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In comparison to non-viral infected individuals, viral-infected SARI ones had significantly lower rates of pneumonia (p=0.004) and admission to the ICU (p=0.000). Patients with influenza virus tended to have significantly different rates of admission to the ICU (p=0.045), and mechanical ventilation (p=0.001), in comparison to those with non-influenza infections. With regards to complications, viral-infected SARI patients had significant differences for developing respiratory failure (p=0.033), and acute respiratory distress syndrome; ARDS (p=0.011), in comparison to those without viral infections.
Overall mortality in SARI-positive patients was 24/1,075 (2.2%) and peaked at 1% in 2014. Overall, only 2(8%) were adults, while 22 (92%) were children. Among children, 18(75%) were aged <5 years. Overall, two-thirds (16/24) had comorbidities. All patients who died were admitted to the ICU and mechanically ventilated. Notably, all patients who died tested positive for a viral pathogen; twelve were positive for RSV, four for influenza virus, two for adenovirus, one for hMPV, one for PIV and four for mixed viral infections, respectively. Among those who died, there was a significant difference between those with (2.2%) and without (5%) viral detection (p = 0.005). Among individual viral pathogens, SARI patients with RSV and influenza had significant deaths (p= 0.045 and 0.006), in comparison to those with non-RSV and non-influenza viral infections. No mortality was reported for patients with atypical bacteria (Table 1).
To the best of our knowledge, this is the largest surveillance Egyptian study that addressed the epidemiological patterns of SARI due to viruses and atypical bacteria in both children and adult population and their relation to the clinical characteristics and outcomes of those patients.
The worldwide distribution of viral etiology as a cause of SARI varies between 2% and up to 78% [7, 11, 13, 14]. In this study, we found a viral etiology in 33.5 % of hospitalized patients with SARI, which is comparable to previous studies conducted in either developing or Middle Eastern countries [9–11, 13]. The finding that two-thirds of SARI cases had no pathogen detected suggests that poor or late specimen collection may have contributed to a lower yield of detected viruses. Interestingly, children <18 years represented the majority (91.2%) of our cohort. Notably, this contradicts findings observed by other studies [14, 15]. In their surveillance for SARI in Northern Vietnam, Nguyen et al observed that 22.7% of their cohort were children <18 years, while 77.3% were adults >18 years. Again, children <5 years represented 83% of our cases. This is in accordance with those surveillance data from Southern Arizona, 82%, lower than those from China (94% in <72 months) and higher than in Kenya,71%.
The highest rates of viral infections were reported for RSV (45.2%), PIV (11.6%), and adenovirus (9.8%), with a relatively low rate (7.2%) for influenza viruses. Not unexpected, RSV was the most predominant respiratory virus with a prevalence of 45%; emphasizing its role as the major cause of SARI in infants and young children worldwide [7, 8, 13–17]. Notably, the proportion of SARI cases positive for RSV in children <5 years in our surveillance (90%) was markedly higher than those reported in surveillance data from Kenya, 21%, Southern Arizona, 31%, and even higher than previous studies in Egypt.
We observed that, SARI cases <5 years were significantly more likely than older patients to be infected with each of the pathogens examined, particularly for RSV and influenza. As the majority of enrolled patients were children (83%), this is not unexpected since these pathogens have a strong association with this age group. This is inconsistent with data that nearly 80% of children are exposed to RSV by age two, 100% to hMPV by age five and 90% to hPIV by age five. Furthermore, hPIV is a significant etiology of LRTI in children, second only to RSV, and adenoviruses are the second most common viral pathogen in children under two years of age.
Notably, our results showed a very minor role for atypical bacteria in causing SARI in our locality. Only 3 cases were positive for Mycoplasma (co-infected with RSV), while only one case of Chlamydia was co-infected with RSV and hMPV. Clinical presentations differed significantly between those with non-viral infected individuals and viral-infected SARI ones. The later had significant viral prodromal symptoms, as well as tachypnea, wheezes, and convulsions. Furthermore, SARI patients with influenza had significant tachypnea, wheezes, and abnormal breath sounds, than those with non-influenza viral infections. The presence of these signs at presentation could help the clinician predicting the likely pathogen causing SARI.
Fifty-three percent of our patients had medical comorbidities, with the predominance of chronic lung diseases (43%). The impacts of medical comorbidities on patients with SARI were addressed in previous surveillance studies [9, 13, 14]. Despite that 83% of our cohort were children less than 5 years, and patients with comorbidities were significantly older compared to those with no comorbidities, patients with and without viral detection differed significantly in the frequencies of chronic respiratory, as well as endocrine, hepatic and neuromuscular disorders.
Comparing the clinical course, complications, and outcomes between viral-infected cases and non-viral detected controls showed interesting results. Patients with identified viruses had significantly lower rates for ICU admission, hospital stay, length of mechanical ventilation, and overall mortality than those without identified viruses. However, there were no differences with regards to ARDS and mechanical ventilation.
Previous studies showed conflicting results on the impacts of viral infections on clinical outcomes in patients with SARI [9, 13, 14, 19, 22, 23]. Differences in patients’ numbers, enrollment criteria, and methodologies could explain these results. Although PCR has been established as a reliable diagnostic assay with high sensitivity and specificity for respiratory viruses, particularly for RSV, the clinical implications of positive laboratory results are still less clear.
Patients with positive viral detection had better clinical outcomes than those with no viral detection, in terms of pneumonia, ICU admission, and overall mortality. Furthermore, compared to patients with no virus identified, patients with RSV-positive infection were significantly less likely to have pneumonia, to be admitted to the ICU, mechanically ventilated, and had less mortality.
Interestingly, analyses to assess associations with severe outcomes in the current study revealed that no infections were independently associated with those outcomes, even after controlling for age and associated medical comorbidities. Despite the predominance of RSV infections among SARI-positive cases (45%), there was strong evidence that individuals with RSV and influenza were less likely to experience a severe outcome than those not infected with each of these pathogens. Furthermore, individuals with multiple infections were no more likely than those with infection with a single pathogen to experience severe outcomes.
Multivariate logistic regression analysis confirmed that individuals with positive results for rhinovirus and adults >18 years were more likely to experience a severe outcome than those not infected with rhinovirus and children <18 years, respectively. However, because of the low prevalence of rhinovirus (2%) and adults (8.8%) in this study, further larger studies are needed to confirm these associations.
Being the most commonly detected virus among our cohort, there was an interest to examine the RSV-positive cases. Interestingly, while patients with RSV-positive infections had significant differences with those with no respiratory viruses identified with regards to clinical signs and symptoms, comorbidities, and outcomes; they had no differences with those tested positive for other viral pathogens with regards to the same parameters.
However, individuals with RSV and associated medical comorbidities were more likely to experience severe outcomes than those with RSV and no comorbidities, after controlling for age and other risk factors.
Again, review of the literature had shown conflicting results for clinical implications of RSV infection [9, 23–28]. While the relationship between RSV infection and clinical disease has been established, as infections among asymptomatic individuals are rare [9, 24–27], no relationship between viral load and disease severity was identified by others [23, 28, 29]. For non-influenza viruses, the clinical features are still unclear. Adenovirus infection levels in asymptomatic children and adults varied [27, 30], though this may be attributable to differences in sampling methodology since throat swabs may detect latent AdV DNA in tonsil tissue. Studies suggest that asymptomatic infection with hMPV is rare among children, but results from adult populations are less conclusive, with reports of varying levels of infection among asymptomatic individuals [25, 32].
Furthermore, the clinical implications of positive laboratory results are further complicated by the presence of co-infections. Multiple viral respiratory pathogens were identified in 16.7% of our cases. Co-infection with 2 or more viral respiratory pathogens has been encountered in previous reports among pediatric populations in the Middle East [13, 18, 33, 34]. Multiple infections complicate diagnosis, as the relative clinical impact of each pathogen is unclear, and certain pathogens, such as adenovirus, are routinely found in the upper airways.
This study has many points of strength; it was the first surveillance that addresses the clinical impacts and epidemiological patterns of viral and atypical bacteria causing SARI in both children and adult Egyptian population, with enrolled large numbers of patients and over a relatively long period. Furthermore, analyses of homogenous populations, rather than different ethnic groups, give the results reliable and strong support. On the other hand, it has some limitations; more time may be needed for properly evaluating the role of atypical bacteria, and the flu vaccine was not used.
Human exposure may occur in many ways – preparing and consuming animal products, washing with, and drinking well water contaminated with animal fecal coliform, animal bites/scratches, and working in occupations involving regular contact with animals, manure, soil, and/or by-products (e.g., farmers, slaughtering plant workers). Even living down-wind of a farm field fertilized with animal manure poses a potential risk. A list of major sources and exposure routes of animal-to-people transmission of viruses and bacteria is shown in Figure 2. Factors influencing the probability of disease transmission involve the proximity and temporal contact with the infectious organism, length of time that the infectious agent is present, virulence of the agent, incubation period, stability of the agent under varying environmental conditions, population density of carrier animals, husbandry practices, and control of wild rodents and insects (31). The type and maintenance of animal housing also may affect the extent to which individuals working in or around such facilities are exposure to zoonotic viruses and bacteria. Often, animal containment structures (e.g., hen houses, pig pens, cattle barns, and horse stables) may be inadequately ventilated and/or have poor waste removal systems, increasing the exposure of animals and their caretakers to dust, fecal matter, and microbes (32).
Infectious agents may be transmitted to humans by direct contact, fomite or mechanical vector, or intermediate hosts in which the agent multiples or develops before transmission to animal or human (i.e., metazoonoses). Examples of infectious agents requiring an incubation period prior to transmission include arboviruses, plague, and schistosomiasis (31). In the case of toxoplasmosis infection, contaminated soil and water represent a key source of infection emanating from an intermediate host (33, 34). Indoor/outdoor cats are a significant carrier/transmitter of Toxoplasma, shedding the organism in its feces (34). Oocysts from Toxoplasma gondii also may be transported by cockroaches and other bugs and deposited onto food and later consumed by animals and humans (35). In a recent study, eating raw oysters, clams, or mussels was identified as a new risk factor for T. gondii infection (36). The T. gondii were believed to have originated from cat feces, which survived or bypassed sewage treatment and traveled to coastal waters through river systems.
All respiratory samples positive for coronavirus by real-time RT-PCR were screened for other respiratory viruses. Among the real-time RT-PCR CoV positive samples, 13% were also positive for Respiratory Syncytial Virus, Parainfluenza 2 and 3, and Rhinovirus (Data not shown). Among the patients harboring respiratory CoVs, detected by qRT-PCR and confirmed by RT-PCR, six (17%) were co-infected with a second respiratory virus.
In the Figure 2, the seasonality of the mainly respiratory pathogens found in each defined clinical group was represented. The HMPV circulated from February to July with a peak in April/May 2010 corresponding to the end of the hot and rainy season. This season is correlated to the highest number of CAP cases (group I). The end of the cool and dry season was correlated to the peak of the other ALRIs cases (group II), where we observed the HPIV and HCoV co-circulation (data not shown). RSV A/B infection shows a significant seasonal variation with a peak in the month of February 2011, during the hot and rainy season correlating with Flu-like illnesses cases (group III) and Influenza virus infection peaks (data not shown). The beginning of the cool and dry season represents the seasonality where we found the largest number of cases in each defined clinical group, except for the group III. Finally, HRV (data not shown) and HAdV circulated throughout the year without any epidemic peak.
This study describes for the first time the etiology of a clinically defined cohort of children with fever and acute respiratory infections living in a malaria endemic rural region of Madagascar. The rural community of Ampasimanjeva consists of seven villages located in south-eastern Madagascar (coordinates 21° 44 ′0 “South/48° 2′ 0” East) dominated by an equatorial climate with high humidity. Recently, 1,549 children under 5 years of age were referenced and among them, 937 presented a fever and were examined at the hospital during the study period. Of these children, 295 presented ARIs clinical signs and a negative test for malaria. To better understand the role of the viral and atypical bacteria agents in nasopharyngeal swabs, we stratified the respiratory clinical symptoms into 4 major groups to obtain defined ARIs cohorts. Seventy five percent (n = 220) of the acute febrile children had a nasopharyngeal sample containing at least one virus or atypical bacterial agent. The low rate of negative specimens shows that the technique used in this study is highly sensitive and the spectrum of pathogens is large, covering most of those implicated in the ARIs. In this study, the frequently encountered pathogens were the HRV, HMPV A/B, HCoV, RSV A/B and HPIV. The most representative pathogens into the defined clinical groups were HMPV, HPIV, HRSV and HAdV for pneumonia, other ALRIs, Flu-like illnesses and URTI, respectively. The human rhinovirus, HMPV A/B and RSV A/B were single detected while HCoV, HPIV and HBoV were most often co-detected. Human rhinovirus was found largely in all clinical manifestations.
HRV has long been considered to be a benign virus causing mild upper respiratory tract infections, but there is evidence that HRV is also involved in ALRIs more specifically in bronchiolitis, but its role is not yet well defined in pneumonia,. HRV is frequently found as asymptomatic carriage,,, a comprehensive study on genotypes from HRV-positive samples would be interesting. As, it seems that the new and potentially more pathogenic HRV-C which has been recently discovered, is correlated with the severity of ARIs,.
Our molecular results showed a large number of respiratory pathogens associated with the different clinical manifestations including a large part in pneumonia. Viral pneumonia is also increasingly described in the literature but it is nevertheless still underestimated,. In children, RSV, HRV and HMPV have become important pathogens most frequently encountered in children with pneumonia in developed countries–. In Ampasimanjeva, although detected in all ARIs clinical manifestations, the human metapneumovirus was better associated with community-acquired pneumonia with a higher prevalence than those described in the literature,,. HMPV is, however, considered to have an important role in pneumonia increasing child morbidity worldwide,. In a study done in Antananarivo (2008/2009), RSV A/B was mainly represented among children with Influenza-Like Illnesses and similarly, our results showed that this virus was primarily associated with group II which we defined here as Influenza-like syndrome.
Atypical bacteria pathogens were also investigated. We detected a low rate of M. pneumoniae (1.7%) and C. pneumoniae (0.7%) distributed in all four clinical groups. Our results correlate to those described in several studies, which show that atypical bacteria prevalence in acute respiratory infections may vary depending on the age of children,–.
Our study has several limitations. Firstly, we did not investigate the viral and atypical respiratory pathogens in control population as asymptomatic carriers. This could limit our interpretation to ascribe the etiological agents to the defined clinical groups. However, some of the potential etiological agents described here are rarely identified or less common in asymptomatic patients, except for rhinoviruses,,. A longitudinal case/control study would be interesting to validate the relevance of these agents in acute respiratory infections despite the difficulty to obtain approval requirements from ethical committee. Our results highlight a significant proportion of viruses among children with ARIs. However, the viral etiology of an infection does not exclude the coexistence of a bacterial infection nor superinfection, often observed, for example, with pneumococci following influenza virus infection. The bacterial etiology could not be evaluated in this study but remains important enough to be investigated further. Using information gathered from clinical records, it appears that 87.5% of children received antibiotics as a result of auscultation. If only viruses are actually mostly the cause of ALRIs in Ampasimanjeva, simple recommendations such as those proposed by WHO and UNICEF could reduce the morbidity and mortality. Secondly, we did not evaluate the proportion of respiratory pathogens among children with malaria (n = 21). In the absence of appropriate diagnostic tools in low income countries, integrated management of childhood illnesses (IMCI) at health facilities is presumptive and symptom-based: fever for malaria, and fever/cough/difficult breathing for pneumonia. These overlapping symptoms, compatible both with malaria and pneumonia, necessitating dual treatment, need to be evaluated in further studies. Unexplained acute febrile illness is the only common factor in children living in endemic malaria region. In this study, we showed that the fever cannot be considered alone to guide clinical diagnosis. Moreover, respiratory pathogens do not seem to be related to fever prognosis except for Influenza viruses. Finally, the interpretation of the fever may be biased by the use of antipyretic treatment, and 24.1% of our patients had evidence of antipyretic use before study enrollment. Finally, this study was conducted over one year, covering both hot/rainy and cold/dry seasons, to get a preliminary description of respiratory pathogens and respiratory pathogens spread during this period. This short time period should be prolonged to deepen our knowledge about these pathogens and perhaps anticipate epidemics in light of improving the health care of children.
In conclusion, the use of molecular assays has allowed us to refine our understanding of the viral etiologies of ARIs among children living in a rural area of Madagascar. Further studies are needed to properly distinguish between infection and colonization. They will lead to comparing findings in different respiratory samples and reference standards. Viruses seem to be commonly involved in pneumonia. While some viruses such as HRV are mainly represented in all clinical presentations, some such as hMPV and RSV are most often associated with pneumonia or influenza-like illnesses. A better understanding of the biodiversity of each pathogen correlated to well-defined clinical ARIs manifestations could be explored.
Acute respiratory viruses cause substantial morbidity and mortality worldwide. Most respiratory viral infections induce self-limiting disease. However, the disease range can vary from common cold, croup, and bronchiolitis to pneumonia, with an array of possible etiological agents, such as parainfluenza, influenza, RSV, adenovirus, rhinovirus, bocavirus, human metapneumovirus and coronavirus. Coronaviruses (CoV) are responsible for a broad spectrum of diseases, including respiratory and enteric illnesses, in humans and animals. Human coronaviruses (HCoV) were identified as the cause of acute respiratory tract disease in the early 1960’s, but their correlation with mild respiratory tract infection outweighed the importance of severe forms of the infection. The emergence of SARS-CoV in humans in 2003 increased scientific interest in CoVs and emphasized the ability of highly pathogenic CoVs, most importantly those of animal origin, to infect humans. Consequently the importance of monitoring circulating coronavirus strains in humans has been reemphasized with the emergence of SARS and Middle East Respiratory Syndrome (MERS) CoV in humans.
The family Coronaviridae was recently subdivided into four genera according to their antigenic and genetic characteristics: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus (http://ictvonline.org/virusTaxonomy.asp?version=2012). Alphacoronavirus (HCoV-229E and HCoV-NL63) and Betacoronavirus (HCoV-OC43, SARS-CoV, HCoV-HKU1 and HCoV-MERS) infect a wide range of mammals [4,7–11], whereas members of the genus Gammacoronavirus and Deltacoronavirus usually infect birds, although a Gammacoronavirus was isolated from a Beluga whale. Feline CoV, an Alphacoronavirus, infects wild and domestic cats causing mild enteritis. However, a lethal systemic disease known as feline infectious peritonitis (FIP) is also associated with FCoV. Feline CoV is closely related to CCoV, TGEV and human coronavirus HCV-229E, especially the Feline aminopeptidase N, which can be used as a functional receptor by these viruses.
The CoVs have a positive-sense, single-stranded RNA genome of 27–32 Kb. Nine to fourteen open reading frames (ORF) have been identified in the CoV genome. ORF1a and ORF1b encode the highly conserved replicase complex. Most RT-PCR assays described in the literature to screen for CoV target the ORF1b region. CoVs show a high frequency of nucleotide mutation and RNA recombination through copy-choice mechanism which, associated with broad receptor and co-receptor usage allow the virus to increase pathogenicity and possibly shift its host range.
Before the SARS-CoV outbreak, only two HCoV respiratory strains, HCoV-229E and HCoV-OC43, had been described. Due to the increased interest highlighted by the SARS outbreak, three new strains were described afterwards; HCoV-NL63, HCoV-HKU1 and HCoV-MERS. This study aimed to investigate the circulation of human respiratory CoV and to determine the genetic variability of HCoV in Arkansas.
A total of 420 oropharyngeal swabs were enrolled from 10 hospitals and 10 CDCs in Guangzhou from 2017 to 2018. Samples were collected from a wide range of ages, with the average age of 27.2 (Table 1). About 55% specimens were from male.
A pathogen‐positive result was determined when the pathogen‐specific fragment(s) was positive, as shown in Figure 1. A negative result was determined when none of the 13 pathogen‐specific fragment was positive, while the controls (huDNA, huRNA, and IC) were positive (Figure 2). In this study, the ResP detected positive results in 141 samples, accounting for 33.6%, while the comparator tests detected positive results in 127 samples, with positive rate 30.2%. Among the detected pathogens, rhinovirus was the most common, followed by adenovirus and influenza virus A pdmH1N1 (2009) (Table 2). Of the 420 specimens, the ResP yielded consistent positive results in 121 specimens (86.5%, 121/141), and consistent negative results in 273 specimens (97.8%, 273/279) comparing with pathogen‐specific PCRs, leading to an overall agreement of 93.8%.
No specimen was detected positive with coronavirus or Chlamydia. In six of the ten detected pathogens, the Cohen's kappa values were over 0.8 with P value <.01 (Table 2). The lowest kappa (0.70) was observed on human metapneumovirus.
Multiplex PCR‐based NAATs have been increasingly used for syndromic diagnosis, due to their high throughput, high sensitivity, high specificity, cost‐effectiveness, and great clinical significance.10, 11, 12 The ResP assay is based on multiplex PCR amplification and capillary electrophoretic separation of PCR amplicons by length. This technique has been used for pathogen detection and subtype classification of pediatric acute lymphoblastic leukemia.13, 14 By comparing the results with a standard size marker of targeted pathogens, pathogens in samples can be separated and identified as expected.15 The subtypes of most viruses were not designed to be further distinguished by this assay, except for influenza virus A. The influenza virus A pdmH1N1 (2009) and H3N2 are the two subtypes which are most popular in China recently. Therefore, a patient whose specimen is positive for influenza virus A but negative for influenza virus A pdmH1N1 (2009) or H3N2 is probably infected by an uncommon influenza virus A, such as H7N9, H5N1, H5N6 avian influenza virus A16, 17, 18 and has to be immediately quarantined once it is confirmed. It should be noted that hospitals, not CDCs, are the first to reach such patients, so this assay helps hospitals identifying such high‐risk patients and make appropriate quarantine measurement in a timely manner to control further spread of avian influenza A virus.
This assay has previously been clinically applied to detection of respiratory pathogens in hospitalized children suffered with community‐acquired pneumonia (CAP)14 or lower respiratory tract infections.19 The assay was evaluated by comparing with Sanger sequencing, showing great performance with 100% positive prediction value (PPV) and 99.85% negative prediction value (NPV).20 To our knowledge, this is the first study evaluating the performance of the ResP in oropharyngeal swab specimens from outpatients with ARIs.
Our study showed almost perfect kappa statistics for the ResP on rhinovirus, adenovirus, influenza virus A pdmH1N1(2009), respiratory syncytial virus, and influenza virus B, suggesting that the performance of ResP on these viruses was as effective as pathogen‐specific PCRs. On human metapneumovirus, the kappa statistics were lower than 0.8, presumably due to the small number of positive cases. Overall, this assay demonstrated 86.5% PPV and 97.8% NPV. This work suggested that the performance of ResP was sufficient enough be used for respiratory pathogen identification in outpatients with flu‐like manifestations.
The major limitation of this study is the small number of human metapneumovirus, parainfluenza virus, Mycoplasma pneumoniae, boca virus, influenza virus A H3N2, coronavirus, and Chlamydia. Further investigation is needed to evaluate the performance of ResP on these pathogens.
In conclusion, the performance of ResP showed a high‐degree agreement with pathogen‐specific PCRs in oropharyngeal swabs from outpatients. The implementation of ResP may facilitate the diagnosis of respiratory infections in a variety of clinical scenarios.
Ad5 and PanAd3 are closely related viruses, both belonging to adenovirus group C. As one aspect of whether PanAd3 vectors are likely to be blocked by pre-existing immunity to Ad5, we tested neutralization of a PanAd3 virus by human sera selected for particularly high neutralizing antibody to Ad5 (titers >1000). As shown in Table S1, many of these high-titered sera had no neutralizing activity on PanAd3. Some of the human sera with very high neutralizing titers ranging from 1628 to 4608 on Ad5 had low neutralizing titers of 28–63 on PanAd3.
Influenza continues to pose a global health problem, as highlighted by the 2009 swine influenza pandemic and sporadic human infections with avian H5N1 influenza viruses. Antigenic changes in influenza virus, primarily in the surface antigens hemagglutinin (HA) and neuraminidase (NA), are referred to as antigenic shift (subtype changes by reassortment) and antigenic drift (mutation). This variability among influenza viruses hinders vaccination efforts. Currently, annual surveillance is necessary to identify circulating viral strains for use in vaccine production. New vaccines are often required, and take about 6 months to become available. Thus new approaches are needed.
In contrast, so-called “universal” vaccines targeting relatively conserved components of influenza virus can provide protection regardless of strain or subtype of virus, and may provide an alternative to the use of traditional vaccines. This immunity to conserved antigens would not necessarily prevent infection completely, but might decrease severity of disease, speed up viral clearance, and reduce morbidity and mortality during the initial stages of an outbreak until strain-matched vaccine became available. Furthermore, vaccines based on T cell immunity could be used in combination with a seasonal vaccine to improve efficacy, especially in the elderly who are at high risk of severe disease and show reduced responses to current flu vaccines.
Peptide scanning of T cell responses of healthy human individuals has shown that matrix 1 (M1) and nucleoprotein (NP) are among the prominent targets of CD8+ and CD4+ T cell cross-recognition, so they are of interest as vaccine candidates. By sequence homology, NP is >90% conserved among influenza A isolates. Both murine and human cytotoxic T lymphocytes induced by NP of one virus strain have been shown to cross-react with NP from different influenza A strains. The strong immune responses to NP in mice contribute to protection against challenge via CD8+ T cells,, as well as contributions from CD4+ cells, and antibodies–. The influenza A matrix (M) gene encodes two highly conserved proteins: an ion channel protein, M2, and the capsid protein, M1. M1 is not a major protective antigen in the mouse and is not well recognized by mouse T cells, but has long been known to be recognized by human T cells. Thus its potential contribution to vaccine protection may be underestimated by mouse studies.
While epitopes providing targets widely shared among influenza viruses have been identified in multiple viral proteins, not all of them are highly immunogenic when presented by classical vaccines. More potent immunization can be achieved using recombinant vectors to express the influenza antigens and focus immunity on these targets. Recombinant adenovirus vectors are especially effective at eliciting strong T cell responses to transgene products–. Recombinant adenovirus vectors expressing NP or both NP and M2, can protect mice against a range of influenza virus challenges, including highly pathogenic avian H5N1 strains. While potential interference by prior immunity to human adenoviruses has been suggested as a barrier, this issue can be circumvented by use of vectors based on animal adenoviruses–. Chimpanzee adenoviruses have been shown to be useful vaccine vectors in a variety of animal studies–, and the prevalence of neutralizing antibodies against chimpanzee adenoviruses is low in human populations–, but not all of them are equally immunogenic.
In this study, we use a simian adenovirus, PanAd3, isolated from the bonobo Pan paniscus. This novel adenovirus strain was identified in a study of more than 1000 adenoviruses isolated from chimpanzees and bonobos in order to increase the available repertoire of vectors. In the large scale screening experiments, PanAd3 was among the most potently immunogenic in mice and was also among the least frequently recognized by neutralizing antibodies in human sera.
We have generated a replication incompetent PanAd3 vector deleted of E1 and E3 regions and expressing a fusion protein of the NP and M1 antigens of influenza A, chosen as targets of broad and cross-reactive T cell immunity in humans. The PanAd3-based vaccine was tested for induction of antibody and T cell responses in the systemic and mucosal compartments in mice, as well as for protection against lethal influenza virus challenge. We demonstrate that PanAd3 expressing conserved influenza virus antigens provided highly effective protection after a single intranasal administration. Thus it shows considerable promise as a vaccine candidate.
Most of the well-known human viruses persist in the population for a relatively long time, and coevolution of the virus and its human host has resulted in an equilibrium characterized by coexistence, often in the absence of a measurable disease burden.
When pathogens cross a species barrier, however, the infection can be devastating, causing a high disease burden and mortality. In recent years, several outbreaks of infectious diseases in humans linked to such an initial zoonotic transmission (from animal to human host) have highlighted this problem. Factors related to our increasingly globalized society have contributed to the apparently increased transmission of pathogens from animals to humans over the past decades; these include changes in human factors such as increased mobility, demographic changes, and exploitation of the environment (for a review see Osterhaus and Kuiken et al.). Environmental factors also play a direct role, and many examples exist. The recently increased distribution of the arthropod (mosquito) vector Aedes aegypti, for example, has led to massive outbreaks of dengue fever in South America and Southeast Asia. Intense pig farming in areas where frugivorous bats are common is probably the direct cause of the introduction of Nipah virus into pig populations in Malaysia, with subsequent transmission to humans. Bats are an important reservoir for a plethora of zoonotic pathogens: two closely related paramyxoviruses—Hendra virus and Nipah virus—cause persistent infections in frugivorous bats and have spread to horses and pigs, respectively.
The similarity between human and nonhuman primates permits many viruses to cross the species barrier between different primate species. The introduction into humans of HIV-1 and HIV-2 (the lentiviruses that cause AIDS), as well as other primate viruses, such as monkeypox virus and Herpesvirus simiae, provide dramatic examples of this type of transmission. Other viruses, such as influenza A viruses and severe acute respiratory syndrome coronavirus (SARS-CoV), may need multiple genetic changes to adapt successfully to humans as a new host species; these changes might include differential receptor usage, enhanced replication, evasion of innate and adaptive host immune defenses, and/or increased efficiency of transmission. Understanding the complex interactions between the invading pathogen on the one hand and the new host on the other as they progress toward a new host–pathogen equilibrium is a major challenge that differs substantially for each successful interspecies transmission and subsequent spread of the virus.
Influenza A virus is an enveloped virus belonging to the Orthomyxoviridae family. It can cause annual epidemics and infrequent pandemics. The Spanish flu pandemic of 1918 as well as the Asian flu of 1957 and the Hongkong flu in 1968 pandemics caused the death of millions of people. In 2009 the pandemic swine origin influenza A H1N1 virus as well as the outbreak of H7N9 in China in 2013 has reminded the world of the threat of pandemic influenza [3–6].
The genome of influenza virus consists of eight segmented negative RNA strands. The envelope bilayer harbors the two spike glycoproteins hemagglutinin (HA) and neuraminidase (NA), and the M2 proton channel. The homotrimeric HA is the most abundant protein on the viral surface. It mediates attachment to the host cell surface via binding to sialic acid (SA) residues of cellular receptors, and upon endocytic virus uptake it triggers fusion of the envelope with the endosomal membrane releasing the viral genome into the cytoplasm. NA cleaves glycosidic bonds with terminal SA facilitating the release of budding virions from the cell.
In diagnostics, antibodies against spike proteins are the preferred tool for identification and serotyping of viruses. Development of therapeutic antibodies against influenza is a challenge, as the high viral mutation rate (antigenic drift) and genetic reassortment of the virus genome (antigenic shift) continuously lead to new strains escaping from neutralization by antibodies [7, 8]. This goes along with adaptation to small molecule inhibitors (e.g. oseltamivir).
Vaccines can only temporarily control the recurring epidemics of influenza, because antigenic changes are typical for HA and NA. 16 avian and 2 bat serotypes of influenza A virus HA (H1—H18) are known, but only three (H1, H2, and H3) have been adapted to humans. Antibodies binding to regions of hemagglutinin conserved among serotypes have been developed which demonstrated broad specificity and neutralization potency [10–15]. However, development, production and quality control of antibodies is expensive and time consuming.
As an alternative, short peptides binding specifically to the spike proteins can be produced in automated high-throughput synthesis at low costs. HA-binding peptides have been recently obtained by phage display, lead structure optimization of natural products and specific toxins, bioinformatics tools and discovery from side effects of known anti-inflammatory peptides [16–23]. Some of them showed antiviral activity [17, 19–23]. A more epitope-oriented accession to binding peptides is the search for paratope-derived peptides from variable regions of specific antibodies. Antibodies against HA have been described, and at least 6 antigenic sites (A-F) on the HA-trimer have been identified, localized either at the receptor binding site, the interface of the three HA-monomers, or at other sites like the stalk [8, 11, 25]. Several structures of HA–antibody complexes have been published deposited in the protein data bank (PDB) [11–14]. Indeed, an antibody was described, whose HA binding is mediated mainly by one CDR, namely HCDR3.
Inspired by this finding, we chose linear peptides corresponding to the CDRs of VH of monoclonal antibody HC19, having the majority of contacts with the HA1 domain of the strain A/Aichi/2/1968 [26, 27]. The antibody and the derived peptides bind to HA at the SA binding site, in particular to the 130-loop and the 190-helix, which belong to the antigenic sites A and B, respectively. This binding site is conserved among several HA serotypes providing a basis for a peptide with broader specificity.
We used complementary experimental and theoretical approaches to select HA binding VH-CDR peptides and to improve their potential to inhibit binding, and finally, infection of cells by influenza A virus. The inhibitory potential of the most efficient CDR-peptide was improved by microarray-based site-directed substitutions of amino acids. We could demonstrate a broader specificity of the selected peptides as they bound to HA of human and avian pathogenic influenza strains.
Influenza viruses pose major threats to public health, as they are responsible for epidemics and pandemics resulting in high morbidity and mortality worldwide. Several pandemics, such as the Spanish flu (1918), Asian flu (1957), and Hong Kong flu (1968), caused millions of deaths in the last century (1). Currently, only two therapies, targeting the viral proteins neuraminidase and M2, are approved to treat influenza. Therefore, novel viral or host targets for antiviral strategies to block viral replication or inhibit cellular proteins necessary for the virus life cycle are urgently needed (2). In this context, host proteases are a group of very promising antiviral targets, because proteolytic cleavage of the precursor hemagglutinin (HA0) into HA1 and HA2 subunits by host proteases is essential for fusion of HA with the endosomal membrane and thus represents an essential step for infectivity of the virus (3, 4). Due to the potential risk of side effects after application of broadband protease inhibitors, the specific inhibition of a single enzyme would convey a huge therapeutic benefit.
The majority of influenza viruses, including low pathogenic avian and human influenza viruses, carry a single arginine (R) residue at the cleavage site. These HAs are cleaved by host trypsin-like proteases (5–8). In vitro studies with cultured human respiratory epithelial cells demonstrated the involvement of several membrane-associated proteases (9). Cell culture studies further identified, among others, the transmembrane serine proteases TMPRSS2, TMPRSS4, and TMPRSS11D as enzymes able to cleave the HAs of influenza virus subtypes H1 and H3 (10–12). We previously showed that deletion of Tmprss2 in knockout mice strongly limits viral spread and lung pathology after H1N1 influenza A virus infection (13). An essential role for TMPRSS2 in cleavage activation and viral spread was also reported for H7N9 influenza A virus (14, 15). We also demonstrated that deletion of Tmprss2 slightly reduced body weight loss and mortality in mice after H3N2 virus infection compared to those for wild-type mice but did not protect mice from lethal infections (13, 15). Therefore, it is likely that in addition to TMPRSS2, other trypsin-like proteases of the respiratory tract are able to cleave the hemagglutinin of H3 influenza viruses.
In this study, we investigated the role of Tmprss4 in the context of influenza A virus replication and pathogenesis in experimentally infected mice. We showed that knockout of Tmprss4 alone did not protect mice from lethal H3N2 influenza A virus infections. In contrast, Tmprss2−/−
Tmprss4−/− double-knockout mice showed massively reduced viral spread and lung pathology and also had reduced body weight loss and mortality.
(Part of this work was performed as Ph.D. thesis work by Nora Kühn at the University of Veterinary Medicine, Hannover, Germany.)
In addition to molecular detection of viruses, this study also presented a look at perceptions of biosecurity practices. Considering the 12 PPE questions, there were clear differences between perception and use for safety glasses, flu vaccinations, showering out of work, and disposable boots. While wearing safety glasses, flu vaccinations, and disposable boots were seen as efficacious but not used, showering out was often done by those who did not see it as an effective means of preventing cross-species infection. These differences could be due to training both for employers and workers, as the majority of farm biosecurity and disease prevention literature does not discuss worker protection against disease risks [34, 38, 39]. While not all 12 PPE items studied have proven effect in preventing cross-species infection or improving farm biosecurity, some listed interventions, such as rubber gloves, have shown marked differences in preventing the spread of zoonotic influenza virus.
The pandemic H1N1 outbreak of 2009 and global threat of H5N1 in recent years have been accompanied by a large amount of laboratory-based experimental research activity using purified viruses and infected tissues and animals. The majority of these studies have focused on either natural infections from the community or induced infections in the laboratory, with very few studies considering the infection risk or outcome of laboratory personnel handling the samples. The potential of an accidental laboratory-acquired infection is well-recognized among laboratory staff and researchers. In 1941, Meyer and Eddie published the first report of laboratory infections due to the Gram-negative bacteria Brucella. In 1949, Sulkin and Pike published a report that summarized 222 laboratory-acquired infections due to viruses. Since then, significant efforts have been made by the oversight committees of research institutes and governmental bodies to establish occupational and environmental safety guidelines to protect workers and the local community alike from laboratory-acquired infections; however, these infections have yet to be eradicated and many have been reported over the past eight decades.
The total number and relative frequency of bacterial laboratory-acquired infections has, in fact, declined dramatically over time. In contrast, the relative frequency of viral laboratory-acquired infections has increased by 60%. Research into the underlying factors responsible for these infections have indicated that the main route of infection, for both bacteria and viruses, is through mucous membranes that are contaminated by inhaling pathogens, not dissimilar from the natural route of infection. Traditionally, the risk of laboratory infection has been minimized by simply practicing good laboratory practice (GLP), which is otherwise necessary for reliability of the laboratory work itself. A detailed examination of the publically available information on all reported laboratory-acquired infections, however, indicated that ~80% were not the result of overt "accidents"; it is, thus, likely that inhalation of aerosolized infectious particles that are liberated by normal laboratory techniques account for a large portion of laboratory-acquired infections.
Research into this theory has indicated that influenza virus transmission and infection can be achieved through aerosols. Many of the routine procedures used to process influenza virus for laboratory research, such as centrifugation or mixing, have a high potential of producing aerosols, and the particle load of each has been estimated to be up to 1–5 μm. In addition, it is expected that larger particles will tend to fall out of the air and contaminate surfaces, by which individuals may be infected by contact or may transmit the particles to a secondary aerosol. Fundamentally, aerosols are suspensions in the air of solid or liquid particles small enough that they will remain transmissible and airborne for a prolonged period of time. Particles of 5 μm or less increase the risk of establishing an infection upon airborne transmission, as they are remarkably capable of penetrating the physical cellular barrier of the respiratory tract and traveling all the way to the alveolar region. As with naturally-acquired infections, most individuals are not diagnosed before onset of symptoms, impeding the time to initiation of treatment.
The A type influenza viruses are commonly spread by the airborne route in normal circumstances. Accordingly, more research on the potential and character of aerosol spread of influenza virus has been carried out, and many studies have used experimental animal models of aerosol infection to mimic the natural process. However, less information is available on the features of laboratory-produced aerosolized influenza virus.
The Australian researcher, Adrian Gibbs, suggested that the A/H1N1 flu virus currently circulating around the world was created in a laboratory. Although the World Health Organization (WHO) eventually dismissed this theory, suspicion and panic were aroused in the general public about laboratory safety. There are many situations that may facilitate the spread of a pathogen from the laboratory, ranging from aerosols produced by routine procedures or misuse of laboratory equipment to uncontrollable natural disasters that impact the structural integrity of the laboratory, such as earthquake or fire. In order to regulate the potential of pathogen transmission from the laboratory, we must first gain a detailed understanding of the experimental operations that produce aerosols. To this end, this study was designed to monitor the presence of aerosolized H5N1 virus produced by normal procedures used to process the virus for experimental research and by the most frequently associated “accidents” for each, such as container breakage and accidental subcutaneous injection. This information will help to guide future experimental practice standards to ensure the safety of laboratories and laboratory personnel, thereby increasing community confidence in laboratory bio-safety.
Feline calicivirus (FCV) is a common viral pathogen in cats worldwide. The prevalence ranges from 10% up to 70% depending on the cat population sampled. Usually, FCV causes painful oral ulcerations, salivation, gingivitis/stomatitis, inappetence, fever and depression with a high morbidity, but low lethality. However, FCV can occur as a very virulent form, causing severe clinical signs, due to systemic infection and inner organ involvement and high mortality rates up to 60% are reported. FCV is a non-enveloped RNA virus with a high tenacity that can remain infectious for approximately one month on dry surfaces at room temperature, and for weeks at colder temperatures. Additionally, the stability of FCV is strain-dependent, and common disinfectants do not inactivate FCV. Viral transmission occurs via direct cat-to-cat contact or indirectly via fomites (e.g., food bowls, contaminated coats). Reports from animal hospitals encountering outbreaks of virulent FCV infections emphasize that indirect transmission is a key factor in viral spread. In human hospitals, environmental testing for common human pathogens is routinely performed to assess the hygienic management. In veterinary facilities or research catteries, nobody has so far investigated environmental contamination with FCV.
It was the aim of this study to investigate the presence and viability of FCV in the environment of a research cat facility following two sequential experimental infections of cats with two different FCV field strains. Oropharyngeal shedding of FCV was tested in parallel. The findings of this study are important to optimize the hygienic management of private practices and veterinary hospitals and to prevent accidental, iatrogenic FCV infections in cats.
Previous studies have reported mixed results regarding the zoonotic risk of PCV2 for those with occupational exposure to pigs or receiving a xenotransplantation [29–33]. While worker nasal carriage of virus could indicate aerosol transmission of virus, it is important to note that the presence of virus in a nasal wash could also be caused by handling contaminated items or fomites and self-inoculation of the nares. The sample size and number of virus-positive samples of worker nasal washes was small in our study, which limits our ability to perform a robust risk factor analysis. However, some trends do align with previous literature on cross-species infection risks and general farm biosecurity threats. For example, participants who reported a household member who had contact with pigs within one meter in the last 30 days had higher PCV2 positivity. This supports a common biosecurity practice on pig farms, asking that workers or visitors of the farm do not visit other farms or even interact with other pig farmers within a certain time period of returning to their own farms.
In addition to individual behaviors typically associated with higher viral carriage in farm workers, characteristics of the facility itself contribute to a higher risk of disease outbreaks or cross-species infection. In this study, PCV2 positivity was associated with larger herd sizes (1000 head or greater). Previous studies have also demonstrated that higher density herds may harbor more zoonotic viruses and generally be more prone to infections. Sites where employees reported seeing rodents “daily”, as opposed to “weekly”, “rarely”, or “never”, were also more likely to have PCV2-positive results in humans. This is notable, as recent studies have shown molecular detection of PCV2 in rats and other rodents, suggesting cross-species transmission [36, 37]. While a positive association with rodents was observed for PCV2, this finding was not consistent when aggregating the nasal wash viral positive results.
The molecular technique revealed the presence of S. pneumoniae in the IS from all asthmatic patients, both elderly and non-elderly, and H. influenzae in half the patients from each group (Table 3). Chlamydophila
pneumoniae was detected in one subject from the elderly group and one from the non-elderly group. All sputa were negative for M. pneumoniae, Legionella, and B. pertussis.
Respiratory viruses were detected in the induced sputum from the majority of patients in both groups: in 11 (73.3%) elderly and 10 (71.4%) non-elderly individuals. The most commonly detected virus was Flu A followed by RSV A and RSV B (Table 3). No differences were observed in the detection rates of viruses between elderly and non-elderly patients.
The Orthomyxoviridae family member influenza A virus is the causal agent of acute respiratory tract infections suffered annually by 5–20% of the human population. There is a significant impact on morbidity, concentrated in people younger than 20 years, with economic consequences running into the billions of dollars during large epidemics. In addition, viral infections are associated with development of chronic asthma and disease exacerbation in both children and adults. In particular, acute influenza infection can amplify airway inflammation in asthmatic patients and induce alterations in epithelial and stromal cell physiology contributing to allergen sensitization, exaggerated bronchoconstriction, and remodeling of airway epithelia. Mortality rates associated with seasonal flu are low, but the aging population is at risk for development of severe congestive pneumonia which kills ∼35,000 people each year in the U.S.. Of continual concern is the threat of emergent high virulence strains such as the Spanish flu (H1N1), Asian flu (H2N2) and Hong Kong flu (H3N2) pandemics which claimed millions of lives world-wide.
Current treatments are focused on vaccines and drugs that target viral proteins. However, both of these approaches have limitations as vaccines require yearly development and lag detection of new strains, while viral proteins have a stunning capacity to evolve resistance to targeted agents. The genome of the influenza A virus consists of 8 negative single-strand RNA segments that encode 11 functional peptides necessary for viral replication and virulence. Thus the viral-autonomous repertoire of gene products is extremely limited and influenza A replication is dependent upon hijacking host-cell biological systems to facilitate viral entry, replication, assembly, and budding. The recognition that a suit of human host proteins are required for IVA infection and replication presents additional targeting strategies that may be less prone to deflection by the highly plastic viral genome.
Here we have employed the cytopathic effects of H1N1 infection in bronchial epithelial cells as a mechanism to isolate host genes that represent intervention target opportunities by virtue of their contribution to H1N1 infection and replication, or by virtue of their contribution to viral virulence factor-dependent evasion of innate immune responses. A primary whole-genome arrayed siRNA screen identified gene depletions that either deflected or promoted bronchial epithelial cell death upon exposure to the H1N1 A/WSN/33 influenza virus and were not cytotoxic to mock infected cells. Integration with orthogonal data sets, describing host gene function–, parsed collective ‘targets’ into four functional classes. 1) Targets that, when depleted, enhance bronchial epithelial cell survival upon H1N1 exposure, and are required for viral replication. This class presumably represents host factors that facilitate viral infection and/or are required to support viral replication. 2) Targets that, when depleted, reduce bronchial epithelial cell survival upon H1N1 exposure, and are required for viral replication. This important and initially unanticipated class, likely represents proviral host factors that deflect cell death checkpoint responses that would otherwise engage upon detection of viral infection. 3) Targets that, when depleted, reduce bronchial epithelial cell survival upon H1N1 exposure and enhance viral replication relative to controls. Recently discovered innate immune pathway components, such as IFITM3 that are responsive to H1N1 infection, are members of this class, which presumably represent antiviral restriction factors that normally oppose infection. 4) Targets, that when depleted, enhance bronchial epithelial cell survival upon H1N1 exposure and enhance viral replication as compared to controls. These host factors are likely responsible for influenza virus-mediated cytopathic effects. Chemical inhibition of gene products from two classes, RABGGTASE and CHEK1, indicated these targets might be pharmacologically addressable for H1N1 intervention in an epithelial cell autonomous context.
Neither asthma severity according to GINA or ATS criteria nor current asthma control assessed by the ACT were found to correlate with the presence of respiratory pathogens in the IS of asthmatics patients. In elderly asthmatics, but not in the non-elderly group, a few associations between the presence of specific respiratory viruses in the IS and respiratory function/immunological parameters were found. Flu A-positive patients had lower FVC% predicted than negative ones (81.8% pred. ±19.9 vs. 100.4 % pred. ±12,9; p < 0.05). The presence of RSV B was associated with a lower percentage of lymphocytes in the IS (28.7% ±12.6 vs. 5.5 % ±9.5; p < 0.05), and the RSV A-positive patients had lower tIgE concentration in the serum than RSV A-negative elderly individuals (19.2 kU/l ±17.7 vs. 85.2 kU/l ±64.1; p < 0.05).
On day 3, after the second FCV challenge, four of the ten cats were shedding replicating FCV as determined in cell culture. By day 22, all cats had stopped shedding FCV (Table 3).
Zoonotic diseases are those infections that can be transmitted between animals and humans with or without vectors. There are approximately 1500 pathogens, which are known to infect humans and 61% of these cause zoonotic diseases (1). The unique dynamic interaction between the humans, animals, and pathogens, sharing the same environment should be considered within the “One Health” approach, which dates back to ancient times of Hippocrates (2, 3).
Bacterial zoonotic diseases can be transferred from animals to humans in many ways (4): (i) The transfer may occur through animal bites and scratches (5); (ii) zoonotic bacteria originating from food animals can reach people through direct fecal oral route, contaminated animal food products, improper food handling, and inadequate cooking (6–8); (iii) farmers and animal health workers (i.e., veterinarians) are at increased risk of exposure to certain zoonotic pathogens and they may catch zoonotic bacteria; they could also become carriers of the zoonotic bacteria that can be spread to other humans in the community (9); (iv) vectors, frequently arthropods, such as mosquitoes, ticks, fleas, and lice can actively or passively transmit bacterial zoonotic diseases to humans. (10); (v) soil and water recourses, which are contaminated with manure contains a great variety of zoonotic bacteria, creating a great risk for zoonotic bugs and immense pool of resistance genes that are available for transfer of bacteria that cause human diseases (11, 12).
Bacterial zoonotic infections are one of the zoonotic diseases, which can, in particular, re-emerge after they are considered to be eradicated or under control. The development of antimicrobial resistance due to over-/misuse of antibiotics is also a globally increasing public health problem. These diseases have a negative impact on travel, commerce, and economies worldwide. In most industrialized countries, antibiotic resistant zoonotic bacterial diseases are of particular importance for at-risk groups such as young, old, pregnant, and immune-compromised individuals (13).
Almost 100 years ago, prior to application of hygiene rules and discovery of neither vaccines nor antibiotics, some bacterial zoonotic diseases such as bovine tuberculosis, bubonic plague, and glanders caused millions of human deaths. The spread and importance of some bacterial zoonoses are currently globally increasing. That is precisely why most of the developing countries are sparing more resources for a better screening of animal products and bacterial reservoirs or vectors for an optimal preventative public health service (14).
Improvements in surveillance and diagnostics have caused increased recognition of emerging zoonotic diseases. Herein, changes in our lifestyles and closer contacts with animals have escalated or caused the re-emergence of some bacterial infections. Some studies lately have revealed that people have never been exposed to bacterial zoonotic infection risks as high as this before (15). It is probably due to closer contact with adopted small animals, which are accepted and treated as a family member in houses. On the other hand, more intensified animal farms, which have a crucial role in the food supply, are still one of the greatest sources of food-borne bacterial zoonotic pathogens in today’s growing world (4, 8).
People who have closer contact with large numbers of animals such as farmers, abattoir workers, zoo/pet-shop workers, and veterinarians are at a higher risk of contracting a zoonotic disease. Members of the wider community are also at risk from those zoonoses that can be transmitted by family pets.
The immune-suppressed people are especially at high risk for infection with zoonotic bacterial diseases. People can be either temporarily immuno-suppressed owing to pregnancy, infant age, or long-term immuno-suppressed as a result of cancer treatment or organ transplant, diabetes, alcoholism or an infectious disease (i.e., AIDS).
This manuscript reviews the most common bacterial zoonoses and practical control measures against them.
To evaluate the hypothesis that macaques can serve as an intermediate host for spillover of PRV, we monitored the occurrence of transmission of PRV3M from experimentally infected to naïve monkeys. Similar to the infected animals, none of the naïve animals displayed any clinical signs of disease and viremia was not detected (data not shown). In contrast to the infected animals, viral RNA was not detected on rectal and oral swabs, with the exception of a trace reading on day 3 post-infection in a rectal swab of one animal (monkey #6310) and in the oral swab of another animal at day 5 post-infection (monkey #6308). Virus isolation was not attempted in this pilot study.
To confirm infection in the absence of clinical signs in both infected and contact animals, serum neutralization tests were performed from all monkeys on days 0, 21, 28, 35 and 42 post-infection (Table 3). All 3 infected animals had seroconverted by day 21 post-infection with titres of 80. One monkey from the contact group (monkey #6310) seroconverted by day 21 post-exposure and the neutralization titre increased until day 42, similar to the infected animals. These results provide evidence of PRV3M transmission between cynomolgus macaques.