and host tropism and therefore is a potential good vector vaccine.218 However, drawbacks of using AAV include: limited capacity for transgenes, presence of pre-existing immunity in humans and the technical challenge of producing high titer stocks. Initially, AAV was not explored as a vaccine vector as it was considered to be poorly immunogenic, however vaccination studies in mice showed that AAV-2 expressing an HSV-2 glycoprotein was immunogenic and a potent inducer of T-cell and antibody responses,219 and currently modifications are being made to AAV to increase immunogenicity.220
A limited number of studies evaluating AAV as a vector for influenza vaccination has been performed (Table 3). Initially, an AAV expressing the HA gene or NP gene was shown to be protective in mice.221,222 A more recent study tested AAV vaccines expressing the HA, NP or M1 genes of H1N1pdm09 in mice. Whereas AAV-HA afforded full protection from H1N1pdm09 infection, AAV-NP protected mice partially and AAV-M1 did not afford protection. Simultaneous vaccination with all 3 constructs afforded protection from homologous challenge infection.223 Recently, in an alternative vaccination approach, AAV was constructed to express a transgene encoding a influenza virus-specific broadly neutralizing antibody. AAV constructs expressing the broadly neutralizing antibody ‘F10’ protected mice from infection with 3 different A(H1N1) strains,224 whereas AAV expressing the broadly neutralizing antibody ‘FI6’ protected mice and ferrets from infection with various A(H5N1) and A(H1N1) viruses.225
Two independent reviewers screened titles and abstracts for their relevance. We included publications that mentioned norovirus in the title or abstract but we excluded papers about food (oyster) and waterborne outbreaks, food surveillance or food related experiments, and oyster/seafood surveillance. We excluded papers on murine noroviruses as models. Papers describing norovirus surveillance in wild mice and papers using mice as model for human norovirus were included (Figure 5).
In a second round, we screened the papers for whether they described (1) animal surveillance studies to detect human or animal norovirus by PCR, sequencing or by serosurveillance including negative results; (2) experimental animal infections with human or animal norovirus; (3) human surveillance studies to detect animal norovirus by PCR, sequencing or by serosurveillance including negative results; (4) animal norovirus characterization including molecular assays and genome announcements.
Clinical manifestations of AvRV infection include mild to severe diarrhea, a varied degree of dehydration, and stunted growth; it also may remain asymptomatic. These variations may be due to the differences in the severity of the particular strain or the interaction between different environmental and management factors. These manifestations alone are not sufficient for confirmatory diagnosis. Therefore, the identification of virus in fecal content or antibody detection in serum should be used to confirm the RV infection. To date, there is no assay for RVD antibody detection. The major methods used for diagnosis of RVs in poultry include:
Electron microscopy: The distinct wheel-like morphology of RV was initially used for detecting RV infection by direct visualization of the virus in feces or intestinal content. Using this technique, RVs of different groups cannot be distinguished. Immune electron microscopy can be used to distinguish serogroups, although it requires the availability of specific antisera. It is a sensitive diagnostic approach, but is also costly and cumbersome.
Virus isolation: AvRV can be isolated in embryonated chicken eggs (via yolk sac route), primary in cell culture (chicken embryo liver cells/chicken embryo kidney cells) or in continuous cell lines (MA104/Rhesus monkey kidney cell line). The isolation is useful only for AvRVAs, but it is not commonly used for diagnosis. It is very difficult to propagate other RV serogroups in cell cultures, and it has been reported that RVD cannot be propagated in MA104 cell culture systems.
RNA Polyacrylamide Gel Electrophoresis (RNA-PAGE): The detection of RV-RNA in feces or intestinal content provides an alternate means of diagnosis. Following RNA extraction, electrophoresis on polyacrylamide gels, and silver staining, RNA can be identified by the pattern of migration of genome segments. RNA-PAGE is a highly specific technique used for the detection of segmented viruses. It detects the electrophoretic migration pattern of all 11 segments of RV, which is different among different groups. According to the distribution of segments in each region, the AvRV-A has a pattern of 5:1:3:2, and the RV-D has a pattern of 5:2:2:2, while the mammalian RV-A shows a pattern of 4:2:3:2. AvRVs RVF and RVG, which shows sporadic shedding, have migration patterns of 4:1:2:2:2 and 4:2:2:2:1, respectively. However, these patterns can’t be totally relied upon, because substantial differences are observed in the electrophoretic pattern of RVs when conditions of gel electrophoresis are varied.
Reverse Transcription-Polymerase Chain Reaction (RT-PCR): This is the most sensitive molecular detection tool available for the diagnosis of RVs, and is mainly based on the VP6 gene segment. For the detection of AvRVs, only a few RT-PCR protocols are available, and most of them solely detect AvRV-A. In 2011, an RT-PCR was developed by Bezerra and co-workers specifically for the detection of the VP6 gene of RVD. Real-time PCR and RT-PCR are now available for the detection of RVD. The sensitivity of real-time RT-PCR was found to be similar to that of conventional RT-PCR when the same primer sets were used for both of the assays.
Serological methods: Serological methods used for the detection of RVs include counter immunoelectrophoresis, radioimmunoassay (RIA), the latex agglutination test (LAT), and enzyme-linked immunosorbent assay (ELISA). AvRVs can be detected using ELISA. Commercialized ELISA kits are available for detection of RVAs, such as the IDEIA RV assay (DAKO, Ely, UK), the RIDASCREEN® assay (r-biopharm, Darmstadt, Germany), etc. However, for the detection of other AvRVs such as RVD, RVF, or RVG, no ELISA is available.
Six day old SPF chickens were infected intra-tracheally with either M41 (n = 5) or Conn A5968 (n = 5) strains of IBV at the dose rate of 2.75 x 104 EID50/bird, 4 birds were treated with PBS as uninfected controls. Upon infection, the experimental chickens were monitored for development of specific and non-specific clinical signs such as huddling under the lamp, ruffled feathers, droopy wings and increased respiratory rates. At 4 dpi, trachea and lung samples were collected into Optimum Cutting Media (OCT) (VWR, Mississauga, Ontario, Canada) for preservation in -80°C with a view of using for staining of macrophages and IBV antigens. In addition, samples of trachea and lungs were fixed in 10% formalin for histological examination. The establishment of IBV infection in the infected animals was confirmed by IBV antigen detection using immunofluorescent technique along with characteristic histological changes in the trachea and lungs.
Influenza A virus has a wide range of hosts. Often the susceptibility of the species is dependent upon the characteristics of the virus and host. Numerous subtypes of influenza A viruses, including influenza A pandemic H1N1 2009 virus, have been shown to cross-species transmission. Since 2009, a novel influenza A virus (H1N1), now called A (H1N1) pdm09 influenza virus, has caused human influenza outbreaks in North America and a worldwide pandemic. To date, it has not only infected human, but also been reported interspecies transmission from humans to other animals, such as pigs, poultry, dogs.
Recently, the reports have shown that cats can also infected A (H1N1) pdm09 influenza virus. Due to frequent cohabitation and close contacts with humans and other animals, cats are uniquely positioned to serve as reservoirs for influenza virus infection both within a household and within the larger farm or rural environment in China. However, prevalence of A (H1N1) pdm09 influenza virus infection in cats in northeastern China is unknown. Therefore, the prevalence of A (H1N1) pdm09 influenza virus infections was performed among cats in northeastern China in this study.
A total of 1140 feline blood samples were collected from 56 different pet hospitals and four small animal shelters around northeastern China, from February 2012 to March 2013. The geographical and prevalent distribution of the samples has been concerned. Haerbin, Changchun and Shenyang were selected since they are the most densely populated area of commerce in northeastern China. Dalian was also included as it is the trade zone with large-scale breeding of poultry and pigs in northeastern China. The geographical location of serum samples of collection in northeastern China was displayed, please see the Figure 1. 660 blood samples from pet cats in hospitals and 480 blood samples from roaming cats were obtained. In each city, we selected the single largest small shelter. These serum samples were septed by centrifugation at 3,000 rpm for 15 min, and supernatants were transferred to a new eppendorf tubes and stored at-20°C until tested for antibodies against influenza A virus. Additionally, in order to have a timely data for pandemic (H1N1) 2009 prevalence in northeastern China, 115 blood samples were retrospectively analyzed from pet dogs and pet cats in Harbin in 2008. All samples were tested by hemagglutination inhibition (HI) and Neutralization (NT) assay, according to the recommended procedures as previously reported. HI titer ≥ 40 and NT titer ≥ 40 are considered as positive and indicate previous infection. Influenza virus used in this study was A/California/7/2009(H1N1pdm09) [pandemic (H1N1) 2009 virus]. We additionally studied the sera for HI antibodies against three other viruses: a human seasonal H1N1 influenza virus A/Brisbane/59/2007(H1N1) and A/canine/Guangdong/2/2011(H3N2), a recently circulating H3N2 canine influenza virus (CIV) in dogs in China. The comparison of categorical variables between cat samples was performed with chi-square test where appropriate. Statistical significance was defined as p < 0.05. The data was analyzed with SAS software, version 9.1.
A total of 1255 serum samples were examined by NT and HI for pandemic (H1N1) 2009 antibodies. The serological screening revealed 21% pandemic (H1N1) 2009 infection in cats in northeastern China based on NT. It also showed a higher prevalence rate of pandemic (H1N1) 2009 infection in pet cats (30.6%) than roaming cats (11%) based on NT (p = 0.0032, Table 1). The results from HI also showed a trend of difference in term of species of cats and it was statistically significant (P = 0.002). The prevalence of the infection also showed a geographical difference in roaming cats as prevalent in Harbin and Changchun (20.8% and 23.3%) and absent in Shenyang and Dalian (Table 1). In addition, the factors of the gender and age of the cats were also analyzed as contributors to pandemic (H1N1) 2009 prevalence. In the Table 2, while no influence of age (seropositive data not shown) was found on cats infection with pandemic (H1N1) 2009, genders associated with the pandemic (H1N1) 2009 seropositivity by both HI and NT assay was significantly (p < 0.05). In addition, a total of 115 serum samples collected in 2008 had no HI or NT antibodies against A/California/7/2009 (data not shown). To rule out non-specific cross-reactivity, 1140 serum samples were titrated against seasonal influenza viruses (H1N1). Only twenty-four samples had a HI titer of 1:40 against H1N1 (Table 3). Only ten of these forty seasonal influenza positive-samples were also HI and NT positive for A/California/7/2009(H1N1pdm09). A total of 111 (9.7%) sera were positive by HI assay against H3N2 CIV (Table 3).
Few seroprevalence studies on pandemic (H1N1) 2009 infections have been attempted in cats worldwide. The prevalence of this virus infection in cats in mainland China remains unknown. This is the first survey on the seroprevalence of pandemic (H1N1) 2009 infection in cats in northeastern China. Of all sera from cats in this study, 21% was identified as pandemic (H1N1) 2009 positive. In another conducting the seroprevalence of antibodies against (H1N1) pdm09 among cats in small cities of southern China was only 1.2% in 2011. Our increased antibody prevalence might be explained a number of ways. Perhaps cats were at a higher probability of infection in northeastern China, due to they exposures in dense populations of humans with high influenza A (H1N1) pdm09 attack rates. The difference might also be explained by the one year temporal difference between cats sampled in southern China in that the northeastern China cats had 1 more years to acquire influenza A (H1N1) pdm09 virus infection. Additionally, the prevalence of seropositive pandemic (H1N1) 2009 in male cats versus female cats suggests that the male cats may be more susceptible (P < 0.05) to the pandemic (H1N1) 2009 infections (Table 2). We hypothesize that relatively high A (H1N1) pdm09 transmission may have occurred between humans and cats during the period of virus infection in the human population. This hypothesis is supported by our observation that pet cats were more likely to have evidence of previous infection with A (H1N1) pdm09 that were roaming cats (30.6% vs11%, P = 0.0032) and also suggests a likely transmission between infected owners and their pets by close contact. Serological evidence of A (H1N1) pdm09 in domestic cats has been reported in the past. In a sero-survey conducted in Italy in 2009, a contrary low prevalence had been observed among dogs, while no cats were reported to have antibodies against A(H1N1)pdm09 in the screen. A similar high prevalence of 21.8% and 22.5% were recorded in a population of cats in the United States, but the study sample comprised animals with a history of respiratory disease. We hypothesized the sustained transmission of the influenza A (H1N1) pdm09 virus in the human population in our study area. In addition, it should be noted that 240 samples from the two small animal shelters in Harbin and Changchun had exposure to pandemic (H1N1) 2009 before sample collection. The higher prevalence of seropositive pandemic A (H1N1) pmd09 among Harbin and Changchun cats versus Shenyang and Dalian is unexplained.
Since cats may be exposed to different influenza virus subtypes, including human-avian and avian-origin influenza viruses, their potential role in the epidemiology of influenza virus should be further investigated. In summary, this study has observed a relatively high seroprevalence of pandemic (H1N1) 2009 in cats in northeastern China, similar seroprevalence studies should be conducted elsewhere. The studies showed that the prevalence for A (H1N1) pdm09 in human was correlated with age and population density. Preexisting antibody may have protected the very old from A (H1N1) pdm09 infection, while original antigenic sin and immunosenescence may have contributed to greater severity once infected. Compare with all serum samples collected in 2008 had no HI and NT antibodies against A/California/7/2009, these results reflect the pandemic (H1N1) 2009 had been spread in cats. Concerns of rapid spread in small animal shelters and household may be needed. These observations highlight the need for monitoring cats in pet hospitals and small animal shelters are necessary for us to understand what roles cats plan in the ecology of influenza A virus.
Another treatment option is the use of anti-viral medications. The two main classes of antivirals available at present are the neuraminidase inhibitors and the adamantanes. There has been an emergence of resistance to adamantanes for seasonal influenza leading many to reconsider them as agents in the treatment of pandemic avian influenza. In preliminary studies using oseltamivir or zanamivir, patients showed a reduction in the duration of symptoms ranging from 1–2 days. Whether a 1–2 day reduction in symptoms will translate into reduced absenteeism, cost-savings and disease transmission is unknown. Additionally, the cost-benefit of stockpiling anti-virals for treatment of pandemic influenza remains unknown. As noted previously, oseltamivir has also demonstrated resistance. Adding to the complexity of managing H5N1 treatment, is once again the manner in which one decides who receives the medication and the fact that the modest reduction in influenza symptoms will depend on timing of administration of the drug. In individuals with confirmed H5N1 influenza that were treated with oseltamivir, mortality was still close to 80%. It has also been noted by Tambyah, that despite guidelines from the World Health Organization concerning the use of anti-virals in pandemic avian influenza, there remains little 'level 1' clinical evidence to support such guidelines. More recently, a group in Singapore has gathered a set of practical guidelines for clinicians encountering H5N1 avian influenza in humans. Despite the lack of scientific evidence for their effectiveness in a pandemic situation, governments and many employers are stockpiling anti-virals to be used not only as therapy for ill individuals, but also as prophylaxis for critical staff. This may be driven by the recognition that once the pandemic is recognized, it will be nearly impossible to purchase these products. It reflects a significant investment: at approximately $3/pill, an eight week course would cost over $200 per employee. A company of 1000 employees would need to invest $200,000 on a product which they hope they will never use, is unproven, and has a limited shelf life. Again, one is faced with decisions regarding dispensing medication – to all workers, critical workers, families?
Enteric infections are one of the principal causes of diarrhea, which results in poor feed conversion efficiency and reduced growth, and hence leads to heavy economic losses for the poultry industry. These infections are caused by different agents, including viruses (rotavirus, coronavirus, astrovirus, reovirus, adenovirus, parvovirus etc.), bacteria (Salmonella, Enterococcus, E. coli) and protozoans (Cryptosporidium and Eimeria). The clinical manifestations of these pathogens are almost similar. Hence, RVD must be differentiated from all of these enteric pathogens, as well as from the other groups of rotaviruses found in poultry.
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.
Vaccination strategies, such as the annual influenza vaccine programs, have been the traditional first line of defense against viral infections. Research is currently being devoted to the development of vaccines as a possible intervention for pandemic influenza. The need for a rapidly deliverable vaccine for pandemic influenza has become more urgent since de Jong et al. reported the emergence of oseltamivir resistance to H5N1. Given the current 4 to 6 month development time, it is unlikely that a vaccination will be available during the first wave of a pandemic. The impact of antigenic drift on vaccination for influenza is an on ongoing challenge and is the reason vaccination for seasonal influenza must be administered annually to protect against the new antigenic strain. Increased demand for vaccine during a pandemic influenza may be tempered by the supply. Specifically, the substrate used for vaccine manufacturing for all major suppliers worldwide is chicken eggs. During a pandemic several times the current supply of eggs would be required. What is even more challenging is that H5N1, which is the current predicted pandemic strain, is lethal in eggs and is also a biosafety level 3 pathogen which decreases the potential of scaling up the manufacture of vaccine for international deployment. One must also consider that poultry workers may be at increased risk of exposure to pandemic influenza zoonotically or may also be stretched from a human resource perspective when measures need to be taken to curb a poultry influenza outbreak. Acambis Labs, and others, are working on the development of a universal influenza vaccination that is based on more stable surface proteins such as M2e, which is found on the surface of all influenza A strains.
The first vaccine approved by the US food and Drug Administration for pandemic influenza is a reverse genetics vaccine and demonstrated low immunogenicity except for high doses with an adjuvant. When this was approved by the FDA it was noted that the vaccine would not be marketed to the general public but rather stockpiled by governments. It has previously been suggested that an appropriate vaccine will likely not be determined until the initial phase of a pandemic. Furthermore, once a vaccine is developed a mechanism needs to be put in place that can provide an adequate supply at an affordable cost globally in lock step with the progression of the pandemic.
A unique challenge for the occupational medicine physician in the event of a pandemic outbreak is to determine who gets priority for receiving vaccination. Maintenance of essential services will be central to the continuity of a functioning society. Health care workers and workers in critical occupations will be a priority for vaccination programs, once available. Decisions on vaccination programs are complicated by the eventual timing of the disease wave, number of employees, nature of the work environment, and the availability of vaccine. For example, should employees who are in close proximity to one another be given priority or only those critical to maintaining business continuity? The Public Health Agency of Canada has created priority lists for receipt of vaccinations. Not surprisingly health care workers are part of group 1, followed by key societal decision makers and critical protection and utility workers (police, fire fighters, sewage workers, public transportation and communications).
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.
While few epidemiologic studies alone provide convincing evidence of an animal microbial basis for cancer, the data nevertheless are suggestive of a possible effect when examined as a whole. Perhaps the excess risk observed for some cancers, but not necessarily the same cancers across studies, may reflect a random cancer susceptibility to infection and inflammation rather than a specific microbe-cancer relationship. By analogy, animal viruses and bacteria may represent a chambermaid’s master key, capable of opening all hotel doors, but only if left unlocked by the guests.
FRZ and HYC designed the experiments. XY, DHZ carried out the test. PW,CGL and FRZ drafted the manuscript. All authors have read and approved the final manuscript.
We used chi-square tests to determine the between-site effects and the effect of bird group on the proportion of positive individuals. A value of P<0.001 was considered statistically significant.
In a medical record-based study of 83 cases and 166 referents individually matched on date of birth, sex, and hospital of birth, children of mothers who had documented evidence of a clinically diagnosed viral infection during pregnancy had an 11-fold odds ratio (OR) [confidence interval (CI) = 1.1–503.2] for childhood neoplasm of the brain compared with unexposed mothers (112). However, none of the noted viral infections (mumps, varicella, herpes zoster, and rubella) were related to animal exposure. Similarly, a 2.4-fold OR (CI = 1.5–4.0, 25 cases) for childhood brain tumors (CBT) was observed in a nested (within Swedish birth-cohorts 1973–1989) case-referent (545 cases, 2798 referents) study of children born to mothers who reported a wide variety of neonatal viral and bacterial infections during the pregnancy of the index child (113). Significantly increased risk estimates were specifically observed for CBT subtypes “low-grade astrocytoma” (OR = 2.7, CI = 1.2–5.8) and “high-grade astrocytoma” (OR = 5.0, CI = 1.0–24.8). Neonatal urinary tract infections were associated with a 7.5-fold OR (CI = 1.3–44.9) for low-grade astrocytoma. This is in contrast to other case-referent studies examining vaginal and genitourinary infections during pregnancy, which did not observe a statistically significant increased OR for CBT (106, 112, 114).