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Most of emerging viruses that are continuously detected belong to the RNA viruses and are often zoonotic in nature with epidemic or epizootic potential in case of transmission to livestock or humans [1–3]. Interestingly, approximately 50% of the highly pathogenic diseases caused by these agents affect the central nervous system [4–6]. Emerging viruses and also viruses highly pathogenic for animal species often arise from animal reservoirs, namely bats, rodents and insectivores. Thus, reliable animal models for the in vivo analysis of host-pathogen interactions in respective reservoir species and the mechanisms that drive crossing of species barriers are urgently needed. This could also allow characterization of transmission routes and maintenance in reservoir populations of these viruses. The order Mononegavirales comprises non segmented negative stranded RNA viruses with a considerable number of highly pathogenic viruses which reside inconspicuously in natural reservoirs, e.g. lyssaviruses, paramyxoviruses and henipaviruses in bats. In case of transmission to susceptible animals or humans they cause fatal disease [7, 8]. Borna disease virus-1 (BoDV-1) also belongs to the order Mononegavirales and was classified within an own and currently growing family named Bornaviridae. A new classification of this family with subdivision into 5 species has been proposed with the classical Borna disease virus-1 as part of the species Mammalian 1 bornavirus. Recently, a variegated squirrel-derived bornavirus (VSBV-1) was found in association with the death of three people indicating the zoonotic potential for this newly discovered bornavirus. Comparably to other reservoir-bound viruses of the order Mononegavirales, BoDV-1 infection can lead to a lethal neurological disorder in accidental hosts such as horses and sheep due to a severe immune mediated non purulent meningoencephalitis. The strictly endemic course of Borna disease with seasonal appearance in spring and early summer, the varying incidence between years with peaks every three to five years as well as the highly conserved viral genome pointed to a natural reservoir for BoDV-1 already for a long time. However, many studies in wild rodents did not reveal any signs of BoDV-1 infection in these species. First evidence of natural BoDV-1 infection in small mammals was provided by the detection of BoDV-1 antigen and RNA in bicolored white-toothed shrews (Crocidura leucodon) originating from an endemic area in Switzerland [14, 15]. This was substantiated by a study based on a geographic information system analysis which connects the prevalence of Borna disease and the distribution of C. leucodon. Recently, similar occurrence of BoDV-1 infection in C. leucodon in endemic areas in Bavaria and in Saxony-Anhalt [17, 18] further underlines the role of this shrew species as BoDV-1 reservoir. Overlapping feature of all BoDV-1-infected shrews—regardless of their endemic origin—is the widespread virus distribution not only in the central nervous system (CNS) but also in peripheral organs capable of shedding virus in secretions and excretions [15, 17, 18]. Experimental BoDV-1 infection of neonatal immune incompetent rats leads to a quite comparable mode of virus distribution. In these animals, persistent infection is achieved by immune tolerance. Obvious neurological signs are lacking but behavioural deficiencies have been noted. In contrast, adult Lewis rats exhibit a severe neurological biphasic disease due to a non purulent meningoencephalitis closely resembling the accidental host situation. Certain mice strains develop a fatal neurological disease only after intracerebral infection of newborns [20, 21]. Thus, outcome of experimental BoDV-1 infection in rodents such as mice and rats depend on the species and even the particular strain and, the age at time point of infection. The latter is most likely explainable by the status of the immune system. This leads to significant differences in virus-host interactions resulting in variable clinical outcome and fatality of disease, reaction pattern of the immune system, virus distribution and shedding.
Whether natural BoDV-1 infection of C. leucodon may fit to any of the known experimental courses or even run a different and so far unknown way of infection remains unknown. Thus, clinical outcome, routes of virus shedding including demonstration of infectivity was characterized in BoDV-1-infected C. leucodon. This contributes to understand not only BoDV-1 pathogenesis but also serve as in vivo model for the analysis of general mechanisms of viral co-existence of reservoir-bound neurotropic viruses in physiologically normal appearing hosts.
Canine morbillivirus (canine distemper virus, CDV) causes canine distemper (CD) in a wide range of mammalian hosts, and may produce systemic, respiratory, cutaneous, bone, and/or neurological manifestations in these animals1,2. CDV produces immunosuppression3 in susceptible hosts by targeting cells that express the signalling activation molecule (SLAM)4, which frequently results in opportunistic infectious diseases caused by agents such as Bordetella bronchiseptica5,6, Candida sp.7, Clostridium piliforme8, Toxoplasma gondii9–11, Dirofilaria immitis11, Mycoplasma cynos12, and Talaromyces marneffei13. Although the occurrence of CD is significantly reduced in domestic dog populations in developed countries due to the use of vaccination14, the disease is endemic and a major cause of canine mortality in urban populations of Brazil15,16, where an estimated 147.5–160.3 million USD is spent annually due to the therapy of the systemic effects of CDV15.
CDV has been diagnosed concomitantly with traditional viral infectious disease agents such as canine parvovirus-2 (CPV-2)17,18, canid alphaherpesvirus-118,19, canine adenovirus-1 and -2 (CAdV-1)20, and (CAdV-2)18,21 in dogs. Moreover, recently CDV has been identified in dogs simultaneously with emerging viral infectious agents including Canine kobuvirus22, Canine pneumovirus23, and Canine respiratory coronavirus6,23. Additionally, studies have detected canine infectious disease agents due to the amplification of nucleic acids in symptomatic6,23–25 and asymptomatic19 dogs by molecular assays. Alternatively studies have combined the pattern of organ disease observed by histopathology with electron microscopy20, immunohistochemistry (IHC)8,12,21,22,25,26 and/or the molecular identification8,10,12,18,22,27 of infectious disease agents of dogs.
Previous studies by our group8,10,18 and others12,21,26,27 have demonstrated the concomitant participation of several infectious disease agents in the development of diseases in dogs, principally puppies. It is proposed that puppies are probably more frequently coinfected by several infections disease agents than has been previously reported, particularly if there is the simultaneous involvement of CDV, and coinfections may result in the death of the affected dog due to multiple organ failure10. The objectives of this retrospective study were to evaluate the frequency of concomitant traditional infectious disease agents in the development of infectious diseases in puppies, correlate the presence of these pathogens with histopathologic patterns, and review specific aspects of the pathogenesis involving these infectious disease agents.
There was no difference in the gender (females, 7; males, 8) of the puppies during this study. Pure breed dogs (73.3%; 11/15) were predominant (Table 1) relative to their mixed breed counterparts (26.7%; 4/15). However, when the head conformation was considered within the purebred dogs28,29, most (54.5%; 6/11) were mesocephalic (medium-headed), followed by the brachycephalic (short-headed) breeds of dogs (36.4%; 4/11), and only one (9.1%) dolichocephalic dog. Additionally, most (72.7%; 8/11) of these were representatives of toy breeds, with only three large breed dogs. Furthermore, most (n = 5) of the cases occurred in 2013, followed by 2014 (n = 3), 2015 (n = 3), and 2017 (n = 3), with only one in 2016.
The principal clinical manifestations described are resumed in Table 1. Bloody diarrhoea (n = 11) was the most frequently described clinical manifestation, followed by anorexia (n = 5), abdominal pain (n = 4), and convulsions (n = 3). One puppy died (#12) without presenting any reported clinical manifestation. The course of clinical manifestations was acute in all puppies, varied between 1–10 days, and resulted in the spontaneous death of all puppies. The immunization history of these puppies was not known.
In order to evaluate the NV potential of the rVSV filovirus GP vectors cynomolgus macaques were inoculated by IT inoculation with 1×107 PFU of either rVSV-ZEBOV-GP (n = 7, Fig. 1A), rVSV-MARV-GP (n = 7, Fig. 1A), rVSV-wt (n = 3, Fig. 1A), or vehicle control (n = 4). Each animal received two inoculations, one per hemisphere, with the left hemisphere receiving the experimental inoculation and the right hemisphere receiving the vehicle control. Animals were then observed for neurologic signs of disease. Clinically, two macaques from the rVSV-wt control group (67-01 and 56-09) developed progressive neurological signs including ataxia, proprioceptive deficits, and tremors, and were euthanized at either day 5 or 6 post inoculation (Table 1). One of the rVSV-wt animals (362-09) did not show any discernable neurological signs. No neurological deficits were observed in any of the macaques in the vehicle control, rVSV-ZEBOV-GP, or rVSV-MARV-GP groups. Hematology and serum biochemistry were also monitored for each animal with no changes being observed in any animal, when compared to a prebleed for each animal, over the course of the study (data not shown).
Emerging infectious diseases under this category were subcategorized into 1a, 1b and 1c. Subcategory 1a covers known pathogens that occur in new ecological niches/geographical areas. A few past examples belonging to this subcategory are the introduction and spread of West Nile virus in North America; chikungunya virus of the Central/East Africa genotype in Reunion Island, the Indian subcontinent and South East Asia; and dengue virus of different serotypes in the Pacific Islands and Central and South America.18,19,20,21,22,23 Factors that contributed to the occurrence of emerging infectious diseases in this subcategory include population growth; urbanization; environmental and anthropogenic driven ecological changes; increased volume and speed of international travel and commerce with rapid, massive movement of people, animals and commodities; and deterioration of public health infrastructure. Subcategory 1b includes known and unknown infectious agents that occur in new host ‘niches'. Infectious microbes/agents placed under this subcategory are better known as ‘opportunistic' pathogens that normally do not cause disease in immunocompetent human hosts but that can lead to serious diseases in immunocompromised individuals. The increased susceptibility of human hosts to infectious agents is largely due to the HIV/acquired immune deficiency syndrome pandemic, and to a lesser extent, due to immunosuppression resulting from cancer chemotherapy, anti-rejection treatments in transplant recipients, and drugs and monoclonal antibodies that are used to treat autoimmune and immune-mediated disorders. A notable example is the increased incidence of progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system that is caused by the polyomavirus ‘JC' following the increased use of immunomodulatory therapies for anti-rejection regimens and for the treatment of autoimmune diseases.24,25,26 Subcategory 1c includes known and unknown infectious agents causing infections associated with iatrogenic modalities. Some examples of emerging infections under this subcategory include therapeutic epidural injection of steroids that are contaminated with Exserhilum rostratum and infectious agents transmitted from donor to recipients through organ transplantation, such as rabies virus, West Nile virus, Dandenong virus or Acanthamoeba.27,28,29,30,31
Infectious diseases have affected humans since the first recorded history of man. Infectious diseases remain the second leading cause of death worldwide despite the recent rapid developments and advancements in modern medicine, science and biotechnology. Greater than 15 million (>25%) of an estimated 57 million deaths that occur throughout the world annually are directly caused by infectious diseases. Millions more deaths are due to the secondary effects of infections. Moreover, infectious diseases cause increased morbidity and a loss of work productivity as a result of compromised health and disability, accounting for approximately 30% of all disability-adjusted life years globally.1,2
Compounding the existing infectious disease burden, the world has experienced an increased incidence and transboundary spread of emerging infectious diseases due to population growth, urbanization and globalization over the past four decades.3,4,5,6,7,8 Most of these newly emerging and re-emerging pathogens are viruses, although fewer than 200 of the approximately 1400 pathogen species recognized to infect humans are viruses. On average, however, more than two new species of viruses infecting humans are reported worldwide every year,9 most of which are likely to be RNA viruses.6
Emerging novel viruses are a major public health concern with the potential of causing high health and socioeconomic impacts, as has occurred with progressive pandemic infectious diseases such as human immunodeficiency viruses (HIV), the recent pandemic caused by the novel quadruple re-assortment strain of influenza A virus (H1N1), and more transient events such as the outbreaks of Nipah virus in 1998/1999 and severe acute respiratory syndrome (SARS) coronavirus in 2003.10,11,12,13,14 In addition, other emerging infections of regional or global interest include highly pathogenic avian influenza H5N1, henipavirus, Ebola virus, expanded multidrug-resistant Mycobacterium tuberculosis and antimicrobial resistant microorganisms, as well as acute hemorrhagic diseases caused by hantaviruses, arenaviruses and dengue viruses.
To minimize the health and socioeconomic impacts of emerging epidemic infectious diseases, major challenges must be overcome in the national and international capacity for early detection, rapid and accurate etiological identification (especially those caused by novel pathogens), rapid response and effective control (Figure 1). The diagnostic laboratory plays a central role in identifying the etiological agent causing an outbreak and provides timely, accurate information required to guide control measures. This is exemplified by the epidemic of Nipah virus in Malaysia in 1998/1999, which took more than six months to effectively control as a consequence of the misdiagnosis of the etiologic agent and the resulting implementation of incorrect control measures.15,16 However, there are occasions when control measures must be based on the epidemiological features of the outbreak and pattern of disease transmission, as not all pathogens are easily identifiable in the early stage of the outbreak (Figure 1). Establishing laboratory and epidemiological capacity at the country and regional levels, therefore, is critical to minimize the impact of future emerging infectious disease epidemics. Developing such public health capacity requires commitment on the part of all countries in the region. However, to develop and establish such an effective national public health capacity, especially the laboratory component to support infectious disease surveillance, outbreak investigation and early response, a good understanding of the concepts of emerging infectious diseases and an integrated country and regional public health laboratory system in accordance with the nature and type of emerging pathogens, especially novel ones, are highly recommended.
Traditionally, emerging infectious diseases are broadly defined as infections that: (i) have newly appeared in a population; (ii) are increasing in incidence or geographic range; or (iii) whose incidence threatens to increase in the near future.6,17 Six major factors, and combinations of these factors, have been reported to contribute to disease emergence and re-emergence: (i) changes in human demographics and behavior; (ii) advances in technology and changes in industry practices; (iii) economic development and changes in land use patterns; (iv) dramatic increases in volume and speed of international travel and commerce; (v) microbial mutation and adaptation; and (vi) inadequate public health capacity.6,17
From the perspective of public health planning and preparedness for effective emerging infectious disease surveillance, outbreak investigation and early response, the above working definition of emerging infectious disease and its associated factors that contribute to infectious disease emergence are too broad and generic for more specific application and for the development of a national public health system, especially in the context of a public health laboratory system in a country. Thus, in this article, emerging infectious diseases are divided into four categories based on the nature and characteristics of pathogens or infectious agents causing the emerging infections; these categories are summarized in Table 1. The categorization is based on the patterns of infectious disease emergence and modes leading to the discovery of the causative novel pathogens. The factors or combinations of factors contributing to the emergence of these pathogens also vary within each category. Likewise, the strategic approaches and types of public health preparedness that need to be adopted, in particular with respect to the types of public health laboratories that need to be developed for optimal system performance, will also vary greatly with respect to each category of emerging infectious diseases. These four categories of emerging infectious diseases and the factors that contribute to the emergence of infectious diseases in each category are briefly described below.
The order Mononegavirales contains four families (Rhabdoviridae, Paramyxoviridae, Filoviridae and Bornaviridae), which include many lethal human pathogens (e.g. rabies, Ebola, and Hendra viruses); highly prevalent human pathogens, such as the respiratory syncytial and parainfluenza viruses; potential ethological agents of some neurobehavioral abnormalities and psychiatric disorders in humans (Borna disease virus); as well as viruses with a major economic impact on the poultry and cattle industries (e.g. Newcastle disease virus and rinderpest virus). All members of this order share a similar genome organization and common mechanisms of genome replication and gene expression, and, as with other RNA viruses with limited coding capacity, they exploit cellular proteins and pathways to facilitate many aspects of their replication cycle. Identification of host-virus interactions can provide new insights into viral biology and developing new ways to combat viral infections via control of host components.
Vesicular stomatitis virus (VSV) is the best studied member of Mononegavirales and the prototypic rhabdovirus. There is now compelling evidence that enveloped virions (including members of Mononegavirales) released from infected cells carry numerous host (cellular) proteins some of which may play an important role in viral replication. Several cellular proteins have been previously shown to be incorporated into VSV virions including tubulin, cyclophilin A, translation elongation factor 1 alpha (EF1a), RNA guanylyltransferase, casein kinase II and heat shock cognate 71 kDa protein (Hsc70, also known as HSPA8). However, to the best of our knowledge, no systematic study has been done to reveal the host protein composition for virions of VSV or any other member of Mononegavirales.
A proteomics approach utilizing mass spectrometry (MS) has been used to successfully identify cellular proteins in a number of enveloped viruses including poxviruses, herpesviruses, orthomyxoviruses, coronaviruses, and retroviruses. Here we attempted the same strategy to identify cellular proteins within purified VSV virions, thereby creating a "snapshot" of one stage of virus/host interaction that can guide future experiments aimed at understanding molecular mechanisms of virus-cell interactions. Using this approach, we confirmed the presence of several previously-identified cellular proteins within VSV virions and identified a number of additional proteins.
Proventricular dilatation disease (PDD) is considered by many to be the greatest threat to aviculture of psittacine birds (parrots). This disease has been documented in multiple continents in over 50 different species of psittacines as well as captive and free-ranging species in at least 5 other orders of birds. Most, if not all major psittacine collections throughout the world have experienced cases of PDD. It has been particularly devastating in countries like Canada and northern areas of the United States where parrots are housed primarily indoors. However, it is also problematic in warmer regions where birds are typically bred in outdoor aviaries. Moreover, captive breeding efforts for at least one psittacine which is thought to be extinct in the wild, the Spix's macaw (Cyanopsitta spixii), have been severely impacted by PDD.
PDD is an inflammatory disease of birds, first described in the 1970s as Macaw Wasting Disease during an outbreak among macaws (reviewed in). PDD primarily affects the autonomic nerves of the upper and middle digestive tract, including the esophagus, crop, proventriculus, ventriculus, and duodenum. Microscopically, the disease is recognized by the presence of lymphoplasmacytic infiltrates within myenteric ganglia and nerves. Similar infiltrates may also be present in the brain, spinal cord, peripheral nerves, conductive tissue of the heart, smooth and cardiac muscle, and adrenal glands. Non-suppurative leiomyositis and/or myocarditis may accompany the neural lesions. Clinically, PDD cases present with GI tract dysfunction (dysphagia, regurgitation, and passage of undigested food in feces), neurologic symptoms (e.g. ataxia, abnormal gait, proprioceptive defects), or both. Although the clinical course of the disease can vary, it is generally fatal in untreated animals.
The cause of PDD is unknown, but several studies have raised the possibility that PDD may be caused by a viral pathogen. Evidence for an infectious etiology stems from the initial outbreaks of Macaw Wasting Disease, and other subsequent outbreaks of PDD. Reports of pleomorphic virus-like particles of variable size (30–250 nm) observed in tissues of PDD affected birds led to the proposal that paramyxovirus (PMV) may cause the disease; however, serological data has shown that PDD affected birds lack detectable antibodies against PMV of serotypes 1–4, 6, and 7, as well as against avian herpes viruses, polyomavirus, and avian encephalitis virus. Similarly, a proposed role for equine encephalitis virus in PDD has been ruled out. Enveloped virus-like particles of approximately 80 nm in diameter derived from the feces of affected birds have been shown to produce cytopathic effect in monolayers of macaw embryonic cells, but to date no reports confirming these results or identifying this possible agent have been published. Likewise, adeno-like viruses, enteroviruses, coronaviruses and reoviruses have also been sporadically documented in tissues or excretions of affected birds yet in each case, follow-up evidence for reproducible isolation specifically from PDD cases or identification of these candidate agents has not been reported. Thus, the etiology of PDD has remained an open question.
To address this question, we have turned to a comprehensive, high throughput strategy to test for the presence of known or novel viruses in PDD affected birds. We employed the Virus chip, a DNA microarray containing representation of all viral taxonomy to interrogate 2 PDD case/control series independently collected on two different continents for the presence of viral pathogens. We report here the detection of a novel bornavirus signature in 62.5% of the PDD cases and none of the controls. These bornavirus-positive samples were confirmed by virus-specific PCR testing, and the complete genome sequence has been recovered by ultra-high throughput sequencing combined with conventional PCR-based cloning.
Bornaviruses are a family of negative strand RNA viruses whose prototype member is Borna Disease Virus (BDV), an agent of encephalitis whose natural reservoir is primarily horses and sheep. Although experimental transmission of BDV to many species (including chicks) has been described, there is little information on natural avian infection, and existing BDV isolates are remarkable for their relative sequence homogeneity. The agent reported here, which we designate avian bornavirus (ABV) is highly diverged from all previously identified members of the Bornaviridae family and represents the first full-length bornavirus genome cloned directly from avian tissue. Subsequent PCR screening for similar ABVs confirmed a detection rate of approximately 70% among PDD cases and none among the controls. Sequence analysis of a single complete genome and all of the additional partial sequences that we have recovered directly from the PDD case specimens suggests that the viruses detected in cases of PDD form a new, genetically diverse clade of the Bornaviridae.
The order Mononegavirales comprises the non-segmented, negative sense, single-stranded RNA viruses in the family Filoviridae along with the families Rhabdoviridae, Paramyxoviridae, and Bornaviridae. The family Filoviridae contains two genera, Ebolavirus (EBOV) and Marburgvirus (MARV),. Infection with EBOV or MARV causes severe and often fatal hemorrhagic fever (HF) with case fatality rates ranging from 23–90% depending on the strain and/or species. The Ebolavirus genus is diverse and consists of four species: Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), and Reston ebolavirus (REBOV). A putative fifth species, Bundibugyo ebolavirus (BEBOV) was discovered during an outbreak in Uganda during 2007. Together, the Ebolavirus genus has accounted for at least 22 outbreaks dating back to 1976 with18 of these occurring within the last 20 years. The Marburgvirus genus has one species, Lake Victoria marburgvirus, that has been responsible for at least nine outbreaks since 1967 with five of these occurring in the last decade. The increased frequency of EBOV and MARV outbreaks along with the fact that these viruses are potential agents of bioterrorism has increased public health concern regarding filoviruses. Presently, there are no licensed vaccines or postexposure treatments available for human use; however, there are at least six different vaccine candidates that have shown the potential to protect nonhuman primates (NHP) from lethal EBOV and/or MARV infection,,,,,,,,,,,,,,,.
The filoviruses contain an RNA genome, approximately 19 Kb in length, which encodes seven proteins that are arranged from 3′ to 5′: nucleoprotein (NP); virion protein (VP)35; VP40; glycoprotein (GP); VP30; VP24; and the polymerase protein (L). The EBOV species express two extra nonstructural proteins from the GP gene referred to as soluble (s)GP and small soluble (ss)GP. Vaccine studies that have shown protection in animals from filovirus infections have primarily employed the GP protein as the immunogen with a few studies also using VP40 and/or NP,,,,,,,,,,,,,,,.
Vesicular stomatitis virus (VSV), a member of the family Rhabdoviridae, is composed of a genome of approximately 11 Kb which encodes five proteins that are arranged from 3′ to 5′: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and the large catalytic subunit (L) of the RNA-dependent RNA polymerase. Over the last decade the use of recombinant (r)VSVs as vaccine candidates has been studied due to the ability to insert and express foreign genes in the simple genome, the ability to propagate the virus to high titers in most mammalian cell lines, the lack of recombination or insertion into the host cell genome, the extremely low percentage of VSV seropositivity in the general population of Central America,, and the minimal pathogenicity of VSV in humans. rVSV vectors have been developed as vaccine candidates against many important human pathogens such as influenza virus, human immunodeficiency virus (HIV),,, measles virus,, respiratory syncytial virus, papillomavirus,, severe acute respiratory syndrome coronavirus, and HF viruses such as Lassa, EBOV, and MARV.
The rVSV filovirus GP vaccine platform, where the VSV glycoprotein (G) is replaced with filovirus GP, has shown promise as both a single-injection preventive vaccine,,,,, and a postexposure treatment against EBOV and/or MARV challenge in NHPs, . Initial studies showed that a single intramuscular (i.m.) vaccination of cynomolgus macaques with a rVSV vector expressing the ZEBOV GP or MARV GP induced strong humoral and/or cellular immune responses and elicited complete protection against a high dose (1000 plaque forming unit [PFU]) i.m. challenge of homologous ZEBOV or MARV given 28 days later. The efficacy of these vaccines to protect by i.m. vaccination against homologous high dose (1000 PFU) aerosol challenge was also tested. Importantly, homologous aerosol challenge with either ZEBOV or MARV 28 days after vaccination resulted in complete protection of the macaques. In addition to vaccinating via the i.m. route, the ability of the rVSV-ZEBOV-GP vaccine to protect cynomolgus macaques by intranasal and oral routes was also studied. Vaccination by these different routes resulted in complete protection against homologous challenge and elicited robust ZEBOV GP-specific humoral responses and T-cell responses that were induced after vaccination and also 6 months after ZEBOV challenge. More recently, we showed that a single injection of a blended vaccine consisting of equal parts of rVSV-ZEBOV-GP, rVSV-SEBOV-GP, and rVSV-MARV-GP completely protected NHPs against lethal challenge with either ZEBOV, SEBOV, CIEBOV, or MARV.
While the rVSV filovirus GP vectors have proven robust as preventive vaccines, these vectors have also shown utility as postexposure treatments with the rVSV-MARV-GP vector protecting 100%, 83%, and 33% of rhesus macaques challenged with MARV and treated 30 minutes, 24 hours, and 48 hours postexposure, respectively,. Treatment of macaques 30 minutes after challenge with a rVSV-SEBOV GP vector protected all animals against a lethal SEBOV challenge while treatment of macaques 30 minutes after challenge with the rVSV-ZEBOV GP vector protected 50% of the animals against a homologous ZEBOV challenge.
To date, the rVSV filovirus GP vectors have been used in over 80 NHPs with no signs of toxicity as a result of vaccination,,,,,. In addition, the rVSV-ZEBOV-GP vector was recently used as a treatment less than 48 hours after a possible, accidental ZEBOV exposure to a laboratory worker in Germany. While the efficacy of the treatment was not conclusive, the treated individual experienced mild fever, myalgia, and headache 12 hours after injection. Although these data suggest that the vectors are innocuous, the use of the rVSV filovirus GP vectors as vaccines and/or postexposure treatments in humans requires further safety testing. This is important considering that the vaccine is replication-competent and there is potential for VSV neurovirulence (NV), as has been reported in rodents,,,,,,,, macaques, cattle, sheep, and horses. Regardless of the potential for rVSV vector NV, replication-competent vaccines that are to be used in humans are generally subjected to NV testing. Typically, NV is evaluated by direct inoculation of the vaccine into the central nervous system (CNS) of a NHP. These NV tests have been developed for measles virus,, mumps virus,, yellow fever virus,, and poliovirus,. Most recently rVSV HIV vaccine variants have been tested for NV by intrathalamic (IT) inoculation with promising results.
In the current study, we evaluated the NV potential of the rVSV-ZEBOV-GP and the rVSV-MARV-GP vectors in cynomolgus macaques. The NV tests were modeled on previous examinations of the yellow fever virus vaccine and rVSV HIV vector variants where cynomolgus macaques were given an IT inoculation with 107 PFU of the vaccine and closely monitored over the course of 21 days.
A wide range of infectious disease drivers can be grouped under this category, including climate change, land-use patterns, global trade and travel, migration, and so on. Climate change involves mean temperature increases in many parts of the world, as well as increased likelihood of adverse or even extreme weather events (11–13). Many infectious diseases are temperature sensitive as many vectors and pathogens are dependent upon permissive ambient conditions. There is thus a substantial body of research that collectively demonstrates that warming will increase the transmission of vector-borne diseases in the geographic ranges of their distribution (14–18). Changing temperature and precipitation patterns can affect the habitats and population growth of cold-blooded disease vectors, such as mosquitoes and ticks, as well as the replication rates of infectious diseases within their hosts, and even the rates at which disease-carrying vectors bite humans (18–20).
Among the best substantiated indicators of the observed effects of climate change on infectious disease is evidence of an altitudinal increase of malaria in the highlands of Columbia and Ethiopia (21) and of the northerly expansion of the disease-transmitting tick species, Ixodes ricinus, in Sweden (22). Many modelling studies project significant shifts in the transmission of vector-borne diseases such as malaria (23, 24), dengue (25), and Chikungunya (26) under climate change scenarios, but it is important to note that the extent of observed changes will depend on the presence or absence of mitigating measures, such as vector control or socioeconomic development (27, 28). Other examples of infectious diseases in Europe anticipated to be affected by climate change include West Nile virus (29), salmonella (30), campylobacter, and cryptosporidium (31, 32).
Land-use patterns, meanwhile, are a crucial driver of infectious disease emergence. It has been estimated that more than 60% of human pathogens are zoonotic (i.e. diseases of animals that can be transmitted to humans) (33). Many human land-use activities, including agriculture, irrigation, hunting, deforestation, and urban expansion, can cause or increase the risk of zoonotic and food- and water-borne diseases (33, 34). For example, one consequence of urban sprawl and deforestation is that wildlife may increasingly need to find new habitats in urban or abandoned environments, which could lead to increased human exposures to infectious pathogens. Meanwhile, the density of human population, also associated with increasing urbanisation, has also been shown to be linked to the emergence of many infectious diseases (35).
Intensified global trade and travel, not to mention migration, render political borders irrelevant and create further possibilities for global disease transmission (36–38). There are numerous examples of the arrival, establishment, and spread of ‘exotic’ pathogens to new geographic locations, including malaria, dengue, Chikungunya, West Nile, and bluetongue in recent years, aided by shipping or other trade routes (36). This process is facilitated when the environmental conditions in different parts of the world share common characteristics (36). Meanwhile, numerous vaccine-preventable diseases, such as polio, meningitis or measles, can also be introduced or reintroduced to susceptible populations as a consequence of international travel (39).
The incidence of various emerging and reemerging infectious diseases continues to pose a substantial threat to the human health throughout the world. During the past two decades newly emerging ones, for example, severe acute respiratory syndrome (SARS), reemerging ones, for example, West Nile virus, and even deliberately disseminated infectious diseases, for example, anthrax from bioterrorism, threaten the health of the hundreds and millions of the people globally. During early nineties, there was a consensus that it was the time to close the book as the battle against infectious disease had been won. But reemergence of cholera to the Americas in 1991, the plague outbreak in India in 1994, and the emergence of SARS outbreak in 2002-2003, Swine flu (H1N1) pandemic in 2009, and most recently Zika outbreak in Brazil in 2015 eventually prove that thought wrong. Ebola virus disease (EVD) is one of the notorious emerging infectious diseases that endanger the human lives from time to time since its appearance in 1976 in Zaire (later renamed the Democratic Republic of the Congo) and Sudan in Africa continent. The recent epidemic of EVD started in Guinea in December 2013. Within a short period of time, it has spread across land borders to Sierra Leone and Liberia, by air to Nigeria and USA, and by land to Mali and Senegal. On August 8, 2014, the World Health Organization (WHO) declared the EVD outbreak in West Africa a Public Health Emergency of International Concern (PHEIC) under the International Health Regulations (2005). On March 29, 2016, PHEIC related to EVD was lifted from West Africa and on June 9, 2016, WHO declared the end of the most recent outbreak of EVD. By the end of the epidemic, total 15227 confirmed EVD cases have been reported with 11310 deaths in Guinea, Liberia, and Sierra Leone. Till date no indigenous EVD case has been reported in India. But no country is free from the threat of EVD outbreak. A precise prediction about transmission and consequences after an EVD outbreak in India will be effective for proper planning and management to combat with the situation.
Precision public health is a state-of-the-art concept in the new era of public health research and its application in health care. The concept of precision public health evolved within the last two to three years. The precision public health can be simply described as improving the ability to prevent disease, promote health, and reduce health disparities in populations by applying emerging methods and technologies for measuring disease, pathogens, exposures, behaviours, and susceptibility in populations and developing interventional policies for targeted public health programs to improve health. The emergent areas of precession public health are improving methodologies for early detection of pathogens and infectious disease outbreaks, modernizing public health surveillance, epidemiology, and information systems, and targeting health interventions to improve health and prevent diseases. Application of information technology and data science, like real time data acquisition, geospatial epidemiological modelling, big data analytics, and machine learning technology, in field of epidemiology paves the way to its transformation to digital epidemiology, which is conceptually more accurate and precise in nature [8, 9].
Geospatial epidemiological modelling, an application of geographic information system (GIS), is an important tool of precision public health to study the dynamics of disease transmission more accurately. This tool can be applied to predict the spread of an outbreak. Various interventional measures and subsequent outcome can also be studied, which will help to develop efficient and effective disease specific outbreak prevention and management strategies.
Keeping the concept of precision public health and geospatial epidemiological modelling in mind, a computer simulation based study, related to hypothetical EVD outbreak in India, was undertaken with following objectives: To simulate the spread of Ebola virus disease after a hypothetical outbreak in India on 01.01.2017 at New Delhi and to predict the number of exposed and infectious persons and deaths due to that EVD outbreak within a span of 2 years.
Emerging infectious diseases have been defined as, “infections that have newly appeared in a population or have existed previously but are rapidly increasing in incidence or geographic range.” Several features may make them particularly threatening. First, recognizing the disease can be difficult when the first cases appear, especially when the symptoms are non-specific. Second, no vaccine or specific treatment may be known initially. Moreover, heterogeneities in disease transmission may create high-risk groups, such as healthcare workers– and high-risk geographical areas, thereby dramatically enhancing the impact of the outbreak.
The 2003 severe acute respiratory syndrome (SARS) outbreak in Hong Kong is remarkably illustrative of the above issues: symptoms were similar to pneumonia; the incubation period was long enough for local and international transmission to occur; no vaccine or treatment was available; as much as 21% of cases worldwide were healthcare workers. The outbreak also demonstrated the possible existence of super-spreading events (SSEs), during which a few infectious individuals contaminated a high number of secondary cases. Hong Kong had two SSEs: the first occurred in Hospital X around March 3 and led to about 125 cases; the second occurred in Housing Estate Y on March 19, and led to over 300 cases,. Despite its particularly threatening features, the outbreak was brought under control.
In this context, once the epidemic is detected, spontaneous changes in behavior will occur, and non-pharmacological measures are usually initiated to control the outbreak. The resulting effects of these two phenomena on disease transmission is not easily quantified.
The effective contact rate, which reflects the combined influences of social proximity (the number of contacts per time unit) and the probability of infection through each contact, is an essential determinant of disease spread. Our aim was to estimate the temporal variation of this parameter in the community and hospitals, over the course of the outbreak.
Previously published mathematical models of parameter estimation addressed the issues of temporal variability, or social heterogeneity,. Here we present an approach that deals with both issues, together with the occurrence of SSEs. Then the method is applied to the 2003 SARS epidemic in Hong Kong (SARSID database).
Exposure to airborne pathogens is a common denominator of all human life. With the improvement of research methods for studying airborne pathogens has come evidence indicating that microorganisms (e.g., viruses, bacteria, and fungal spores) from an infectious source may disperse over very great distances by air currents and ultimately be inhaled, ingested, or come into contact with individuals who have had no contact with the infectious source [2–5]. Airborne pathogens present a unique challenge in infectious disease and infection control, for a small percentage of infectious individuals appear to be responsible for disseminating the majority of infectious particles. This paper begins by reviewing the crucial elements of aerobiology and physics that allow infectious particles to be transmitted via airborne and droplet means. Building on the basics of aerobiology, we then explore the common origins of droplet and airborne infections, as these are factors critical to understanding the epidemiology of diverse airborne pathogens. We then discuss several environmental considerations that influence the airborne transmission of disease, for these greatly impact particular environments in which airborne pathogens are commonly believed to be problematic. Finally, we discuss airborne pathogens in the context of several specific examples: healthcare facilities, office buildings, and travel and leisure settings (e.g., commercial airplanes, cruise ships, and hotels).
Because we applied stringent inclusion criteria for the above-described association analysis study, a number of ABV (+) and ABV (-) samples were excluded. From these materials, six additional ABV isolates were detected – 5 derived from cases considered clinically suspicious and a sixth isolate derived from a confirmed PDD case for which only GI content and liver specimens were available. Additional PCR screening of a set of 12 PDD control crop biopsy specimens provided to us unblinded again yielded solely ABV PCR (-) and GAPDH (+) results. These samples were excluded from the association analysis because we knew their clinical status prior to screening. We note that inclusion of these samples in statistical analyses would not diminish the association of ABV with known or suspected PDD.
A “disease” is any condition that impairs the normal function of a body organ and/or system, of the psyche, or of the organism as a whole, which is associated with specific signs and symptoms. Factors that lead to organs and/or systems function impairment may be intrinsic or extrinsic. Intrinsic factors arise from within the host and may be due to the genetic features of an organism or any disorder within the host that interferes with normal functional processes of a body organ and/or system. An example is the genetic disease, sickle cell anaemia, characterized by pain leading to organ damage due to defect in haemoglobin of the red blood cell, which occurs as a result of change of a single base, thymine, to adenine in a gene responsible for encoding one of the protein chains of haemoglobin. Extrinsic factors are those that access the host's system when the host contacts an agent from outside. An example is the bite of a mosquito of Anopheles species that transmits the Plasmodium falciparum parasite, which causes malaria. A disease that occurs through the invasion of a host by a foreign agent whose activities harm or impair the normal functioning of the host's organs and/or systems is referred to as infectious disease [1–3].
Infectious diseases are generally caused by microorganisms. They derive their importance from the type and extent of damage their causative agents inflict on organs and/or systems when they gain entry into a host. Entry into host is mostly by routes such as the mouth, eyes, genital openings, nose, and the skin. Damage to tissues mainly results from the growth and metabolic processes of infectious agents intracellular or within body fluids, with the production and release of toxins or enzymes that interfere with the normal functions of organs and/or systems. These products may be distributed and cause damage in other organs and/or systems or function such that the pathogen consequently invades more organs and/or systems.
Naturally the host's elaborate defence mechanism, immune system, fights infectious agents and eliminates them. Infectious disease results or emerges in instances when the immune system fails to eliminate pathogenic infectious agents. Thus, all infectious diseases emerge at some point in time in a given population and in a given context or environment. By understanding the dynamics of disease and the means of contracting it, methods of fighting, preventing, and controlling are developed [2, 5, 6]. However, some pathogens, after apparent elimination and a period of dormancy, are able to acquire properties that enable them to reinfect their original or new hosts, usually in increasingly alarming proportions.
Understanding how once dominant diseases are reappearing is critical to controlling the damage they cause. The world is constantly faced with challenges from infectious diseases, some of which, though having pandemic potential, either receive less attention or are neglected. There is a need for constant awareness of infectious diseases and advances in control efforts to help engender appropriate public health responses [7, 8].
Bornaviruses are enveloped, 80 to 100 nm in diameter with a non-segmented genome of single-stranded negative sense RNA of around 8900 nucleotides in length, belonging to the order Mononegavirales. Bornaviruses replicate in the nucleus of the nerve cells of various organs and establish persistent, non-cytolytic infections by exploiting the cellular splicing mechanisms to efficiently use its genome, organized into six open reading frames (ORFs) (Figure 1). Alternative transcription start and stop sites and splicing produce mRNAs that are translated to produce the viral-encoded proteins (Figure 1). The first transcription unit contains an ORF for the nucleoprotein (N), the second transcription unit contains two overlapping ORFs for the phosphoprotein (P), and the X protein (X) (Figure 1). The third transcription unit is spliced differently, and also has different transcription initiation and termination signals, enabling polymerase read-through during transcription, which results in expression of the matrix protein (M), the glycoprotein (G), and the RNA-dependent RNA-polymerase (L) (Figure 1). The P and X ORFs overlap; as well as, the M and G ORFs (Figure 1). The immunogenicity of phosphoprotein, as well as, the degree of conservation of the phosphoprotein and its gene, within and between bornavirus species, make them good candidates as universal targets in laboratory diagnosis. Once the family Bornaviridae is expanding speedily, producing knowledge about highly conserved regions within phosphoprotein will be useful for the development of sensitive laboratory diagnostic tools. So far, genus Carbovirus, Cultervirus and Orthobornavirus have been identified, which comprise 11 species. From those, 10 species are associated with the development of severe neurological and/or gastrointestinal disease and death of its hosts [5–15] (Figure 2). The disease has been reported in humans, several species of pets, production and wild animals [5–15]. Namely, two species infect mammals (Mammalian 1 to 2 orthobornavirus), five infect birds (Passeriform 1 to 2 orthobornavirus, Psittaciform 1 to 2 orthobornavirus and Waterbird 1 orthobornavirus) and three infect reptiles (Queensland carbovirus, Southwest carbovirus and Elapid 1 orthobornavirus) (Figure 2). However, some Mammalian 1 orthobornavirus showed the ability to also infect farmed ostriches and wild birds (mallards and jackdaws). Wild birds are hosts of avian bornaviruses (e.g. strains of Waterbird 1 orthobornavirus and Psittaciform 1 orthobornavirus) [13–15,17] and mammalian bornaviruses (e.g. genotypes of Mammalian 1 orthobornavirus). Therefore, co-infection may play a role in the emergence of new pathogenic and zoonotic bornavirus species; once X and P proteins of PaBV-4 look like to have different ancestors.
In Psittaciformes, parrot bornavirus 1 to 8 (PaBV-1 to 8) can cause proventricular dilatation disease (PDD), characterized by a flaccid and distended proventriculus impacted with feed, as a result of the inability of seeds’ digestion (however throughout the gastrointestinal tract can occur variable distention). Psittaciformes can also show uncoordinated movements, postural disorders, apathy, blindness, and behavioural disorders, such as loss of appetite and self-mutilation (resulting from lesions in the central nervous system). Within captive birds, the virus has become relevant for Psittaciformes housed in reserves, in breeding projects of rare species, in private collections and zoos, because of the severe effects it may cause for bird welfare, economy, and biodiversity levels. Analyses of molecular epidemiology suggested that a world trade of psittacines without biosafety measures has been carried out. There is, to the best of our knowledge, no publications identifying and characterizing the avian bornaviruses infecting pet parrots in Portugal. Moreover, there are still unresolved questions on the epidemiology of bornaviruses, such as the role of waterbirds in the emergence and dissemination of new pathogenic and zoonotic species, and the localization of highly conserved regions within P gene inter- and intra-species of bornaviruses.
The aim of this study was to identify and phylogenetically characterize the etiologic agent associated with clinical signs and necropsy findings consistent with avian bornavirus infection in two pet parrots in Portugal, as well as to produce molecular epidemiologic knowledge on bornaviruses.
For a long time, children’s infectious diseases have been the number one disease type to harm children’s health and threaten children’s lives. With the continuous development of medical undertakings, although human beings have made brilliant achievements in controlling and defeating children’s infectious diseases, the harm and threat of children’s infectious diseases are still very serious today. Children’s infectious diseases are prone to various complications threatening children’s lives; therefore, understanding the occurrence and changes of children’s infectious diseases is of great significance to the prevention and treatment of infectious diseases and the promotion of children’s health.
Infection surveillance is important in infectious disease management and prevention. The surveillance of notifiable diseases in China was first initiated in the 1950s. Accurate and timely surveillance of infectious diseases laid the foundation for effective disease control and prevention in China. After the severe acute respiratory syndrome (SARS) crisis in 2003, the Chinese government strengthened the construction of the public health information system. China officially initiated the China Information System for Disease Control and Prevention (CISDCP) in January 2004. This system is the most comprehensive and macroscopic notifiable disease surveillance system in China. Timely analysis of notifiable disease surveillance data to understand epidemic trends and their main characteristics is the basis for the prevention and control of infectious diseases.
Zhejiang province, located in the southeastern coast of China, has moist air, a mild climate, a developed economy, and large population mobility. It covers an area of 101,800 km2 and is one of the most densely populated provinces in China. By 2017, the population has reached up to 56 million, and the population aged 0–14 years is about 7.5 million.
In this paper, we described epidemiological characteristics of notifiable diseases in children aged 0–14 years reported in Zhejiang Province in 2008–2017, for the purpose of providing a reference for the prevention and control of infectious diseases in children in Zhejiang Province. The results are reported as follows.
Genomic information offers the opportunity for more personalized treatment and prevention in clinical practice and public health settings. Until recently, such efforts have focused largely on common, complex diseases (for example, cancers, heart disease, neurodegenerative diseases) and less common inherited diseases; examples of such efforts include risk screening, diagnostic sequencing and pharmacogenomics. Now there is growing interest in the application of genomics to the management of infectious diseases and epidemics, which are among the top global public health burdens. Rapid and large-scale sequencing of pathogen genomes, which provides stronger and more accurate evidence than was previously possible for source and contact tracing, is being applied widely for disease outbreak management - most recently and publicly in the case of the Ebola outbreak in West Africa. Additional uses include precise diagnosis of microbial infection, describing transmission patterns, understanding the genomics of emerging drug resistance and identifying targets for new therapeutics and vaccines. There is growing evidence that, as well as pathogen genetic factors, host genetic factors and the interaction between host, vector and pathogen influence variability in infection rates, immune responses, susceptibility to infection, disease progression and severity, and response to preventive or therapeutic interventions. As such, genomic research is improving our understanding of infectious disease pathogenesis and immune response and may help guide future vaccine development and treatment strategies [11–18].
While the past few years have seen substantial federal and private research funding for infectious disease genomics research, there has been little discussion of the possible ELSIs - for individuals, groups or larger society - of using genomic information in the management of infectious disease. This gap may be explained in part by the current paucity of scientific advances in genomics that have practical applications to infectious disease management. Although it may be premature, we must nevertheless anticipate the possibility of ELSI-associated challenges in the future. This Opinion aims to anticipate what some of these issues might be and under what conditions they could arise. We argue that these considerations - even as the science is still developing - should become part of the agenda of researchers, clinicians, policymakers and public health officials so that the benefits of genomic applications to infectious disease are maximized while potential harms to individuals and populations are minimized.
We begin by acknowledging the existing scholarship on ELSI issues in the genomics of non-communicable diseases, and the ethical and legal issues surrounding infectious disease management. Then we briefly describe some of the epidemiologic characteristics and recent genomic advances associated with four particular infectious diseases - Ebola, pandemic influenza, hepatitis B and tuberculosis - that have large-scale public health consequences but differ in terms of ease of transmission, chronicity, severity, preventability and treatability, factors which affect a range of ELSI issues. In this section we also consider the situations under which the use of genomic information might or might not be appropriate in the management of infectious diseases. Finally, we describe some of the major ethical, legal and social issues that arise in the context of genomics and how they may play out in the management of these four specific infectious diseases.
In the Republic of Korea (ROK), the "Prevention of Contagious Diseases Act" was first enacted in the year 1954 and this law laid the foundation of the "National Notifiable Disease Surveillance System (NNDSS)", by designating 20 infectious diseases for mandatory reporting. The first major revision of this law in 2000 provided the current structure of the NNDSS, which collects individual patient information using an electronic reporting system. As of August 2008, this system covered 50 infectious diseases1).
Recently, as of December 30, 2010, the "Prevention of Contagious Diseases Act" and "Parasite Diseases Prevention Act" were merged and completely revised to the "Law for Control and Prevention of Infectious Diseases" and "Quarantine Act". Major changes in the "Law for Control and Prevention of Infectious Diseases" included a change in terminology from "contagious diseases" to "infectious diseases" which includes both contagious and non-contagious diseases, and extended disease entities, to enable the government to conduct surveillance or management. This new law classifies infectious diseases into 11 categories with 78 disease entities2). Table 1 shows these details.
Compared to the past, environmental and hygienic conditions have improved with economic developments in the ROK, and incidence of most infectious diseases, especially vaccine-preventable diseases (VPDs), has remarkably decreased due to active immunization with the developed level of health care3). However, with advances in diagnosis of specific diseases or international travel becoming more common, other diseases, such as those that are acquired through travel abroad, and re-emerging or newly emerging diseases, are increasing in incidence4).
In this review, the past and recent status of infectious diseases in the ROK was investigated with reference to data accumulated in the NNDSS5). The range of infectious diseases is too broad; therefore, the analysis was limited to significant infectious diseases that fall under categories I, II and III of the currently revised law.
Tetanus data has been collected since it was designated as a category II infectious disease in 1976. In 1980, the DTaP vaccination rate exceeded 90% and few neonatal tetanus cases were reported, and after the 1990s, about 10 cases have been reported yearly. However, in the 2000s, 10 to 20 cases have been reported yearly (Fig. 2).
For the past decade, the total number of reported cases was 107, and the number of cases patients aged <10 years and 10 to 19 years was 0 and 1, respectively. Few cases occurred in the pediatric age group, and those aged 40 years or more accounted for 94.4%5).
In 2008–2017, morbidity of Class B infectious diseases showed a significant downward trend, from 185.34/100,000 in 2008 to 54.36/100,000 in 2017 (χ2trend = 11,093.22, p < 0.05), with an annual morbidity of 90.39/100,000; morbidity of Class C infectious diseases showed a fluctuating upward trend, from 1352.97/100,000 in 2008 to 2549.03/100,000 in 2017 (χ2trend = 97,595.69, p < 0.05), with an average annual morbidity rate of 2412.47/100,000 (Table 1).
The top 5 reported Class B infectious diseases were dysentery, scarlet fever, measles, Influenza A (H1N1) and syphilis. The morbidity of measles, dysentery and syphilis showed a decline (measles: χ2trend = 10,156.59, p < 0.05; dysentery: χ2trend = 6301.75, p < 0.05; syphilis: χ2trend = 3376.99, p < 0.05); and that of scarlet fever was on the rise in recent years (χ2trend = 4185.20, p < 0.05). Influenza A (H1N1) was classified as a Class B infectious disease in 2009; 5805 cases of influenza A (H1N1) were reported in 2009, ranking first among Class B infectious diseases reported in the same year. This disease showed a decline in 2010 (χ2 = 5126.04, p < 0.05), and the number of cases reported was between 3 and 259 in 2010–2013. Since 1 January 2014, it was removed from Class B to Class C under the management of existing influenza (Figure 1).
The top 5 reported Class C infectious diseases were hand-foot-and-mouth disease (HFMD), other infectious diarrheal diseases, mumps, influenza and acute hemorrhagic conjunctivitis, among which the morbidity of HFMD, other infectious diarrheal diseases, and influenza were on the rise, while the morbidity of acute hemorrhagic conjunctivitis and mumps were decreasing year by year. In 2010, 11,789 cases of acute hemorrhagic conjunctivitis were reported, and thereafter the number of cases reported decreased rapidly (Figure 2).
Hepatitis B is found in virtually every region of the globe. Of the more than 2 billion people who are or have been infected, 350 to 400 million are carriers of the chronic disease; the remainder undergo spontaneous recovery and production of protective antibodies. Nearly 100% of infected infants (that is, those born to HBV-infected mothers) become chronically infected. The risk of developing a chronic infection decreases with age.
At least 30% of those with chronic HBV infection experience significant morbidity or mortality, including cirrhosis and hepatocellular carcinoma. Most people do not know they are infected until they present with symptoms of advanced liver disease, which means that infected individuals can spread the infection unknowingly, sometimes for many years. Although oral antiviral therapies are effective at stopping HBV replication, they do not cure the disease. Therefore, therapy is usually lifelong. Treatment is also complicated by the development of drug resistance and side effects. A vaccine against HBV is safe and effective in 90 to 95% of people; however, the individuals who are most at risk of becoming infected are often those with limited access to the vaccine, such as marginalized populations or people living in resource-limited countries.
There is substantial evidence that an individual's likelihood of recovering from an acute HBV infection or developing severe sequelae from infection is influenced, in part, by genes [39–45]. Candidate gene and genome-wide association studies have identified variants associated with HBV-related disease progression or hepatocellular carcinoma in various populations [46–52]. Treatment response to interferon (IFN)-α has been associated in some, but not all, studies with IFNλ3 polymorphisms. Finally, specific gene variants (HLA and non-HLA alleles) have been associated with vaccine response and non-response [54–57].
Infectious diseases remain among the leading causes of death and disability worldwide. About 15 million (>25%) of 57 million annual deaths are estimated to be related directly to infectious diseases (1). Newly emerging and re-emerging infectious diseases constitute an urgent and ongoing threat to public health throughout the world. The discovery of acquired immune deficiency syndrome (AIDS) has led to renewed appreciation of the consequences of the emergence of infectious diseases. Severe acute respiratory syndrome (SARS) emerged in southern China in 2002 and has had a profound impact on public health (2). Influenza viruses possess evolutionary agility and the capacity to jump between fowl, farm animal and human species (3). Just as troubling are chronic infections, which create persistent social and economic havoc. Recent studies have shown that the burden of morbidity and mortality associated with certain infectious diseases falls primarily on infants and young children (4), with long-term social and economic consequences.
Surveillance and early response to infectious diseases depend on rapid clinical diagnosis and detection, which, if in place, are able to ameliorate suffering and economic loss. Biomarkers, molecules that can be sensitively measured in the human body, are by definition potentially diagnostic. The efficacy of biomarkers to infectious diseases lies in their capability to provide early detection, establish highly specific diagnosis, determine accurate prognosis, direct molecular-based therapy and monitor disease progression (5). They are increasingly important in both therapeutic and diagnostic processes, with high potential to guide preventive interventions. Vast resources have been devoted to identifying and developing biomarkers that can help determine the treatments for patients. Furthermore, there is growing consensus that multiple markers will be required for most diagnoses, while single markers may serve in only selected cases. Despite intensified interest and research, however, the rate of development of novel biomarkers has been falling (6), suggesting that a resource that leverages existing data is overdue. At present the databases containing information about biomarkers are focused predominantly on cancer: early detection research network (7), gastric cancer knowledgebase (8), integrated cancer biomarker information system (9) and database for cancer, asthma and autism for children's study (10). Even here, although 15–20% of cancers are linked to infectious diseases and chronic infection causes cancer (11), no systematic effort has been described for integrating information from the cancer biomarker and the infectious disease domains.
In order to advance our understanding of biomarkers and the roles in early infection processes, we have developed an integrated user-friendly relational database that catalogs putative and validated biomarkers relates them to infectious diseases processes. In addition, we have added value by hosting various bioinformatics tools that can be used to analyze and visualize the biomarker data. This freely accessible resource will be a valuable research tool and a contribution to improved public heath.
The financing, provision, and quality of healthcare systems; the availability of vaccines, antivirals, and antibiotics medicines, and appropriate compliance to treatment protocols are all important determinants of infectious disease transmission. Although the correlation between healthcare system financing and efficacy is not perfect, recent budget cuts to healthcare are an important consideration when anticipating infectious disease risk. In part related to the global economic crisis, it has been reported that many high-income governments have introduced policies to lower spending through cutting the prices of medical products and, for example, through budget restrictions and wage cuts in hospitals (54). There are many indirect and direct pathways through which budget cuts could affect disease transmission; to provide just one example, it has been estimated that 20–30% of healthcare-associated infections are preventable with intensive hygiene and control programmes2 – should investments in this area diminish, then healthcare-acquired infections could become an even more problematic issue. There are currently roughly 4.1 million healthcare-associated infections each year in the EU alone.3
A broader issue related to healthcare provision is population mobility for both healthcare professionals and patients who might increasingly seek work or healthcare in other countries – the provision of cross-border healthcare and the mitigation of cross-border health threats will necessitate collaboration across borders (55, 56) and solutions for the brain-drain of medical personnel from resource-poor countries (57). Also related to the healthcare provision and practice is the over-prescription or overuse of antibiotics. In combination with a lag in pharmaceutical innovation, rapid transmission, and poor infection control measures, this has driven resistance of organisms such as methicillin-resistant Staphylococcus aureus, or extended-spectrum beta-lactamases, and carbapenemase-producing gram-negatives such as Klebsiella pneumoniae carbapenemase (KPC) (58). Antimicrobial resistance is currently one of the major health risks facing society (59).
Food production systems remain a persistent source for human infectious diseases. Attempts are underway to estimate the global burden of food-borne disease (60), which is likely substantial. Many factors in food production affect human health. A vast range of familiar human pathogens can be acquired through the consumption of animal products and other disease drivers, such as global travel, further provoke this (61). In addition to farmed animals, the hunting and slaughtering of wild animals has led to the emergence of more exotic pathogens: SARS originated in wildlife markets and restaurants in southern China (62) and HIV and Ebola have both been linked to the hunting or slaughtering of primates and other wild animals (33, 63, 64). The density and health of livestock, meanwhile, have been linked to disease in humans (65, 66). Although inconclusive, there is some evidence to suggest that livestock production may lead to increased antibiotic resistance in human pathogens. There are certainly many pathways by which drug resistant pathogens could transmit from livestock to humans, including environmental contamination by excreted veterinary antibiotics (33, 67, 68).