Dataset: 11.1K articles from the COVID-19 Open Research Dataset (PMC Open Access subset)
All articles are made available under a Creative Commons or similar license. Specific licensing information for individual articles can be found in the PMC source and CORD-19 metadata.
More datasets: Wikipedia | CORD-19
Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
Funded by The Federal Ministry for Economic Affairs and Energy; Grant: 01MD19013D, Smart-MD Project, Digital Technologies
First isolated in 1947 from an infected monkey in Uganda and re-isolated from Aedes mosquitoes in the same area during 1948 (Dick et al., 1952), ZIKV infections in humans have sporadically occurred in Africa and Asia, but in 2007 the virus continued spreading, causing outbreaks in small island countries located in the Pacific Ocean, such as Yap Island (Duffy et al., 2009), French Polynesia (Cao-Lormeau et al., 2014) and Easter Island (Tognarelli et al., 2016). In early 2015, an epidemic of ZIKV infections, originating from Brazil, spread through most of North and South America and the Caribbean with tens of thousands of people over 80 countries infected (WHO, 2017), as well as thousands of imported cases from travelers returning to their home countries after visiting outbreak areas. The epidemic was declared over by the World Health Organization (WHO) on November 2016 (WHO, 2017), but many countries are still dealing with the long-term impact of ZIKV infections. Infections of ZIKV are typically asymptomatic, but if present they are mild in nature and includes fever, joint pain, maculopapular rash, and bloodshot eyes (Simpson, 1964). While no deaths have been reported from ZIKV infections, mother-to-child transmission during pregnancy may result in congenital Zika syndrome with abnormalities in the central nervous system (microcephaly, intellectual development, seizures and vision impairment) (Boeuf et al., 2016). ZIKV infections in adults is associated with Guillain–Barré syndrome (Frontera & da Silva, 2016). Distinct from other flavivirus infections, sexual transmission of ZIKV from male-to-male (Deckard et al., 2016), male-to-female (D'Ortenzio et al., 2016; Hills et al., 2016) and female-to-male (Davidson et al., 2016) have been documented.
Infection of wild-type 129Sv/Ev mice SC with 106 pfu of ZIKV MP1751 did not result in any observable clinical symptoms or histological changes, despite the virus being detected at low levels in the blood, spleen and ovaries (Dowall et al., 2016). In their study, Dowall et al. challenged 5–6 week old Ifnar–/– mice (129Sv/Ev background) under the same conditions as above, and showed that all animals succumbed to disease at 6 dpi with 20% body weight loss. High levels of virus could be detected by RT-qPCR at 3 and 7 dpi in the blood, spleen, brain, ovary and livers of these animals. Pathology studies show that inflammatory as well as degenerative changes could be seen in the brains of infected Ifnar–/– mice (Dowall et al., 2016). In another study, Lazear et al., (2016) inoculated 5–6 week old Ifnar–/– mice (C57BL/6 background) with 102 pfu of ZIKV strain H/PF/2013 or MR766 via the SC route in the footpad. The results show that Ifnar–/– mice all died within 8–10 dpi after challenge with H/PF/2013, and 80% death with MR766, with death between 9–13 dpi. Additionally, an SC challenge with 103 focus forming units (ffu) of ZIKV strain Dakar 41671, 41667 or 41519 in Ifnar–/– mice results in uniform death by 6 dpi (Lazear et al., 2016). In a third study, Rossi et al. (2016) inoculated 3-, 5- and 11-week old Ifnar–/– mice (C57BL/6 background) with 1×105 pfu of ZIKV FSS13025 via the SC route. The results showed 100% lethality in 3-week old animals with death occurring at 6–7 dpi, but only 50% death in 5-week old animals and no deaths in 11-week old animals (Rossi et al., 2016), indicating that the disease caused by ZIKV infection in these animals is age-dependent.
Severe fever with thrombocytopenia is a newly recognized disease in rural areas of northeastern and central China, with several cases in Japan and South Korea (Promedmail, 2013). Caused by SFTSV, the transmission route of the virus is still unknown, but most likely involves arthropod vectors or animal hosts since the virus has been detected in ticks collected from domestic animals (Tian et al., 2017), and the animals (i.e., goats, cattle and dogs) also have high levels of SFTSV-specific antibodies (Jiao et al., 2012). Patients infected with SFTSV present with fever, vomiting, diarrhea, thrombocytopenia, leucopenia, and increased liver enzyme levels, in which severe cases of SFTSV eventually result in multiple organ failure resulting in death (Yu et al., 2011). The fatality rate amongst hospitalized patients can be up to 30%, and hundreds of cases are reported annually in China (Liu et al., 2015).
Infection of wild-type mice (BALB/c, C57BL/6) results in limited weight loss but the animals do not succumb to disease (Chen et al., 2012; Jin et al., 2012). In one study, Liu et al. (2014) infected 6–10 week old Ifnar–/– mice (129/Sv background) SC with 106 ffu of SFTSV strain YL-1. The mice were highly susceptible to challenge, with all mice appearing ill by 3 dpi, resulting in death between 3–4 dpi. Blood and major organs (brain, heart, kidney, intestine, liver, lung and spleen) were collected from infected Ifnar–/– mice daily, and results showed high levels of virus replication with systemic spread to all organs. In particular, the spleen and intestine had the highest peak virus titers at death (Liu et al., 2014). In another study, Matsuno et al. infected 6–12 week old Ifnar–/– mice (C57BL/6 background) with either a high dose (105 TCID50 per animal) or a low dose (102 TCID50 per animal) of SFTSV strain SD4 via the intradermal (ID), IP, IM or SC routes. The results showed that the Ifnar–/– mice were susceptible to infection via all routes, with animals succumbing to death at 4 and 6 dpi in the high and low dose groups, respectively (Matsuno et al., 2017).
Coronaviruses (CoVs) prior to the SARS outbreak were only known to be the second cause of the common cold after rhinoviruses. At least four different species can cause mild, self-limiting upper respiratory tract infections in humans: alphacoronaviruses HCoV-229E and HCoV-NL63, and betacoronaviruses HCoV-HKU1 and HCoV-OC43. More recently, two more additional pathogenic human-CoV were identified: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV).23 SARS-CoV was first identified in China in February 2003, and 4 months later, >8000 cases had been reported with about 800 deaths in 27 different countries worldwide.24 SARS-CoV has a wide host range and it is associated with wildlife meat industry. The natural history of the virus involves bats as primary hosts that then transmitted it to the intermediate amplifying hosts – as mask palm civets and raccoon dogs – that then could spread it to humans.23,25 Human-to-human transmission follows and can lead to large numbers of infected patients and is considered the main route of transmission in large-scale epidemics.9
MERS-CoV is phylogenetically related to SARS-CoV and share with SARS-CoV the origin in bats.23,26,27 Several CoVs have been identified in insectivorous and frugivorous bat species in various countries, indicating that bats may represent an important reservoir of these viruses.23 MERS-CoV was first identified in Saudi Arabia in 2012 and then spread to other countries causing hundreds of deaths.26,28 Clinical features of MERS-CoV are similar to SARS-CoV, although this virus has also been associated with several extrapulmonary manifestations, such as severe renal complications. Recent studies have indicated that dromedary camels may be the intermediate hosts and potential source of the virus for humans.26,29 In addition, the first experimental infection of bats with MERS-CoV has been described. The virus maintains the ability to replicate in the host without clinical signs of disease, supporting the general hypothesis that bats are the ancestral reservoir for MERS-CoV.30 Human-to-human transmission has also been reported. Based on epidemiological data, both animal-to-human and human-to-human transmission are considered to be important elements in MERS outbreak.26
Paramyxoviridae constitute a wide viral family that includes human and animal pathogens. Several bat-borne paramyxoviruses have been recognized such as parainfluenza type 2 virus, Mapuera, Menangle and Tioman viruses and two infectious agents of emerging diseases, such as Nipah and Hendra viruses.20
Nipah and Hendra viruses, classified as the genus Henipavirus, are capable of causing severe, potentially fatal diseases in humans.20 Fruit bats of the Pteropus genus are the common reservoir hosts of the Nipah and Hendra viruses.20
Nipah virus (NiV) first emerged in 1998 in Malaysia, causing an outbreak of respiratory illness and encephalitis in pigs.21 Pig-to-human transmission of Nipah virus – associated with severe febrile encephalitis – was described and it was thought to occur through close contact with infected animals. Although uncommon, human-to-human transmission of virus was also described.21 In two other outbreaks in Bangladesh and India, an intermediate animal host was not identified, suggesting bat-to-human and human-to-human transmissions.
Hendra virus (HeV) causes a fatal respiratory disease in both humans and horses.20,22 Several outbreaks of HeV have occurred in Australia. Horse is the intermediate host and the virus is likely transmitted via ingestion of feed, pasture or water contaminated with urine, saliva and feces of infected bats. Horse-to-human transmission occurs when there is close contact with ill animals.20 To date, human-to-human transmission has not been observed.
LPAIV H7N9 was identified as a newly emerging zoonotic pathogen in early 2013. It has caused since then a total of 680 cases of zoonotic infection, with a case-fatality rate of about 20%, principally in adult and elderly individuals. With an incubation time of 2–8 days, H7N9 virus infection can progress from initial symptoms of high fever and other influenza-like signs to more severe lower respiratory tract infection, respiratory distress and associated complications. Exposure to infected poultry is considered the primary risk factor for human infection. A total of 556 outbreaks have been reported in domestic poultry, including chickens, ducks, geese, pigeons and pheasants, largely concurrently to zoonotic cases of infection (Table 1). A few cases were reported in wild bird species. Because of their low pathogenic nature, H7N9 viruses typically cause asymptomatic or mild infections in birds.
Most animal outbreaks and zoonotic cases of low pathogenic avian influenza H7N9 virus infection occurred in mainland China, while imported zoonotic cases were identified in Canada and Malaysia (Fig. 1). The first epidemic of H7N9 virus infection in poultry peaked in April 2013 soon after the first identification of the virus as a cause of a zoonotic case of infection. Epidemics subsequently re-occurred in winter 2014 and 2015, with the highest reported numbers of animal outbreaks and zoonotic cases of infection during the months of January–February of each year.
LPAIV H7N9, in contrast to most other avian influenza viruses, can bind to the cellular receptors used by seasonal influenza viruses,. This ability is associated with one or two specific amino-acids in the hemagglutinin glycoprotein. Because seasonal influenza viruses and LPAIV H7N9 peak coincidentally during the winter months, they may co-infect an individual and subsequently reassort. This may give rise to a transmissible variant, against which the human population has little pre-existing immunity, and may be at the origin of a new influenza pandemic. Strict monitoring and isolation measures are therefore essential to limit the risk of seasonal influenza and reassortment in individuals with zoonotic H7N9 virus infection.
Nipah is paramyxovirus of the genus Henipavirus (family Paramyxoviridae) with a high fatality rate (69). Infection in humans usually causes severe encephalitic and respiratory disease (70). After inoculation with Nipah virus (NiV), Syrian hamsters also develop characterisitic neurological disease (12). Similar to symptoms after human infection, pathological lesions are the most severe and extensive in the hamster brain and viral antigen and RNA can be detected in neurons (11), lung (71), kidney, and spleen (11). The Syrian hamsters in the majority of NiV infection studies are treated by intraperitoneal (IP) injection or intranasal (IN.) delivery and these models have revealed that different inoculation method can cause diverse pathological responses (11). In Wong's work, IP injection of NiV in Syrian hamsters caused primarily neurological disease, while IN delivery developed neurological symptoms as well as labored breathing due to lung infection in the final stages of disease (11). Disease progression is usually much rapid and the time to death post-infection is shorter following intraperitoneal rather than intranasal inoculation (72). Since the Syrian hamster has shown suitability for studying NiV infection, it was further used to study the viral transmission (73–75), demonstrating that Nipah virus is transmitted efficiently via direct contact and inefficiently via fomites, but not via aerosols. Regarding the use of these models for development of disease treatment and prophylaxis, recent studies have shown that pretreatment with Poly(I)-poly(C12U) can significantly decrease the mortality caused by NiV infection of Syrian hamster (76). In addition, the model was used as a platform for evaluation of vaccines for NiV (77–80). Walpita et al. discovered purified NiV-like particles (VLP) can protect the Syrian hamster using either multiple-dose or single-dose vaccination regimens followed by NiV challenge (81).
PCRs testing were repeated on the 50 fruit bats original samples including the Kidney, heart, lung, liver, spleen, intestine, rectal swab sample, and brain samples. Two bat’s QPCRs results were positive. One bat’s QPCRs result was positive in the lung, intestine sample (Cangyuan virus isolated) and rectal swab sample, and the Ct (Threshold Cycle) of QPCR were 19.86 ± 0.056, 19.52 ± 0.041, 19.64 ± 0.061 respectively. The Ct of another bat’s PCR were 23.07 ± 0.253, 22.53 ± 0.171 in the intestine sample and rectal swab sample, respectively.
To establish the evolutionary relationship between Cangyuan virus and other known orthoreoviruses, Homology were compared (Table 2, Table 3 and Additional file 1: Table S1, Additional file 2: Table S2 and Additional file 3: Table S3) and phylogenetic trees were constructed based on the nucleotide sequences of the L genome segments (Figure 2), the M genome segments (Figure 3) and the S genome segments (Figure 4). The Cangyuan virus L1-L3, M1-M3 segments sequence identity were 81.6% –94.2%, 83.8%–97.9%, 85.9%–97.6% ( Additional file 1: Table S1), 82.2%–94.1%, 78. 1%–95.0%, and 83.0%–93.9% (Table 2, Additional file 2: Table 2), respectively, by alignment with Pteropine orthoreovirus (PRV) species group. The phylogenetic trees for L2, L3, M1 and M2 segments demonstrated that Cangyuan virus was most closely related to Melaka and Kampar viruses, and was placed in Pteropine orthoreovirus (PRV) species group which covers all known bat-borne orthoreoviruses together with Nelson Bay orthoreovirus.
To better understand the genetic relatedness of Cangyuan virus to other known bat-borne orthoreoviruses, the published sequences for the S genome segment of bat-borne orthoreoviruses known for causing acute respiratory disease in humans were retrieved from GenBank and used to compare homology (Table 3 and Additional file 2: Table S2) and construct phylogenetic trees (Figure 4). The Cangyuan virus S1-S4 segments sequence identity were 55.3%–94.7%, 86.2%–95.5%, 86.5%–97.9%%, and 83.5%–98.2%, respectively (Table 3 and Additional file 2: Table S2). The S1 segment demonstrated a greater heterogeneity than other S segments in Pteropine orthoreovirus (PRV) species group.
Through systematic evaluation of data reported in the scientific literature on zoonotic viruses, we identify several key virus characteristics and transmission mechanisms that are synergistic to zoonotic virus spillover, amplification by human-to-human transmission, and global spread. The majority (94%) of zoonotic viruses described to date (n = 162) are RNA viruses, which is 28 times higher (95% CI 13.9–62.5, exact P < 0.001) than the proportion of RNA viruses among all vertebrate viruses recognized, indicating that RNA viruses are far more likely to be zoonotic than DNA viruses, as has been reported among human pathogens6. Epidemiological circumstances involved in recent zoonotic transmission from animals to people are summarized here for 95 viruses with data on human activities enabling direct and indirect contact disease transmission and animal host taxa implicated in transmission. In general, wild animals were suggested as the source of zoonotic transmission for 91% (86/95) of zoonotic viruses compared to 34% (32/95) of viruses transmitted from domestic animals, and 25% (24/95) with transmission described from both wild and domestic animals (see Supplementary Table). Wild animals, which include a taxonomically diverse range of thousands of species, were significantly more likely to be a source for animal-to-human spillover of viruses than domesticated species (exact P = 0.001). Wild rodents were implicated as a source of spillover for 58% (55/95) of zoonotic viruses, particularly for zoonotic arenaviruses (n = 8/8, exact P = 0.019) and zoonotic bunyaviruses (n = 20/24, exact P = 0.004). Primates were implicated as a source of zoonotic retroviruses (exact P = 0.017), while bats were more implicated for zoonotic paramyxoviruses (exact P = 0.011) and most zoonotic rhabdoviruses (6/8, exact P = 0.002).
Emerging pathogens have been noted for their ability to infect a range of animal hosts578910. We find that most (63%) zoonotic viruses infecting humans were reported in animal hosts from at least two different taxonomic orders, and 45% were reported in four or more orders, in addition to humans. The virus-host unipartite network illustrates high connectivity among host groups sharing zoonotic viruses and the central role domestic animals play in cross-species transmission (Fig. 2). In a Poisson model predicting host range and evaluating common hosts and high-risk transmission interfaces, viruses with domestic animal hosts occurred in twice as many host orders than other viruses (Table 1). Most domestic animal groups clustered in the middle of the host network with high centrality measures and a high number of shared viruses (Fig. 2), indicating that domestic animals play a key role in cross-species transmission of zoonotic viruses. Among viruses from wildlife, we found higher host plasticity (ie, hosts from a higher number of taxonomic orders) in viruses transmitted at high-risk interfaces involving wild animals kept as pets, maintained in sanctuaries or zoos, and sold at markets, which were collapsed into one category due to similar effect and significance in the final Poisson model. We also found that vector-borne viruses were reported in three times the number of host taxonomic groups than non-vector-borne viruses, indicating that vector-borne pathogens have significantly broader host range than non-vector-borne viruses.
Based on data published to date, transmission of zoonotic viruses to humans occurs by direct or indirect contact with wildlife in a diverse array of interconnected animal-to-human interfaces, with little overlap with viruses transmitted primarily by vectors (Fig. 3). Zoonotic virus spillover from wildlife was most frequent in and around human dwellings and in agricultural fields, as well as at interfaces with occupational exposure to animals (hunters, laboratory workers, veterinarians, researchers, wildlife management, zoo and sanctuary staff). Primate hosts were most frequently cited as the source of viruses transmitted by direct contact during hunting (exact P = 0.051) and in laboratories (exact P = 0.009), while rodent hosts were more likely to be implicated in transmission by indirect contact in and around human dwellings (exact P < 0.001) and in agricultural fields (exact P = 0.001). Approximately 40% of zoonotic viruses involving wild animals required arthropod vectors for transmission to humans, with vectors providing an effective bridge for transmission of diseases from wild animals that do not normally contact humans. Zoonotic viruses with wild avian hosts were most likely to involve vectors (exact P < 0.001). Network analysis of disease transmission from wild animals illustrates that vector-borne viruses were the least connected to other transmission interfaces (Fig. 3), consistent with effective control of vector-borne diseases by elimination of vectors or contact with vectors. In contrast, 22% of viruses transmitted from domestic animals to humans were by vector only, with close proximity interactions with domestic animals enabling direct pathogen transmission to humans.
Once animal viruses have spilled over into humans, human-to-human transmission of zoonoses facilitates sustained spread of disease with a rapidity and reach infeasible for zoonotic viruses requiring contact with animal hosts for each transmission opportunity. Human-to-human transmissibility was described for 20% of zoonotic viruses investigated here (Supplementary Table). We find virus host plasticity to be positively correlated with capability for human-to-human transmission (Table 1). In a logistic regression model predicting virus capability for human-to-human transmission, we find viruses were significantly more likely to be human-to-human transmissible with each increase in virus host plasticity (count of host orders and ecological groups). Furthermore, we find viruses in the arenaviridae and filoviridae families to be more likely to possess human-to-human transmissibility, along with viruses transmitted by direct contact with hunted and consumed wildlife (Table 1). Hunting poses special risk for cross-species disease transmission of blood-borne zoonotic viruses1112 as evidenced by re-emerging threats, including ebolaviruses13 and primate retroviruses141516. Our findings therefore support speculation that hunting of high-risk host species carries an increased probability of spillover of zoonotic viruses that can be further spread by human-to-human transmission13.
We further characterized zoonotic virus capacity for spread by categorizing viruses according to geographic range in a single country (16%), >1 country in 1–3 World Health Organization-defined (WHO) regions (55%), or ≥4 WHO regions (29%), and used ordinal logistic regression to evaluate characteristics of viruses in broader range categories. We find viruses were more likely to be in broader geographic range categories with increasing host plasticity (Table 1). Among all high risk interfaces and hosts, only viruses transmitted to humans by contact with wild animals in the wildlife trade and in laboratories, such as lymphocytic choriomeningitis virus17, monkeypox virus18, herpes B virus19, and Marburg20, were more likely to have broader geographic reach.
YFV is an arthropod-borne virus of the genus Flavivirus (family Flaviviridae) and has high morbidity and mortality rates in regions of sub-Saharan Africa and South America (53). It was one of the first viruses of humans to be identified, isolated, propagated in vitro and studied by genomic sequencing (54). The study of infection mechanism of YFV has historically been hindered by the lack of appropriate small animal model and non-human primate (NHP) models have typically been used. More recently, several research groups have generated animal models using Syrian hamsters that can be successfully infected with YFV (55–58). McArthur et al. reported adapted viral strains (Asibi/hamster p7) allow the reproduction of yellow fever disease in hamsters with features similar to the human disease (59). Further, studies have also shown that infection of Syrian hamster results in immune responses that correspond to those observed in infected humans, with marked increases in IFN-γ, IL-2, TNF-α in the spleen, kidney, and heart, but reduced levels of these seen in the liver. In addition, these studies found increased levels of IL-10 and reduced levels of TGF-β in the liver, spleen, and heart in early and mid-stages of infection (60). Syrian hamster can be used both to study the pathogenesis of the YFV infection, and to validate antiviral drugs and antiviral therapies. Recent findings have shown that treatment with the anti-viral compounds 2′-C-methyl cytidine (61), T-1106 (62), IFN alfacon-1 (63), and BCX4430 (64) pre- and post-YFV exposure can significantly improve Syrian hamster survival. In a study by Julander et al. immunization with DEF201, an AdV type-5 vector expressing IFN alpha (IFN-α), can effectively reduce the viral titer in hamster's liver and serum post-YFV infection (65). Immunoprophylaxis with XRX-001, a vaccine containing inactivated yellow fever antigen with an alum adjuvant, can elicit high titers of neutralizing antibodies in vivo to protect Syrian hamsters from YFV infection (66, 67). Interestingly, Xiao et al. (67) and Tesh et al. (68) demonstrate that prior exposure of Syrian hamsters to heterologous flaviviruses reduces the risk of YFV infection.
HPAIV H5N1 emerged in Hong Kong in 1997, causing 18 cases of zoonotic infection, including 6 fatalities. After containment of the outbreak in Hong Kong, the virus re-emerged in mainland China in 2003. It infected an unmatched diversity of wild and domestic avian and mammalian species, and subsequently spread over much of Asia, Europe and Africa, evolving into many co-circulating antigenically-distinct clades and lineages. The severity of the disease is highly variable across animal species, ranging from asymptomatic infections, e.g., in dabbling ducks, to severe systemic disease with high mortality rates in other avian species as well as in most mammalian species found infected.
Since 2003, HPAIV H5N1 has caused a total of 834 cases of zoonotic infection in 18 countries, with a case-fatality rate of about 55% (Table 2). As for LPAIV H7N9, exposure to infected poultry is considered the primary risk factor for human infection. However, in contrast to LPAIV H7N9 infection, more than half of the cases were identified in children,. Unusually pathogenic, HPAIV H5N1 can present a long incubation time, ranging between 2 and 17 days. Severe signs of lower respiratory tract infection and extra-respiratory symptoms, such as gastro-intestinal signs, typically rapidly supersede high fever and other influenza-like signs and symptoms.
Since 2014, a wide diversity of reassortants containing the highly pathogenic H5 gene emerged and caused massive outbreaks in poultry and wild birds worldwide. Of these reassortants, only HPAIV H5N6 is reported to have caused zoonotic infections (Table 3). Epidemics of the novel HPAIVs of the H5 subtype typically peaked during the winter and early spring months of December–March. A major exception is the H5N2 virus that emerged and spread in poultry in North America in 2015. Although it emerged during winter, the epidemic peaked in spring during the months of April–May (Fig. 2).
Outbreaks of HPAIVs of the H5 subtype were reported in poultry globally, whereas cases in wild birds were more often detected and reported in North America and Europe. Interestingly, the new reassortant viruses, which are highly pathogenic in poultry, appear to cause asymptomatic or mild infections in most wild birds found infected to date.
Currently, zoonotic cases of H5 virus infection chiefly occur in Egypt, which experienced last winter the largest H5N1 virus outbreak since its emergence in Africa. Zoonotic cases of H5N1 virus infection are also occasionally (and possibly under-) reported in South-East Asia (Fig. 3).
The expanding diversity of HPAIVs of the H5 subtype is worrisome as it may increase opportunities for evolution towards a pandemic variant. The presence of a diverse array of reassortants in wild bird populations worldwide also indicates a major change in the epidemiology of avian influenza viruses in their bird reservoirs. Before the emergence of HPAIV H5N1, HPAIVs were thought to only evolve and spread in poultry populations, where containment and stamping-out measures contributed to their eradication. The reassortant HPAIVs of the H5 subtype represent unprecedented threats to the poultry industry. As did HPAIV H5N1, they have the potential to widely spread, if not establish, in poultry populations. Wild bird populations may represent a direct source of infection for poultry, calling for strict biosecurity measures.
Each year in the United States, there are approximately 76 million cases of food-borne illness, including 325,000 hospitalizations and 5,000 deaths. In an estimated 2 to 3% of these cases, chronic sequelae develop. These sequelae include renal disease, cardiovascular diseases, gastrointestinal disorders, neural disorders, and autoimmune disease. The estimated cost of food-borne illness in the United States is $23 billion annually. Mishandling of food is believed to be responsible for 85% of all outbreaks of food-borne disease in developed nations, primarily due to a lack of education. Food-borne pathogens [see Additional File 3] are also important because they represent one of the largest sources of emerging antibiotic-resistant pathogens. This is due in part to the administration of sub-therapeutic doses of antibiotics to food-producing animals to enhance growth. For example, certain strains of Salmonella show resistance to eight or more antibiotics. Studies have shown that antibiotic resistance in Salmonella cannot be traced to antibiotic use in humans, suggesting that antibiotic use in animals is the primary cause of resistance.
While much is known about the major microbes responsible for diseases, there are still many undiagnosed cases of infectious disease. It has been estimated that as many as three-fifths of the deaths from acute gastroenteritis per year in the United States are caused by an infectious organism of unknown etiology. Four of the major causes of food-borne infections (Campylobacter jejuni, Escherichia coli O157:H7, Listeria monocytogenes, and Cyclospora cayetanensis, Figure 2) were only recently recognized as causes of food-borne illness.
Several review articles have described and discussed animal models for MERS-CoV infection,,,. In this section, the current status of animal models for MERS disease reproduction is briefly summarized.
After the identification of MERS-CoV in 2012, the efforts were directed to develop an animal model to study pathogenesis and to test the efficacy of vaccines and/or treatments in vivo. Similar to SARS-CoV, rhesus macaques have demonstrated susceptibility to MERS-CoV,,. A work led by Munster demonstrated that the common marmoset is also suitable as a MERS-CoV model. They showed that this model recapitulates the disease observed in humans; therefore, findings in the evaluation of potential therapeutic strategies might be implemented in humans. However, small animals are required for controlled, large and comprehensive studies. While, at first, experiences with SARS-CoV turned out to be very helpful for the research on MERS-CoV, the development of a small animal model for MERS was a more difficult task,. Raj and collaborators rapidly identified dipeptidyl peptidase-4 (DPP4) as the functional receptor for MERS-CoV, and DPP4 is present in lung cells of many rodents. Thus, rodents were expected to be susceptible for MERS-CoV. However, and as predicted by the crystal structure analysis of the MERS-CoV receptor binding domain (RBD) with the human DPP4 (hDDP4) extracellular domain, so far, no rodent model is naturally permissive for MERS-CoV infection. In Syrian hamster, the DPP4 receptor was shown to be expressed on bronchiolar epithelium, but inoculation of MERS-CoV via aerosols or intratracheal routes with different doses did not lead to productive infection. Wild type and immune-deficient mice were also tested for MERS-CoV infection without success. Since then, several groups have been focused on new strategies to develop a small animal model susceptible to MERS-CoV infection. It was found that mouse cells could be made permissive for MERS-CoV when expressing hDPP4. Consequently, the hDPP4 was transduced into mouse lungs using an adenovirus vector, which resulted in animals susceptible to MERS-CoV infection. These mice exhibited pneumonia and extensive inflammatory-cell infiltration with the presence of virus in the lungs. Recently, a transgenic mice model expressing hDPP4, highly susceptible to MERS-CoV infection and able to display systemic lesions, has been developed. As demonstrated for several diseases, transgenic animal models have become an important tool to improve medical research. On the other hand, glycosylation of the murine DPP4 is a major factor impacting the receptor function by blocking the binding to MERS-CoV. Therefore, the modification of the mouse genome to match the sequence in the hDPP4 made this species susceptible to MERS-CoV infection. Accordingly, these newly established mice models are useful to evaluate the efficacy of vaccines and therapeutic agents against MERS-CoV infection,,,. VelocImmune and VelociGene technologies have been used to develop a humanized mouse model for MERS-CoV infection; these methodologies can be also applied for other pathogens in future emerging epidemics.
Bats (order Chiroptera) have been implicated as natural reservoir hosts for numerous zoonotic viruses including coronaviruses1, filoviruses2, lyssaviruses3 and paramyxoviruses4, 5. Although much insight on the natural history of virus infection in bats has been gained from experimental infections3, 6–11 and mathematical modeling12–15, with the exception of Nipah and rabies viruses16, 17, relatively little is known about the long-term dynamics of the host immune response following primary virus infection. Of particular interest is whether or not long-term protective immunity is established following virus infection. This gap in knowledge can be attributed to: 1) the difficulties associated with obtaining serial biological samples from individual bats comprising large colonial, interconnected populations and 2) the uncertainty of whether short-term experimental models of virus infection in bats recapitulate natural bat-virus infection dynamics. Nonetheless, obtaining empirical data on the long-term dynamics of the bat immune response following virus infection is critical to understanding how bat-borne viruses are maintained in nature and identifying factors leading to virus spillover into humans.
The marburgviruses (family Filoviridae, genus Marburgvirus, Marburg virus (MARV) and Ravn virus (RAVV)) cause outbreaks of hemorrhagic disease in sub-Saharan Africa characterized by human-to-human transmission and high case fatality ratios18. The cave-roosting Egyptian rousette bat (ERB; Rousettus aegyptiacus) has been identified as a natural reservoir host for the marburgviruses and a source of virus emergence in humans2, 19, 20. A longitudinal ecological study of marburgvirus infection in large ERB populations at Python Cave and Kitaka Mine, Uganda revealed an age-associated cyclical pattern of virus infection in which pups (0.0% PCR prevalence) are seemingly protected from virus infection through maternal antibodies until becoming independent, young juveniles at roughly 3 months of age (2.7% PCR prevalence, 4.1% seroprevalence)19. Acute virus infection levels increase in the juvenile population, peaking at 6 months of age (12.4% PCR prevalence, 14.8% seroprevalence), coincidental with the timing of the biannual birthing seasons. Juveniles enter the adult population at 7–8 months of age; a population that experiences year-round, consistent levels of virus infection (2.4% PCR prevalence, 21.5% seroprevalence). A susceptible-exposed-infectious-resistant (SEIR) mathematical model of marburgvirus transmission in a closed ERB population of 40,000 individuals with a twice-yearly birth pulse and a 21-day latent period predicted a prevalence of active infection (<2.0%) comparable to that observed in the Python Cave ecological study (2.5%), but predicted a seroprevalence (100.0%) remarkably higher than that which was observed in adults14. This discrepancy is likely due to waning marburgvirus antibody levels that may or may not be indicative of diminished protective immunity14.
Serological data gathered from experimental studies of MARV infection in captive ERBs8–11 corroborate marburgvirus seroprevalence predictions generated by the SEIR model of marburgvirus transmission in ERBs14. Shortly after experimental inoculation of ERBs with MARV, the virus can be detected in the blood from 1-16 days post infection (DPI; 100% of bats for a mean duration of 6.0 d)11, the oral mucosa from 5–19 DPI (91.7% of bats for a mean duration of 4.6 d)11, multiple tissues from 2–12 DPI8–10 and the spleen up to 28 DPI (66.7% of bats at this time point)8. MARV IgG antibodies peak by 28 DPI and then rapidly decline8–11, falling below the threshold of seropositivity by 3 months post infection (MPI)11. Short-term protective immunity against viral replication and shedding has been demonstrated in seropositive ERBs challenged with homologous virus 48 days following experimental inoculation with a moderately high dose of MARV9. However, whether natural MARV infection generates long-term immunity sufficient to fully protect seronegative ERBs from viral reinfection, replication and shedding remains unclear.
We previously demonstrated horizontal MARV transmission between experimentally infected and naïve contact ERBs11. In this study, we assess whether MARV infection confers long-term protective immunity against reinfection, replication and shedding by challenging groups of ERBs that had been experimentally or “naturally” infected 17–24 months prior during the previous transmission study with homologous virus. Following challenge, evidence of MARV replication in the blood and viral shedding from the oral mucosa is monitored for 14 days, MARV IgG antibody responses are monitored for 21 days and tissues obtained at necropsy at 21 days are tested for the presence of MARV RNA. Herein, we show that no bats in either group exhibit evidence of MARV replication or shedding. Further, all bats develop virus-specific secondary immune responses, demonstrating that infection of ERBs with MARV induces long-term, and likely lifelong, protective immunity against reinfection.
Dromedary camels are the main source of MERS-CoV zoonotic transmission (reviewed in). In experimental intranasal inoculations with MERS-CoV, only mild clinical signs (i.e. nasal discharge) with URT infection were observed. Viral RNA was detected in nasal swabs, in upper and lower respiratory tracts, and also in extra-pulmonary tissues (i.e. lymph nodes, tonsil, intestine, liver, adrenal gland, etc.). In contrast, infectious virus was only detected in the URT, trachea, large bronchus and tracheobronchial lymph node. Gross lesions were not observed in dromedary camels, but inflammation in the nasal cavity, trachea and bronchus was present. The virus replication in dromedaries was only detected in epithelial cells in the URT,.
Llamas and alpacas, also known as domestic new world camelids, developed a similar clinical-pathological picture to that of dromedaries after experimental MERS-CoV infection. In both species the virus was inoculated via intranasal route, and either no clinical signs (alpacas) or mild mucus secretion (llamas) was observed. MERS-CoV was detected in nasal swabs, and in the URT and trachea of both llamas and alpacas. None of the species showed lesions macroscopically, but microscopically mild to severe rhinitis was detected in alpacas as well as metaplasia of the epithelium of the turbinate in alpacas. Similar to dromedaries, the epithelial cells in the URT were the main target cells for virus replication. Concomitant to an antibody response, the virus was cleared from the URT 7 to 10 days after experimental infection,,.
Serum samples collected from all the persons, who came into contact with the index patient, showed negative activity in the neutralization antibody test, in spite of the fact that one of the patient's family members and three of his caregivers in the hospital had experienced fever and sore throat within one week of the contact. These data suggest that human-to-human transmission of the virus did not easily occur.
The Ebola virus (EBOV) is an enveloped, negative-strand RNA virus belonging to the family filoviridae in the order of mononegavirale. Four of the five ebolavirus species, Zaire (ZEBOV), Sudan, Tai Forest, and the recently discovered Bundibugyo ebolavirus, are endemic in continental Africa and cause a severe form of viral hemorrhagic fever with high mortality in humans and non-human primates. Reston ebolavirus (REBOV) is sporadic in the Philippines and has caused several epizootics in cynomolgus macaques. REBOV was first isolated in 1989 from cynomolgus macaques imported from the Philippines for medical research in the United States. About 1,000 monkeys died or were euthanized in a quarantine facility in Reston, Virginia. Subsequently, 21 animal handlers at the Philippine exporter and four employees of the quarantine facility were found to have antibodies to the virus, indicating that they had been infected. Epizootics in monkeys in the Philippines were then reported in 1992 and 1996, and all the epizootics have been traced back to a single monkey facility, in Calamba, Laguna in the Philippines. Since the closure of the facility in 1997, no REBOV epizootics in cynomolgus monkeys have been reported.
In October 2008, REBOV infection was confirmed for the first time in swine associated with multiple epizootics of respiratory and abortion-related diseases in the Philippines. In several pools of swine samples collected from geographically distant swine farms, co-infection with REBOV and porcine reproductive and respiratory syndrome virus (PRRSV) was confirmed. Serological studies of limited scale on 13 swine sera in the affected farms failed to detect REBOV antibodies in ELISA, although PRRSV antibodies were detected. It is still unclear how REBOV was spread among swine during the epizootic. Moreover, it is not clear if REBOV infection in the swine population is either sporadic and incidental or common in the Philippines. To try to answer these questions, we prepared multiple serodiagnosis systems for detecting REBOV infection in swine and analyzed swine sera obtained from the affected farms and from farms not associated with any epizootics in the Philippines. The results showed a high prevalence of REBOV infection in swine in the affected farms at the epizootics in 2008; however, REBOV antibodies were not detected in the swine population not associated with the epizootics, indicating that REBOV infection in swine in the Philippines is not common, at least in some parts of Tarlac.
To investigate viral shedding after SUDV infection, oral and rectal swabs, as well as nasal washes collected from the animals were used to determine virus at various time points by RT-qPCR and TCID50. Virus was detected earlier and was generally higher in ferrets that received IN inoculation compared to the IM infection, including nasal washes (IM: 101-103 GEQ/ml and 102-104 TCID50/ml; IN: 102-104 GEQ/ml and 102-109 TCID50/ml) (Supplementary Figures 3B, 4A) and oral swabs (IM: 101-104 GEQ/ml and 102-104 TCID50/ml; IN: 102-105 GEQ/ml and 102-106 TCID50/ml) (Supplementary Figures 3C, 4B). In contrast, rectal shedding was only detected in 1 or 2 animals per group (101-103 GEQ/ml and 103-104 TCID50/ml) (Supplementary Figures 3D, 4C).
In order to assess systemic viral spread to different organs, liver, spleen, kidneys, heart, and lungs were harvested at time of death and assessed for viral titers. In both IM and IN groups, SUDV had spread systemically and had infected the majority of internal organs in each animal. Most organs in both IM and IN groups consistently reached a titer of ∼107 -108 GEQ/g tissue, although the average GEQs in the IN group were slightly higher (Figure 4A). Similarly, most tissues contained infectious virus as measured by TCID50 and titers in the IN group were generally higher than in the IM group, particularly in the lungs (Figure 4B).
Many emerging infectious diseases are caused by zoonotic transmission, and the consequence is often unpredictable. Zoonoses have been well represented with the 2003 outbreak of severe acute respiratory syndrome (SARS) due to a novel coronavirus. Bats are associated with an increasing number of emerging and reemerging viruses, many of which pose major threats to public health, in part because they are mammals which roost together in large populations and can fly over vast geographical distances. Many distinct viruses have been isolated or detected (molecular) from bats including representatives from families Rhabdoviridae, Paramyxoviridae, Coronaviridae, Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae, Arenaviridae, Herpesviridae, Picornaviridae, Filoviridae, Hepadnaviridae and Orthomyxoviridae.
The Reoviridae (respiratory enteric orphan viruses) comprise a large and diverse group of nonenveloped viruses containing a genome of segmented double-stranded RNA, and are taxonomically classified into 10 genera. Orthoreoviruses are divided into two subgroups, fusogenic and nonfusogenic, depending on their ability to cause syncytium formation in cell culture, and have been isolated from a broad range of mammalian, avian, and reptilian hosts. Members of the genus Orthoreovirus contain a genome with 10 segments of dsRNA; 3 large (L1-L3), 3 medium (M1-M3), and 4 small (S1 to S4).
The discovery of Melaka and Kampar viruses, two novel fusogenic reoviruses of bat origin, marked the emergence of orthoreoviruses capable of causing acute respiratory disease in humans. Subsequently, other related strains of bat-associated orthoreoviruses have also been reported, including Xi River virus from China. Wong et al. isolated and characterized 3 fusogenic orthoreoviruses from three travelers who had returned from Indonesia to Hong Kong during 2007–2010.
In the present study we isolated a novel reovirus from intestinal contents taken from one fruit bat ( Rousettus leschenaultia) in Yunnan province, China. In the absence of targeted sequencing protocols for a novel virus, we applied the VIDISCR (Virus-Discovery-cDNA RAPD) virus discovery strategy to confirm and identify a novel Melaka-like reovirus, the “Cangyuan virus”. To track virus evolution and to provide evidence of genetic reassortment PCR sequencing was conducted on each of the 10 genome segments, and phylogenetic analysis performed to determine genetic relatedness with other bat-borne fusogenic orthoreoviruses.
How to cite this article: Johnson, C.K. et al. Spillover and pandemic properties of zoonotic viruses with high host plasticity. Sci. Rep.
5, 14830; doi: 10.1038/srep14830 (2015).
The Filoviridae family consists of the Ebolavirus, Marburgvirus and Cuevavirus genera. Historically, Ebola virus (EBOV; Zaire ebolavirus species) has been the most common and deadly of the filoviruses. Therefore, the research community has largely focused on the development of EBOV animal models, tools, vaccines and therapeutics and has been successful in producing several compounds that have reached the late stages of clinical trials. In light of this success, it is now possible to extend further research towards the discovery of pan-filovirus vaccines and therapeutics. However, animal models that are susceptible to all ebolaviruses species will need to be established first in order to directly evaluate whether pan-filovirus vaccines and therapeutics provide cross-protection.
Nonhuman primates (NHP) most closely mimic clinical manifestations of filovirus infections in humans and have provided invaluable insight into the pathogenesis and course of filovirus disease. Yet due to ethical, cost and space restraints that accompany NHP studies, smaller animal models such as mice or guinea pigs are typically the first choice for initial filovirus drug, vaccine and pathogenesis studies. Although wild-type filoviruses do not cause significant disease in adult, immunocompetent rodents, these viruses have been adapted to rodents so that virulence and lethality are observed. Even though these rodent models do not reproduce all hallmark clinical signs of filovirus disease, their relative ease-of-use and low cost make them attractive first options for evaluating anti-viral prophylactics and therapeutics.
In this study we focused on characterizing ferrets as a novel intermediate animal model for Sudan virus (SUDV; member of the Sudan ebolavirus species), for bridging experimental results from rodents to NHPs. SUDV is endemic in South Sudan and the Republic of Uganda and is highly lethal to humans with an average case fatality rate of 53%. The 2000-2001 SUDV outbreak in Uganda was the second largest filovirus outbreak to date, and resulted in 224 deaths in 425 total cases (CFR of 53%). Unlike EBOV, there is a comparative lack of experimental medical countermeasures against SUDV, and animal models for SUDV are just beginning to emerge. In 2014, it was shown that AG129 (alpha/beta/gamma interferon receptor knockout) mice are susceptible to wild-type SUDV infections. In addition, we recently characterized a guinea pig-adapted variant, which was uniformly lethal to guinea pigs.
However, a better strategy would be to screen candidate drugs in immunocompetent small animals using wild-type SUDV to avoid the need to develop rodent-adapted models, before progression to studies in NHPs. Ferrets and pigs initially emerged as excellent models of human respiratory diseases as their lung physiology closely mimics that of humans. Interestingly, among characterization of many respiratory virus infections such as various influenza strains, respiratory syncytial virus, Nipah virus, and coronaviruses, other viruses have also recently been tested in ferrets including hepatitis E, and three species of ebolavirus.
Infection of wild animals such as apes, monkeys, and antelopes with bat-borne infectious agents may also play a role in the transmission chain to humans, such as for Ebola virus. In the case of the severe acute respiratory syndrome (SARS) coronavirus, civets (Paguma larvata) got infected with a virus circulating in horseshoe bats (Rhinolophus sp.) and would have then acted as an intermediate amplifying host. Natural bat predation by other animals (e.g., monkeys, domestic cats) and its consequences on infectious agents transmission are poorly documented but could also favor spillover opportunities to other hosts.
In addition to wild animals, the role of livestock as intermediate and amplifying hosts between wild animals and humans has been clearly demonstrated in several outbreaks, such as for Filovirus and Henipavirus. Indeed, in Malaysia, the growth of commercial pig farms with fruit trees on the farm has created an environment where bats could drop partially eaten fruits contaminated with Nipah virus into pig stalls.
In contrast to rapid and short-time spillover events, long-time and silent circulation of viruses in livestock before transmission to humans may also occur, as is strongly suspected for the ongoing outbreak of Middle East respiratory syndrome (MERS). Although bats are likely to be a source of MERS-like coronaviruses, dromedary camels (Camelus dromedaries) act as the natural reservoir host in which the MERS coronavirus could have circulated for more than 30 years before its first detection in humans. Other animals such as llamas (Lama glama) and wild boars (Sus scrofa) have shown susceptibility to MERS coronavirus infection, suggesting a large host species range. The endemic human coronavirus 229E may also constitute a descendant of camelid-associated viruses and further supports that livestock plays a key role in the long-time establishment of bat-borne viruses in humans.
Ebolavirus is part of the Filoviridae family, which consists of three genera: Marbugvirus, Cuevavirus, and Ebolavirus. There are currently six known, genetically distinct, species of Ebolavirus—Ebola virus (EBOV), Sudan Ebolaviurs (SUDV), Tai Forest Ebolavirus (TAFV), Bundibugyo Ebolavirus (BDBV), Reston Ebolavirus (RESTV), and Bombali Ebolavirus (BOMV). No virus has triggered fear in the general population more than the filovirus Ebolavirus. EBOV is categorized among the deadliest viruses, with mortality rates up to 90%. The zoonotic origin of outbreaks are often the result of transmission from primates, although the suspected natural reservoir for EBOV, bats, is still being questioned. Since it was first identified in 1976 in Zaire (the actual Democratic Republic of Congo), 27 confirmed outbreaks, mainly in the central part of Africa, have occurred, and each outbreak was accompanied by high case fatality rates up to 88%, including the new declared outbreak ongoing in the North Kivu Province of the Democratic Republic of the Congo. The 2013–2016 Ebola outbreak is the largest (both by number of cases and geographical extension) ebolavirus outbreak ever reported, resulting in 28,610 cases and 11,308 deaths, with fatality rates of 70% in Guinea and Sierra Leone and 41% in Liberia. The number of cases in this single outbreak is far greater than the total number of all cases and deaths of the past outbreaks over the last 40 years. The reasons of such an extended outbreak are linked to societal factors (poverty, urbanization, population migration patterns, and changes of socio-economic conditions), together with the concomitant invasion of animal habitats, climate change, and deforestation. In fact, the emergence and re-emergence of such viruses in Africa or their potential introduction into new countries have usually been related to the mobility and international transport of infected animals or animal products, thus making ebolavirus and filoviruses a worldwide public health concern. Moreover, despite almost 40 years of research, filovirus transmission remains incompletely understood. In humans, EBOV has been found in a variety of body fluids, including blood, stool, breast milk, semen, urine, and saliva. There are multiple routes of transmission for EBOV. However, information about transmission in humans is incomplete, and defining the modes of transmission would greatly increase the ability of public health structures to limit the disease, as well as enable health care workers to avoid any unnecessary risk. So far, our understanding of EBOV transmission in humans mainly relies on epidemiological observations and contact with body fluids from EBOV-positive patients remain the most likely route of transmission. Notably, the number of past outbreaks and associated epidemiological studies carefully examining transmission patterns are small.
Ebola Virus Disease (EVD) is commonly associated with multiple organ systems, including the liver, renal organs, and lungs. So far, little is known about the involvement of the respiratory tract and EBOV pathogenesis in the lung. However, little evidence in filovirus animal outbreaks and animal studies highlights the involvement of the lungs and the respiratory tract in filovirus pathology. Over the years, there has been an increasing concern regarding the possible involvement of the lung in EBOV infection. This concern further increased during the 2013–2016 EBOV outbreak, which offered evidence of viral shedding in the lung, leading to a risk of aerosol transmission. The aim of this review is to highlight the pulmonary involvement in EVD, with a special focus on the new data emerging from the 2013–2016 Ebola outbreak.
Although bat bites may be the main transmission route coming to mind, pathogen transmission involving bat bites has been documented mostly for rabies virus (Rhabdoviridae). The common vampire bat (Desmodus rotundus) can, for instance, naturally transmit rabies to other species when biting to feed on blood, particularly to livestock and sometimes to humans. Mycoplasma has also been detected in common vampire bat blood and saliva and might be transmitted between bats, for instance, during aggressive behaviors. Obligate blood-feeding bats are, however, restricted to Central and South America and represent only a very small proportion of the bat species diversity (<0.005%; 3/1,200). Most bat species do not naturally bite humans unless intentional contacts occur (e.g., veterinarian and field biologists involved in bat capture and handling, people trying to remove bats from houses).
Contact with bat body fluids (saliva, urine, and feces) is increasingly recognized as an important mechanism of pathogen spillover to humans. Human encroachment into bat habitats as well as increasing urbanization, which facilitates bat roosting in artificial structures, are likely to increase contact with bat body fluids. For example, Nipah virus (Paramyxoviridae) human infection cases reported in Bangladesh were associated with the consumption of raw sap from date palm trees contaminated with fruit bat saliva and urine. In the case of Marburg virus (Filoviridae), experimental studies indicate that bat-to-bat transmission may occur via saliva and aerosols, suggesting that the virus may be transmitted to other hosts by a similar mechanism. This hypothesis is supported by investigations revealing that most humans infected with Marburg virus had entered bat (Rousettus aegyptiacus) caves before becoming sick and reported regular contacts with bats or their secretions.
Hunting, preparation, and consumption of bats as bushmeat have also been pointed out as a potential source of infection, especially for Ebola virus. For instance, the putative first human case of the 2007 Ebola outbreak in the Democratic Republic of Congo would have bought freshly killed bats for consumption. The fruit bat Eidolon helvum, which is the most frequently hunted and traded bat species in many African countries (e.g., more than 120,000 E. helvum are sold yearly in markets in Ghana), has been shown to be infected with Henipa-related viruses. This highlights the substantial exposure of local hunters and consumers to viruses of potential zoonotic importance.
Miyazaki-Bali/2007, together with the other species of Nelson Bay orthoreovirus, formed a cluster that was independent to avian, mammalian, and baboon reoviruses (Fig. 2). Miyazaki-Bali/2007 was found to be most closely related to HK23629/07, HK46886/09, and HK50842/10 based on the phylogenetic analyses with S2- and S4-segments.,. However, Miyazaki-Bali/2007 did not form a subcluster with HK23629/07, when analyzed with S1-segment sequences (Fig. 2A). Furthermore, Miyazaki-Bali/2007 formed a subcluster with HK23629/07, but not with HK46886/09 and HK50842/10, when analyzed with S3-segment sequences (Fig. 2C), although all the 4 viruses including Miyazaki-BaliHK23629/07, HK46886/09, and HK50842/10 originated from Indonesia.
In the developing world, nearly 90% of infectious disease deaths are due to six diseases or disease processes: acute respiratory infections, diarrhea, tuberculosis, HIV, measles, and malaria [see Additional File 1]. In both developing and developed nations, the leading cause of death by a wide margin is acute respiratory disease. In the developing world, acute respiratory infections are attributed primarily to six bacteria: Bordetella pertussis, Streptococcus pneumonia, Haemophilus influenzae, Staphylococcus aureus, Mycoplasma pneumonia, Chlamydophila pneumonia, and Chlamydia trachomatis. These bacteria belong to four different taxonomic classes and illustrate how similar parasitic lifestyles can evolve in parallel within unrelated bacterial species (Figure 2). Major viral causes of respiratory infections include respiratory syncytial virus (Figure 5), human parainfluenza viruses 1 and 3 (Figure 5), influenza viruses A and B (Figure 5), as well as some adenoviruses (Figure 4).
The major causes of diarrhoeal disease in the developing and developed world have significant differences due to the great disparity of availability of pure food and water and the general nutritional and health status of the populations. Important causes of diarrhoeal disease in the developing world are those that tend to be epidemic, especially Vibrio cholera, Shigella dysenteriae, and Salmonella typhi. These organisms are gammaproteobacteria (Figure 2) that use many different metabolic pathways to ensure their survival in a wide range of environments. In the United States there is a much lower incidence of diarrhoeal disease overall, and a relatively greater impact of direct human-to-human infectious transmission. The most important causes of diarrhoeal disease in the United States are bacteria such as Escherichia coli, Campylobacter species, Clostridium difficile, Listeria monocytogenes, Salmonella enteritidis, and Shigella species (Figure 2); viruses, such as Norwalk virus (Figure 6) and rotaviruses (Figure 7); and parasites such as Cryptosporidium parvum, Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia, while microsporidia are responsible for a smaller number of cases (Figure 3).
Infectious disease agents important to the public health in the U.S. are monitored by the CDC and listed in Additional File 2 [see Additional File 2]. There are no set criteria for inclusion on the notifiable disease list; rather, the list is created by the CDC in cooperation with state health departments. As diseases occur less frequently and new diseases emerge, the notifiable disease list changes. The list provides links to case definitions of each disease, including the etiological agent(s) responsible. In cases where the etiological agent was not listed or was unspecific (i.e. Brucella spp.), further research was done to determine an etiological agent and this information is in Additional File 2 [see Additional File 2].