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Sections from the lip and nasal planum of Sheppard (cluster 1) showed diffuse ulcerative exudative necrotic cheilitis and nasal dermatitis, respectively–the ulcer on the nasal planum was superficially colonized by mixed bacteria. Sections from the skin nodule showed similar ulceration, exudation, and necrosis, but also showed some areas with intact epidermis and hair follicles. Keratinocytes in the epidermis and in some hair follicle walls showed extensive disruption and hydropic degeneration, often accompanied by one to several large, angular, eosinophilic, cytoplasmic inclusion bodies. The combination of the necrotic and ulcerative inflammation and the cytoplasmic epithelial inclusion bodies led to a presumptive diagnosis of cutaneous poxviral infection, with suspicion of CPXV infection. Sections of the skin at the site of the toe wound from Top Cut (cluster 2) showed very similar histological lesions, comprising ulcerative necrotic dermatitis, folliculitis, and perifolliculitis, again with similar cytoplasmic eosinophilic inclusion bodies in keratinocytes, supporting the presumptive diagnosis above.
Starting in 2013, all cheetahs were vaccinated with Modified Vaccinia Ankara (MVA) smallpox vaccine, following the vaccination regime as recommended by the producer. However, another outbreak occurred in September 2014 in the park (enclosure A1) where three female siblings were living (Nova, Novi, Heidi). The 2.5-year-old Nova showed severe skin lesions consistent with cowpox in the face, on her body, and her legs. She received daily oral antibiotics (5 mg/kg enrofloxacin SID p.o.) and improved after 11 days. Her two sisters did not show any lesions.
Throughout recorded history, infectious diseases have plagued human existence. One effective approach to limiting these diseases has been vaccination. For example, in a recent report by Roush and colleagues at the U.S. Centers for Disease Control and Prevention (CDC), ever since the introduction of vaccines the incidence of infectious diseases like diphtheria, mumps, pertussis, tetanus, hepatitis A and B, Haemophilus influenza and varicella zoster has declined by more than 80% in the U.S. Furthermore, after the introduction of vaccines, large scale transmission of measles, rubella, and polio has been eliminated in the U.S., while smallpox has been eradicated worldwide. However, new emerging infectious pathogens such as HIV (human immunodeficiency virus), SARS coronavirus (severe acute respiratory syndrome virus), and highly pathogenic avian influenza (H5N1) viruses have adapted strategies to rapidly change their genetic compositions. As the influenza pandemic of 1918 (H1N1) killed approximately 20 to 50 million people worldwide, massive disease and death is similarly feared from newly emerging pathogens. In addition, the current novel swine derived H1N1 pandemic further exemplifies the need for a rapid and effective vaccine against emerging pathogens. Thus a vaccination strategy to control emerging diseases will require a more effective and rapid response than available from conventional approaches such as live-attenuated vaccines, inactivated vaccines, or protein subunit vaccines. Plasmid DNA vaccines, as reviewed in this article, may be an option to effectively combat current emerging infectious diseases.
Depending upon the involvement of etiological agent, the infectious respiratory diseases of small ruminants can be categorized as follows [9, 14]:bacterial: Pasteurellosis, Ovine progressive pneumonia, mycoplasmosis, enzootic pneumonia, and caseous lymphadenitis,viral: PPR, parainfluenza, caprine arthritis encephalitis virus, and bluetongue,fungal: fungal pneumonia,parasitic: nasal myiasis and verminous pneumonia,others: enzootic nasal tumors and ovine pulmonary adenomatosis (Jaagsiekte).
Manytimes due to environmental stress, immunosuppression, and deficient managemental practices, secondary invaders more severely affect the diseased individuals; moreover, mixed infections with multiple aetiology are also common phenomena [5, 8, 13, 15].
These conditions involve respiratory tract as primary target and lesions remain confined to either upper or lower respiratory tract [7, 16]. Thus, these diseases can be grouped as follows [5, 8, 14, 17].Diseases of upper respiratory tract, namely, nasal myiasis and enzootic nasal tumors, mainly remain confined to sinus, nostrils, and nasal cavity. Various tumors like nasal polyps (adenopapillomas), squamous cell carcinomas, adenocarcinomas, lymphosarcomas, and adenomas are common in upper respiratory tracts of sheep and goats. However, the incidence rate is very low and only sporadic cases are reported.Diseases of lower respiratory tract, namely, PPR, parainfluenza, Pasteurellosis, Ovine progressive pneumonia, mycoplasmosis, caprine arthritis encephalitis virus, caseous lymphadenitis, verminous pneumonia, and many others which involve lungs and lesions, are observed in alveoli and bronchioles.
Depending upon the severity of the diseases and physical status of the infected animals, high morbidity and mortality can be recorded in animals of all age groups. These diseases alone or in combination with other associated conditions may have acute or chronic onset and are a significant cause of losses to the sheep industry [3, 10]. Thus, the respiratory diseases can also be classified on the basis of onset and duration of disease as mentioned below [3, 9, 14, 18]:acute: bluetongue, PPR, Pasteurellosis, and parainfluenza,chronic: mycoplasmosis, verminous pneumonia, nasal myiasis, and enzootic nasal tumors,progressive: Ovine progressive pneumonia, caprine arthritis encephalitis virus, caseous lymphadenitis, and pulmonary adenomatosis.
Over the past two decades, there has been mounting interest in the increasing number of viruses causing unexpected illness and epidemics among humans, wildlife and livestock. All too often outbreaks have seriously stretched both local and national resources at a time when health-care spending in the economically developed world has been constrained. Importantly, capacity to identify and control emerging diseases remains limited in poorer regions where many of these diseases have their origin.
Emerging disease is a term used with increasing frequency to describe the appearance of an as yet unrecognized infection, or a previously recognized infection that has expanded into a new ecological niche or geographical zone and often accompanied by a significant change in pathogenicity.1 The key message is that these are representative of constantly evolving infections responding to rapid changes in the relationship between pathogen and host.
Among 1400 pathogens of humans over 50% of these have their origins in animal species, that is, “are diseases or infections naturally transmitted between vertebrates and humans” (World Health Organization). According to Woolhouse and colleague2 emerging or re-emerging pathogens are far more likely to be zoonotic. Viruses are over-represented in this group. Moreover, viruses with RNA genomes account for a third of all emerging and re-emerging infections. Emerging pathogens are typically those with a broad host range, often spanning several mammalian orders. Almost certainly many of these infections have been the result of the development of agricultural practices and urbanization (Figure 1).
Recent interest in emerging infections has focused on three key areas. First, how the interplay of climate, environment and human societal pressures can trigger unexpected outbreaks of emerging disease. Second, the understanding of how viruses can transmit between a reservoir and new host species, Third, identifying those aspects of the disease process that offer opportunities for therapy and prevention. To these must be added a broader understanding of how viruses evolve over time, clues to which are now being uncovered through looking closely at genetic elements of the host genome responsible for resisting virus invasion. Meeting these objectives will provide a more rigorous basis for predicting virus emergence.
Small ruminants particularly sheep and goats contribute significantly to the economy of farmers in Mediterranean as well as African and Southeast Asian countries. These small ruminants are valuable assets because of their significant contribution to meat, milk, and wool production, and potential to replicate and grow rapidly. The great Indian leader and freedom fighter M. K. Gandhi “father of the nation” designated goats as “poor man's cow,” emphasizing the importance of small ruminants in poor countries. In India, sheep and goats play a vital role in the economy of poor, deprived, backward classes, and landless labours. To make this small ruminant based economy viable and sustainable, development of techniques for early and accurate diagnosis holds prime importance. Respiratory diseases of small ruminants are multifactorial and there are multiple etiological agents responsible for the respiratory disease complex. Out of them, bacterial diseases have drawn attention due to variable clinical manifestations, severity of diseases, and reemergence of strains resistant to a number of chemotherapeutic agents. However, sheep and goat suffer from numerous viral diseases, namely, foot-and-mouth disease, bluetongue disease, maedi-visna, orf, Tick-borne encephalomyelitis, peste des petits ruminants, sheep pox, and goat pox, as well as bacterial diseases, namely, blackleg, foot rot, caprine pleuropneumonia, contagious bovine pleuropneumonia, Pasteurellosis, mycoplasmosis, streptococcal infections, chlamydiosis, haemophilosis, Johne's disease, listeriosis, and fleece rot [3–10].
The respiratory diseases represent 5.6 per cent of all these diseases in small ruminants. Small ruminants are especially sensitive to respiratory infections, namely, viruses, bacteria, and fungi, mostly as a result of deficient management practices that make these animals more susceptible to infectious agents. The tendency of these animals to huddle and group rearing practices further predispose small ruminants to infectious and contagious diseases [6, 9]. In both sheep and goat flocks, respiratory diseases may be encountered affecting individuals or groups, resulting in poor live weight gain and high rate of mortality. This causes considerable financial losses to shepherds and goat keepers in the form of decreased meat, milk, and wool production along with reduced number of offspring. Adverse weather conditions leading to stress often contribute to onset and progression of such diseases. The condition becomes adverse when bacterial as well as viral infections are combined particularly under adverse weather conditions. Moreover, under stress, immunocompromised, pregnant, lactating, and older animals easily fall prey to respiratory habitats, namely, Streptococcus pneumoniae, Mannheimia haemolytica, Bordetella parapertussis, Mycoplasma species, Arcanobacterium pyogenes, and Pasteurella species [2, 4, 7–9, 12, 13]. Such infections pose a major obstacle to the intensive rearing of sheep and goat and diseases like PPR, bluetongue, and ovine pulmonary adenomatosis (Jaagsiekte) adversely affect international trade [2, 9, 10, 13], ultimately hampering the economy.
Coronaviruses (CoV) are known to cause mild upper respiratory tract infections in humans. This paradigm was challenged when severe acute respiratory syndrome (SARS)-CoV emerged in 2002. SARS-CoV causes mainly lower respiratory tract infections, such as bronchitis and pneumonia. Approximately 10% of SARS-CoV patients developed severe complications and succumbed to this disease. This virus originated from bats and was transmitted to humans through civet cats, highlighting its zoonotic capacity. It spread worldwide and infected ~ 8000 individuals within a year, but was fortunately contained in 2003. There is currently no evidence of SARS-CoV circulating in the human population. However, a SARS-like CoV that is able to directly infect human cells has been recently identified in horseshoe bats in China; therefore, continuous surveillance for these viruses remains necessary.
A decade after the SARS-CoV epidemic, another novel CoV was isolated from a 60-year-old Saudi Arabian man who presented with acute pneumonia. He subsequently developed acute respiratory distress syndrome and renal failure with a fatal outcome. This virus, later called the Middle East respiratory syndrome (MERS)-CoV, attracted public interest due to its resemblance to SARS-CoV. So far, at least 1800 individuals have been infected with an ~ 35% fatality rate. Different from SARS, some individuals infected by MERS-CoV remain asymptomatic or develop only mild clinical manifestations,. Efforts to develop effective preventive and therapeutic intervention strategies are currently ongoing. Current interventions are mainly based on setting up surveillance studies and public health measures that include patient isolation and quarantine. Although these actions resulted in successful containment of the SARS outbreak, MERS-CoV still remains a problem, mainly in the Arabian Peninsula. The widespread circulation of MERS-CoV in dromedary camels is most likely the driving force of these outbreaks as novel zoonotic introductions of MERS-CoV may occur frequently. Therefore, different intervention approaches may be necessary to treat MERS patients, control zoonotic and nosocomial transmission. Here we describe the affected groups in the ongoing MERS-CoV outbreak and how distinct intervention strategies for each of them may curb the spread of the virus.
Poxviruses are double-stranded DNA viruses with large genomes (up to 300 kb) belonging to the family Poxviridae. The family is divided into the invertebrate-infecting entomopoxvirinae and chordate-infecting chordopoxvirinae. The latter subfamily is further divided into ten genera and contains many important infectious agents of both animals and humans. The now-eradicated Variola virus (VARV, the causative agent of smallpox) illustrates the potential consequences of poxvirus infections having arguably caused more deaths in human history than any other infectious agent. Aside from humans, chordopoxviruses are also found in a multitude of terrestrial, aquatic and arboreal animal species from diverse taxa e.g., crocodiles, sea lions, birds, camels, etc. and many poxviruses are capable of infecting multiple host species and cause cross-species (including zoonotic) infections. For example, monkeypox virus has been recognized as a zoonotic agent since the 1970s and is classed a bioterrorism agent. Further to human disease burdens, cross species infections of poxviruses between non-human species can also have devastating consequences e.g., the near-extinction of red squirrels in the UK after the introduction of squirrelpox with grey squirrels from the USA. Owing to the significance of these zoonotic and cross-species poxvirus infections, poxvirus host range is a key area of research.
Poxviruses exhibit a heterogeneous host range with some poxviruses having a very broad host range (e.g., cowpox infects rodents, dogs, cats, horses, cows, primates including humans), and others being very specific (e.g., VARV is a human only pathogen). Although some poxvirus genera are known to exhibit broad host tropisms (e.g., orthopoxviruses) and are consequently thought to manifest greater zoonotic risks, phylogenetic relatedness among viruses is not indicative of poxvirus host range. In fact, determinants of poxvirus host range are poorly understood and viral tropism is not typically restricted at the level of cellular entry. Due to highly conserved virion proteins, most poxviruses can enter a wide variety of host cell types, with restriction of infection occurring downstream of entry (either through a lack of host factors or through the innate immune system). Consequently, changes in poxvirus host range are typically determined by changes in virus genome complement (e.g., gene duplication/gain/loss) that allow for subversion of host restriction rather than point mutations, as is the case for some viruses e.g. parvovirus and influenza. Genes that are known to cause shifts in poxvirus host range generally have functions relating to the interplay of the host innate immune mechanisms with the virus. These genes are termed poxvirus host range genes and although approximately 15 have already been identified, more work is needed to fully understand their restriction mechanisms and to identify novel determinants of poxvirus host range.
Bats are an ancient, highly diverse order of mammals that are known to be reservoirs for a large number of viruses. “Bats” is the collective term for some approximately 1200 species of mammals thought to have diverged some 50 million years ago (mya; comparatively humans and great apes are thought to have diverged ~5 mya). Second only in diversity to rodents, bats are subdivided into two suborders, commonly called megabats and microbats, on the basis of behavioral and physiological traits as well as molecular evidence. There has been a recent increase in interest regarding the relationship of bats with viruses (Figure 1) as some species of bats are reservoir hosts for lethal viral zoonoses such as SARS coronaviruses, paramyxoviruses (e.g., Nipah and Hendra viruses), and filoviruses (e.g., Ebola and Marburg virus) and numerous lyssaviruses. Outbreaks of disease attributable to bat-related zoonoses have high economic and human costs and their discovery has resulted in concerted research effort to isolate and characterize viruses from bat populations. Consequently, large numbers of previously unknown viruses have since been identified in bat populations for which the zoonotic potential is unknown, including novel influenza types and hepadnaviruses. As a result, there has been well-grounded speculation that owing perhaps to physiological, ecological, evolutionary, and/or immunological reasons, bats may have a “special” relationship with viruses and be particularly good viral reservoirs with exaggerated viral richness. Indeed, a recent intensive study found that a single bat species likely carries ≥58 different viral species from only nine viral families. As well as the obvious first step of considering the zoonotic potential of newly identified bat viruses, further exploring the impacts of these findings and the opportunities they present for multiple research fields is necessary to capitalize on these discoveries.
Poxvirus infections have recently been identified in bats, comprising part of the increase in viral families newly identified in this taxonomic order. Here, we review the current evidence of poxvirus infections in bats, present the phylogenetic context of the viruses within the Poxviridae, and consider their zoonotic potential. Finally, we speculate on the possible consequences and potential research avenues opened following this marrying of a pathogen of great historical and contemporary importance with an ancient host that has an apparently peculiar relationship with viruses; a fascinating and likely fruitful meeting whose study will be facilitated by recent technological advances and a heightened interest in bat virology.
Increasing morbidity from zoonoses is a significant problem in terms of global health, and they are currently considered exotic in Europe. Zoonoses are infectious or parasitic diseases transmitted by animals to humans (Spahr et al. 2018). These infections as aetiological factors can develop in humans in several ways:
by the digestive tract, where the microorganism gets into the body via infected feed (meat) or water, which is quite often in large-scale farming. Therefore, Escherichia and Salmonella transmission to people occurs mainly through ingestion or frequent contact with infected birds. The above microorganisms can live in the external environment for a long period of time without damage to the pathogenic properties.by skin laceration; a break in the continuity of the skin promotes infection by pathogens of the staphylococci and streptococci families. In addition, the infection is intensified by the release of toxins into the host system.by the respiratory system (by inhalation of dust in which the pathogens are raised); infection occurs through direct contact of a healthy individual with contaminated excretion or through indirect contact (low hygiene at the slaughterhouse) with contaminated faeces and secretion on bird feathers (Hugh-Jones and de Vos 2002).
Humans are more susceptible to zoonoses carried by mammals than birds, and they share more diseases with them. This sharing is due to a higher degree of similarity between the intracellular environment of mammals (to which they belong), rather than birds. Many microorganisms need proper conditions and parameters to determine their host, for example, the presence of its receptor on the surface of the cells. These receptors can serve as a site for attachment and penetration into cells, which provides a pathway for the development of infection. The above situation determines the susceptibility of one animal species to a pathogen and resistance of another species. Vectors, such as insects, are also involved in the transmission of various pathogens, which may have an effect on the immune system. In the case of infecting a human with an avian zoonosis, the course of the disease is usually severe with general life-threatening symptoms. People who have been infected with an avian zoonosis require in-hospital treatment in isolation. Avian zoonoses in humans may end in death or a chronic disease requiring prolonged administration of antibiotics (Hugh-Jones and de Vos 2002).
Hence, the aim of this work is to present the aetiological factors of bird zoonoses, which are currently the most threatening to the European population. In addition, the epidemiological and economic analysis of the above infections in humans is presented. In general, zoonoses from birds can be divided by the type of the infectious agent: bacterial, viral and fungal.
Antimicrobial resistance (AMR) is the resistance of bacteria, viruses or other micro-organisms to antimicrobial drugs. The most common and concerning form of AMR is antibiotic resistance against important bacteria. Many multi-resistant bacteria have emerged over the past century. AMR is driven by selective evolutionary pressure, and relates to the volume of antibiotic use through over-use or misuse in humans, animals and food production. AMR can also occur through random genetic mutations. Efforts to control antibiotic use have focused on human and animal health. AMR is an increasing concern globally, and can increase the overall impact of any infection by reducing or removing the ability to treat infections successfully. In this scenario the rate of illness and death would be the same as that seen in untreated infection.
Epidemic and pandemic diseases must be differentiated from endemic diseases, such as malaria and tuberculosis (TB), which can exist in high numbers in a population and cause high burden of disease, but with a constant rate or slow change in rates. A true epidemic has a rise in case rates over days or weeks, whereas an endemic disease may rise or fall over years or decades. The words epidemic and pandemic are often misused. A pandemic is simply a global epidemic, and an epidemic is an outbreak of disease that attacks many people at about the same time and spreads through a defined population. It is defined by rate of growth of the epidemic curve. Epidemics have a sudden and immediate impact on the health system and require surge capacity. For transmissible diseases, epidemics have a mathematical definition related to the reproductive number, R0. A R0 of 1 is the epidemic threshold, and any R value greater than 1 presents necessary conditions for an epidemic. The rapid increase in cases observed during an epidemic or pandemic is what causes immediate impacts on health systems, stressing these systems beyond normal operating capacity. A pandemic of a highly infectious microbe will evolve rapidly and affect many people within a short period of time. For example, an influenza pandemic once it begins, would be expected to reach its peak within 2 months. A working group commissioned by the World Health Organization (WHO) has listed diseases with pandemic potential, but some of these, such as malaria, TB and AMR organisms, are usually endemic diseases. Endemic diseases may occur in very high numbers, but their rate is constant or changes slowly, over months or years, sometimes decades. Sporadic diseases occur at a rate too low to be endemic or epidemic. They are typically zoonotic infections that occasionally infect humans. Figure 1 shows the difference in the three main patterns of disease – epidemic, endemic and sporadic.
AMR has been a chronic, slowly increasing phenomenon worldwide, and causes long term impact on the health system, as well as severe, immediate impact on affected individuals. Hospital infections such as Methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant TB are well known examples, but increasingly common causes of urine infection and pneumonia are also becoming resistant. AMR is not an epidemic, but an endemic condition.
The most pest-prone species of poultry are primarily hens, quail and turkeys. The condition is caused by a virus belonging to the Herpesvirus genus. The way they penetrate the organism is through the respiratory system or gastrointestinal tract. Infection usually occurs immediately after hatching. The virus contained in the exfoliated warts of the pen still retains its virulence for more than 12 months after initiation. Infected birds show weight loss and paroxysmal symptoms. However, it often occurs that the course of this disease is very violent and no clinical symptoms were observed in humans (Ryan and Ray 2004; Koelle and Corey 2008; Johnston et al. 2011; Schiffer et al. 2014).
The precise mechanism of the induction of immunity after pDNA vaccination is complex and multi-factorial (Figure 1).
It is thought that after immunization, transfected muscle cells may produce antigen or foreign proteins that then directly stimulate B cells of the immune system, which in turn produce antibodies. Transfected muscle cells could possibly transfer the antigen to so-called antigen presenting cells (as demonstrated by cross priming) which then transport the proteins via distinct pathways (the MHC I for CD8+T cells or MHC II for CD4+T cells) that result in the display of different processed fragments of expressed proteins (antigens). Finally, direct transfection of antigen presenting cells (such as dendritic cells) with subsequent processing and display of MHC-antigen complexes may also occur. Because the process of antigen production by host cells after DNA vaccination mimics the production of antigens during a natural infection, the resulting immune response is thought to be similar to the type induced by pathogens. Indeed, DNA vaccination generates antigens in their native form and with similar structure and function to antigens generated after natural infection.
When MERS patients are admitted to hospitals their clinical symptoms mostly include fever, cough, expectoration and shortness of breath,. Ground glass opacities and consolidation in the lungs are commonly reported in chest radiographs or computed tomography scans. However, these characteristics overlap with other lower respiratory tract infections and are not pathognomonic for MERS-CoV, indicating the need to develop laboratory-based diagnostic assays with high sensitivity and specificity.
Upon its discovery, MERS-CoV was found to replicate to high titers and induce cytopathic effects in various different cell lines, thus enabling its rapid full genome characterization,. Two large replicase open reading frames, ORF1a and ORF1b cover the 5′ region of the MERS-CoV genome, whereas the 3′ end of the genome encodes structural proteins, i.e. spike (S), membrane (M), nucleocapsid (N), envelope (E), and several accessory proteins (3, 4a, 4b, 5 and 8b). The nucleotide sequence of MERS-CoV was used as a template to design primers for genome-based assays, i.e. real-time reverse-transcription polymerase chain reaction (RT-PCR) and sequencing,. Primer pairs targeting a region upstream of E (upE), N, ORF1a, ORF1b and RdRp genes were then developed and shown to be highly sensitive and specific not only for the EMC isolate but also for other MERS-CoV isolates,,. It is currently suggested to use upE RT-PCR as a screening assay and another target gene as a confirmatory assay.
Despite being highly specific and sensitive, RT-PCR-based assays still have limitations as MERS-CoV can only be detected when it is actively shed by the host. Serology-based assays were subsequently developed to distinguish those individuals that had been exposed to MERS-CoV in the past. Indirect immunofluorescence assays (IFA) and neutralization tests (plaque reduction neutralization test and microneutralization test) were set up using susceptible cell lines and whole virus particles,. These assays require biosafety level 3 facilities to work with the infectious MERS-CoV in-vitro, limiting their usage. In addition, whole virus IFA showed limited specificity to MERS-CoV due to cross-reactivity with other human CoV,. Alternative assays using a pseudoparticle virus and specific MERS-CoV antigens were then developed to solve this issue. Two CoV structural proteins known to be highly antigenic are the N and S proteins. Both proteins have been used to develop serology-based assays in various platforms, i.e. recombinant IFA, western blot, enzyme-linked immunosorbent assay (ELISA), luciferase-based antibody detection assay and protein microarray,,,,. The N protein is relatively conserved among CoVs, whereas the S1 domain, located in S, is more divergent among CoVs, making it an ideal candidate for CoV specific diagnostic serological assays. However, it is important to note that none of the serological assays available to date has been fully validated for specificity and sensitivity, therefore due care must be taken in interpreting the results of large serosurveillance studies. Possible cross reactivity and/or low sensitivity of these assays can lead to failure in determining the prevalence of true MERS-CoV positive cases in a given population. In turn, this has an impact on the calculated fatality rate of the viral infection. Further studies using a set of well-characterized sera are required for the determination of cut-off values and assessing cross-reactivity between MERS-CoV and other human CoVs. It is crucial to properly determine the MERS-CoV prevalence at a population level to develop adequate control programs.
If natural smallpox was initiated through the upper respiratory mucosa, then an early asymptomatic mucosal infection would be expected. To investigate this, Sarkar and colleagues performed pharyngeal swab surveys of household contacts (Sarkar et al., 1973a, 1974) 4–8 days following onset of rash in the index cases. They found that contacts with positive throat cultures often did not develop smallpox. In one survey, (Sarkar et al., 1973a) 10% (Westwood et al., 1966) of 328 contacts had positive swabs, but only 12% (Kaplan et al., 2002) of those with positive swabs developed smallpox. Among 59 unvaccinated contacts 27% (Miller, 1957) were culture positive, but only one developed smallpox. All subjects were vaccinated at the time of examination. However, vaccination four or more days after exposure is usually considered to be too late to prevent disease. The observation that disease did not develop in 94% of persons with mucosal infection suggests that, even in unvaccinated contacts, mucosal infection may not have been sufficient to initiate disease.
Sarkar and colleagues also showed that the oropharyngeal excretion of virus was greatest during the first days after the rash erupted and generally resolved at most 2 weeks following onset of rash (Sarkar et al., 1973b). Rao et al. found that oropharyngeal excretion was greatest in the most severe, hemorrhagic cases and corresponded with the period of infectiousness (Rao et al., 1968). In contrast to oropharyngeal excretion, scabs contained large quantities of virus regardless of disease severity (Mitra et al., 1974) and were shed for another week or more after throat cultures were negative. Scabs alone, however, were not associated with further cases (Rao et al., 1968; Mitra et al., 1974).
The apparent lack of infectiousness of scab associated virus has been attributed to encapsulation with inspissated pus (Fenner et al., 1988). Henderson's theory about the importance of small particles may provide a straightforward mechanism for why encapsulated virus, simply by entrapment in large particles, had low infectious potential.
Sarkar et al. (1973a) were concerned that asymptomatic contacts could have been infectious because their throat swab viral titers were similar to those of milder smallpox cases. A paradox arose from these data because there was never evidence of infection arising from asymptomatic household contacts. Yet, oropharyngeal secretions were thought to be the primary source of infectious virus particles. An explanation may be that oropharyngeal excretion of virus was merely temporally correlated with excretion of virus from elsewhere in the respiratory tract and not the actual source of fine particles virus aerosols.
The large spray of particles from sneezing visualized by high speed photography consists of particles down to about 10 μm in diameter (Papineni and Rosenthal, 1997). Smaller particles may also be dislodged from the upper airways by the turbulence of sneezing, coughing, and talking, but will mostly be larger than 2.5 μm in diameter. Recent studies, however, show that the healthy lung generates abundant fine particles (100–1000/l with size <0.3 μm diameter) during normal breathing (Fairchild and Stampfer, 1987) that do not arise from the oropharynx; condensates of these particles are the subject of recent reviews (Mutlu et al., 2001; Hunt, 2002). Such particles could carry variola virus (0.2–0.3 μm diameter), would remain airborne in indoor air for many hours, and would be deposited primarily in the lower airways after inhalation.
There is some evidence that variola was present in the lung and potentially available for aerosolization. Animals infected by inhalation produced high concentrations of variola in the lung (Hahon and Wilson, 1960). Fenner et al. (1988) regarded bronchitis and pneumonitis as a part of the normal smallpox syndrome, especially in the more severe cases which were also the most infectious, (Rao et al., 1968) although specific lesions were less frequent in the lower trachea and bronchi. Systematic evaluations of viral excretion in the lower respiratory tract of non-fatal cases were not reported. Thus, if some degree of pneumonitis with pulmonary excretion of virus and exhalation of fine particle variola aerosols was a feature of clinical smallpox but was not a feature asymptomatic household contact with positive throat cultures, then the paradox would be resolved.
Next, all of the above findings were considered in conjunction with the literature data on the transmission ecology collated for each of the 36 viruses in Figure S1a. Pieced together on this basis was an outer- to inner-body line-up of viruses by organ system or combination of organ systems, guided by the one-to-four virus infiltration score, the corresponding virus organ system tropism, the matching virus transmission modes, length of the infection and shedding periods, infection severity level, and virus environmental survival rate, see Figure 3 and, also, Figure S1d.
Infectious diseases have historically affected the development and advancement of human societies. During the early- and mid-20th century, mortality associated with infectious diseases declined dramatically due to advances in medicine and public health; however, they remain a major public health burden worldwide. Recent data presented by the World Health Organization indicated that more than a quarter of the estimated 59 million deaths that occur globally each year are associated with infectious disease (12).
Acute respiratory illnesses are the leading cause of death from infectious diseases around the world, and occasional outbreaks of particularly virulent strains are potential public health disasters. In 2002, a few cases of a life-threatening respiratory disease caused by corona virus in China (34), ultimately resulted in a global epidemic of severe acute respiratory syndrome. Recently, a large outbreak of fatal Middle East respiratory syndrome-coronavirus (MERS-CoV) occurred following a single patient exposure in the emergency department (ED) of our institution, a tertiary-care hospital in Korea, which resulted in significant public health and economic burden (56).
EDs are one of the major gateways to hospital entry and have substantial burdens associated with infectious disease-related visits (78910). Thus, accurate categorization of patients is required, and determination of the initial isolation level is one of the most difficult issues faced by ED physicians, especially when treating patients with a suspected contagious respiratory illness (111213). After the 2015 outbreak of fatal MERS-CoV at our institution (514), a febrile respiratory infectious disease unit (FRIDU) with a negative pressure ventilation system was separately constructed outside the ED; to prevent the spread of contagious diseases within the hospital, this unit triages and determines isolation levels for all emergency patients prior to their admission to the ED or hospital. However, data on the utility of such screening units are limited.
We compared patients' initial FRIDU-determined isolation level with the level associated with their final diagnosis and assessed the limitations of the screening system. We hope this study will help efforts to integrate isolation strategies into ED contagious disease management procedures.
Our environment is changing on an unprecedented scale. Climate change needs to be distinguished from climate variation: change is where there is statistically significant variation from the mean state over a prolonged period of time.
The most notable manifestations have been the increasing climatic conditions initiated by changes in sea surface temperatures in the Pacific, known as the El Niño Southern Oscillation. In the summer of 1990, an El Niño event occurred, which in turn led to a period of prolonged drought in many regions of the Americas and the emergence of hantavirus pulmonary syndrome. Conversely, a sudden reversal in sea temperature in the summer of 1995 resulted in heavy rainfalls, especially in Columbia, resulting in resurgence of mosquito-borne diseases such as dengue and equine encephalitis.
Vector-borne diseases are judged as highly sensitive to climatic conditions, although the evidence for climatic change and altered epidemiology of vector-borne disease is generally regarded as particularly sensitive to temperature. Even a small extension of a transmission season may have a disproportionate affect as transmission rates rise exponentially rather than linearly as the season progresses. Climatic change can also bring about altered vector distributions if suitable areas for expansion become newly available. Again, the effect may be disproportionate, particularly if the vector transmits disease to human or animal populations without pre-existing levels of acquired immunity with the result that those clinical cases are more numerous and potentially more severe. Increased temperatures and seasonal fluctuations in either rainfall or temperature favor the spread of vector-borne diseases to higher elevations and to more temperate latitudes.5,6
Aedes aegypti, a major vector of dengue, is limited to distribution by the 10 °C winter isotherm, but this is shifting, so threatening an expansion of disease ever northward.7
The relentless change inflicted by humans on habitats in the name of progress has also had a marked effect on rodent habitats. Outbreaks of Bolivian hemorrhagic fever in Bolivia and hantavirus pulmonary syndrome in the United States have been clearly associated with abnormal periods of drought or rainfall, leading to unusually rapid increases in rodent numbers. Of all species of mammals, rodents are among the most adaptable to comparatively sudden changes in climate and environmental conditions. Small climatic changes can bring about considerable fluctuations in population size, inhabiting desert and semidesert areas, particularly in food quantity and quality. A prolonged drought in the early 1990s in the Four Corners region of the United States led to a sharp decline in the numbers of rodent predators, such as coyotes, snakes and birds of prey. But at the end of the drought, heavy rainfall resulted in an explosion in piñon nuts and grasshopper populations, which in turn resulted in a rapid escalation of rodent numbers, among them deer mice carrying hantaviruses.
A similar set of circumstances occurred in the Beni region of Bolivia in the 1960s when a period of prolonged drought was followed by rain: an exponential rise in the numbers of Calomys callosus field voles followed, exacerbated by the use of dichlorodiphenyltrichloroethane (DDT) in use at that time to reduce mosquito numbers. This had the unfortunate consequence of reducing the local peridomestic cat population that had hitherto kept feral rodent numbers in check. The consequence of these sharp climatic changes was the emergence of Bolivian hemorrhagic fever caused by the arenavirus Machupo. This pattern of severe oscillations of rain and drought markedly affect murine species and insect vector numbers and act as an indicator that disease emergence may occur in the period following such changes. A similar pattern of events occurred in 1994 when in Venezuela an outbreak of what originally thought was due to dengue virus was in fact another example of the emergence of a novel arenavirus.8
Evolving in the Old World, murines are a comparatively recent introduction into the New World, most probably via the Bering land isthmus some 20–30 million years ago. Whilst other rodents have declined in number, murine rodents have thrived, especially in peri-urban areas. This means that, although species diversity has become less with fewer genera represented, those remaining have multiplied many times over. It is among species of the family Muridae that reservoir hosts of arenaviruses and hantaviruses are to be found in South America.
Deforestation has accelerated exponentially since the beginning of the twentieth Century and in the Amazonian basin and parts of Southeast Asia has had a profound effect on local ecosystems, particularly by constraining the range of natural predators instrumental in keeping rodents, insects and other potential carriers of infectious disease under control.9 The reduction in biological diversity can trigger the invasion and spread of opportunistic species, heralding the emergence of disease through increased contact with local human populations.
Arthropod-borne infections such as Congo-Crimean hemorrhagic fever could pose a substantial risk to both humans and livestock in Europe should climatic conditions raise further the ambient spring temperature. Infected immature ticks carried on migratory birds would molt in much greater numbers although such an enhancement in molting might be offset by a significant reduction in the number of migratory birds.10
Egg drop syndrome is a viral disease, caused by the egg drop syndrome virus (EDSV), officially called duck adenovirus 1 (DAdV-1), belonging to species Duck adenovirus A, genus Atadenovirus, family Adenoviridae. EDSV was first reported in 1976, it has also been known as adenovirus 127 and egg-drop-syndrome-76 (EDS-76) virus. EDS is characterized by the production of soft-shelled, thin shelled, shell-less, and discolored eggs in otherwise healthy chickens. The natural hosts of the EDSV are ducks and geese, however, the virus can also infect chickens, resulting in major economic losses on egg production [3, 4]. EDSV was involved in severe respiratory disease in 1-day-old goslings where the presence of EDSV DNA was found in different organs of the naturally and experimentally infected goslings. Severe acute respiratory symptoms with coughing, dyspnea, and gasping were reported in 9-day-old Pekin ducklings in 2013. For diagnosis of EDSV, five serological methods have been used and tested. In the recent years, several PCR studies have been published, for diagnosis of all avian adenoviruses that are of relevance for poultry production [8–10]. Molecular amplification methods were commonly used to diagnose EDSV infection.
Loop-mediated isothermal amplification (LAMP) is a method that can amplify DNA under isothermal conditions. It was first developed by the Japanese researchers, the LAMP employs a DNA polymerase and a set of four specially designed primers that recognize a total of six distinct sequences on the target DNA. Later, LAMP was supplemented by using additional primers, termed loop primers which prime strand displacement DNA synthesis. Moreover, LAMP has some advantages in comparison with PCR methods, including improved sensitivity and specificity, as well as time efficiency. Since LAMP was published, a range of LAMP methods have been developed. The RealAmp is one of them, which attempted to improve the method for diagnosis by using a simple and portable device capable of performing both the amplification and detection by fluorescence in one platform. Currently, the LAMP assays are utilized to detect bacterial and viral pathogens including Mycobacterium tuberculosis, Acinetobacter baumannii, avian influenza virus, Middle East respiratory syndrome coronavirus and hemorrhagic enteritis virus [15–19].
Various LAMP procedures have been successfully employed for DNA amplification using DNA templates extracted from the samples. The purpose of this study was to evaluate the usability of the RealAmp method for a rapid detection of the EDSV in a diverse range of samples without a prior need for nucleic acid extraction. Therefore, we infected both duck embryos and duck fibroblast cell culture with EDSV, then the viral samples were collected and employed to the assay directly by serial dilutions.
The three detections of poxviruses in bat populations are distinct and inherently incomplete stories with very few common threads; high-prevalence detection in throat swabs from apparently healthy African megabats, severe joint disease in several North American microbats and, negligible though comorbid skin disease in an endangered Australasian microbat. Further to their varied clinical impact, the partial genetic characterization of the former two viruses shows that these viruses are genetically diverse. The two viruses are most closely related with the very distinct poxviruses, Molluscum contagiosum virus and Cotia virus respectively (Figure 2), and although only partially genetically characterized, a small (100 amino acids) region of overlap in their RAP94 proteins has only 62% amino acid identity (please see Table S1 in the Supplementary files). That this is as far as these new viruses can be contrasted demonstrates the dearth of information currently available for further investigation of poxviruses in bats.
B cell responses were examined in nine patients infected with the pandemic 2009 H1N1 influenza virus. These patients had varying courses and severity of disease. The cases ranged from mild disease with rapid viral clearance within a few days after onset of symptoms to severe cases that shed virus for several weeks and required hospitalization with ventilator support. A majority of the patients were treated with antiviral drugs. The diagnoses were confirmed by pandemic H1N1-specific RT-PCR and serology. All patients had neutralizing titers of serum antibodies at the time of blood collection. A summary of the clinical patient data are shown in Table I. The majority of samples were obtained around 10 d after the onset of symptoms, with the exception of a particularly severe case where sampling was done 31 d after symptom onset.
Antigen-specific plasmablasts appear transiently in peripheral blood after vaccination with influenza or other vaccines (Brokstad et al., 1995; Bernasconi et al., 2002; Sasaki et al., 2007; Wrammert et al., 2008), but the kinetics of their appearance and persistence during an ongoing infection remain unclear. Here, we have analyzed the magnitude and specificity of the plasmablast response in blood samples taken within weeks after onset of clinical symptoms of pandemic H1N1 influenza virus infection. Using a virus-specific ELISPOT assay, it was possible to show a significant number of pandemic H1N1-reactive plasmablasts in the blood of the infected patients, whereas none were detectable in a cohort of healthy volunteers (Fig. 1, A and B). These cells were also readily detectable several weeks after symptom onset in the more severe cases. Fig. 1 (A and C) illustrates that, of the total IgG-secreting cells, over half of the cells were producing antibodies that bound pandemic H1N1 influenza virus. Moreover, plasmablasts specific for HA occurred at 30–50% the frequency of virus-specific cells (Fig. 1, C and D), the specificity most likely to be critical for protection. Most patients also had a relatively high frequency of plasmablasts, forming antibodies that bound to past, seasonal influenza strains (Fig. 1 C) or recombinant HA from the previous annual H1N1 strain, A/Brisbane/59/2007. Based on the overall frequency of pandemic H1N1-specific cells, it is likely that the cells binding other strains were overlapping populations and cross-reactive. None of the induced plasmablast cells bound to recombinant HA from the H3N2 strain from the same vaccine (A/Brisbane/10/2007). These findings demonstrate that influenza-specific human plasmablasts are continuously generated throughout an ongoing infection and that a fairly high proportion of these cells make antibodies that also cross-react with previous annual H1N1 influenza strains.
To analyze the specificity, breadth, and neutralizing capacity of these plasmablasts, we used single-cell PCR to amplify the heavy and light chain variable region genes from individually sorted cells (defined as CD19+, CD20lo/−, CD3−, CD38high, CD27high cells; Fig. 1 E; Wrammert et al., 2008; Smith et al., 2009). These genes were cloned and expressed as mAbs in 293 cells, and the antibodies were screened for reactivity by ELISA. Thresholds for scoring antibodies as specific to the influenza antigens were empirically determined based on being two standard deviations greater than the background level of binding evident from 48 naive B cell antibodies (Fig. S1 A). Of 86 antibodies generated in this fashion, 46 (53%) bound pandemic H1N1 (Fig. 1 F) and one third (15 antibodies) were reactive to HA (Fig. 1 G and Fig. S2 A), most of them at sub-nanomolar avidities (based on surface plasmon resonance analyses; Fig. S2 B). On a per donor basis, 55% of the mAbs bound to purified pandemic H1N1 virions (range: 33 to 77%). Of the virus-specific antibodies, 31% bound to recombinant HA (range: 14 to 55%). We conclude that virus-specific plasmablasts are readily detected after pandemic H1N1 influenza virus infection and that virus-specific human mAbs can be efficiently generated from these cells.
For the epithelial, outer-body viruses it turned out that the length of the infection and shedding periods, as well as the virus environmental survival rate generally increased from respiratory tract to alimentary tract to skin. The respiratory viruses transmitted on the basis of aerosols, direct contact or fomites. Alimentary tract viruses were found to transmit on the basis of a fecal-oral cycle, through direct contact, contamination of feed and water, or involving fomites, persons and vehicles. Viruses infecting both respiratory and alimentary tract featured a mix of these transmission modes. Mostly, these viruses caused rather severe infections. Among the skin viruses, the more infiltrative viruses affecting all layers of the skin caused slowly healing lesions. The transmission of these deep-rooted skin viruses was found to rely on abrasion or biting flies rather than on direct touch or on indirect contact, more typical for superficial skin lesions. Some of the epithelial viruses are shed in feces over a prolonged time period, also in the absence of clinical signs, and these infections were considered to feature a systemic component. Next, the epithelial herpesviruses establishing latently in peripheral nerves and ganglia were found to cause a recurrence or persistence of the mucosal and/or skin infection, including of the distal urogenital tract and external genitalia.
Lumpy skin disease (LSD) affects primarily cattle and occasionally buffalo [1, 2]. It causes pyrexia, generalized skin and pox lesions of internal organs, as well as generalized lymphadenopathy [3, 4]. The disease exists in three forms, acute, subacute or unapparent. LSD is caused by an enveloped double-stranded DNA virus called LSD virus (LSDV), which together with sheep poxvirus (SPV) and goat poxvirus (GPV) constitutes the genus Capripoxvirus of the Chordopoxvirinae subfamily of the Poxviridae family [6, 7].
The origin of LSDV is unknown. It was reported for the first time in Zambia in 1929 as a hypersensitivity reaction of cattle to insect bites [8, 9]. In Egypt, LSDV was first reported in Suez and Ismailia Governorates in May and October 1988 and thereafter spread throughout Egypt leading to 50,000 infected cattle and 1,449 mortalities in 1998 [10, 11]. During epizootics LSDV is mainly transmitted mechanically by blood feeding insects e.g. Aedes aegypti. Due to the rapid spread of LSDV and the severe economic losses caused, the Office International des Epizooties (OIE) includes LSDV in the listed notifiable disease of cattle.
Diagnosis of LSD depends initially on clinical signs. Definite diagnosis can be performed via virus isolation, electron microscopy, identification of antigen by immunofluorescence, serum neutralization, agar gel precipitation, antigen capture ELISA and Dot ELISA [3, 14]. In addition, conventional and real-time polymerase chain reactions (PCR) for the detection of the LSDV have been described [3, 15–18]. All the above-mentioned methods are not suitable for screening cattle under field conditions or at quarantine stations, as they require highly skilled staff and a well-equipped laboratory. Simple, portable, and rapid tests to detect LSDV at the point of need could improve initiation of control measures as early as possible. This study describes the development and evaluation of a real-time RPA assay for the detection of LSDV genome.
Controversy exists regarding the best method of protecting the public against the potential release of smallpox as a biological weapon (Bicknell, 2002; Fauci, 2002; Halloran et al., 2002; Kaplan et al., 2002; Mack, 2003). Infectious disease modeling plays an important role in this dialog, and the biology of the transmission pathway, the focus of this review, is critical to producing appropriate predictive models and understanding which controls will work best under varying conditions (Ferguson et al., 2003).
The rapidity with which smallpox would spread in a developed nation is not known and is a major source of uncertainty in models used for public health planning (Ferguson et al., 2003). The basic reproductive number (R0), which describes the tendency of a disease to spread, has been estimated for smallpox from historical data and outbreaks in developing countries (Gani and Leach, 2001; Eichner and Dietz, 2003). Because R0 is a function of the contact rate between individuals, it can be affected by changes in the environment (Anderson and May, 1991). A potentially important difference between contemporary environments and those used to estimate R0 is that today many buildings, including hospitals, mechanically recirculate air. If smallpox was almost entirely transmitted by mucosal contact with large droplets (aerodynamic diameters >10 μm), which can only occur following “face-to-face” exposure over distances of a few feet, then change in the built environment would not change the contact rate between individuals. If, however, smallpox was frequently transmitted from person-to-person by airborne droplet nuclei [fine particles with aerodynamic diameters of ≤2.5 μm capable of remaining suspended in air for hours and of depositing in the lower lung (Hinds, 1999)] then mechanically recirculated air systems would increase the contact rate, R0, the risk of epidemic spread, and the difficulty of hospital infection control. Unfortunately, leading authorities disagree regarding the relative importance of fine and large particle routes of transmission; some state that smallpox was transmitted primarily via airborne droplet nuclei, (Henderson et al., 1999) while others emphasize “face-to-face” contact and state that, airborne transmission was rare (Centers for Disease Control, 2002; Mack, 2003). This paper reviews the evidence for each of these modes of transmission.
Avian infectious bronchitis (IB) is an economically important poultry disease affecting the respiratory, renal, and reproductive systems of chickens. Although IB was first identified in North Dakota, USA, epidemiological evidences confirmed the circulation of several IBV serotypes in different parts of the world. Currently, both classic and variant IBV serotypes have been identified in most countries, thus making IB control and prevention a global challenge [2, 3]. The disease is associated with huge economic losses resulting from decreased egg production, poor carcass weight, and high morbidity. Mortality rate could be high in young chickens especially with other secondary complications such as viral and bacterial infections.
Vaccination has been considered to be the most cost effective approach to controlling IBV infection. However, this approach has been challenged by several factors including the emergence of new IBV serotypes (currently over 50 variants) that show little or no cross protection. Importantly, some IBV strains to which vaccines become available might disappear as new variants emerged and thus necessitate the development of new vaccines. Until recently, most IBV vaccines are based on live attenuated or killed vaccines derived from classical or variant serotypes. These vaccines are developed from strains originating from the USA such as M41, Ma5, Ark, and Conn and Netherlands, for example, H52 and H120, as well as European strains such as 793/B, CR88, and D274. However, studies have shown that vaccines against these strains often lead to poor immune response especially against local strains. Live attenuated IB vaccines have also been shown to contribute to the emergence of new pathogenic IBV variants [7, 8]. Notably, changes in geographical distribution and tissue tropism have been observed in QX-like strains that initially emerged in China and spread to cause great economic loss to poultry farmers in Asia, Russia, and Europe [11–14]. This review is aimed at describing progress and challenges associated with IBV vaccine development. Some aspects of viral-induced immune responses are discussed.