Posts Tagged ‘Emerging disease’
The Archaea, the so-called Third Domain of life, are thought of in an environmental context, influencing natural environments and ecosystems including extreme environments such as salt lakes and soda lakes. But what if some species were capable of capable of causing human disease? Currently, there is no substantial evidence supporting the pathogenic properties of Archaea. This free review article considers why.
I’m interested in Middle East Respiratory Syndrome Coronavirus (MERS-CoV) for a number of reasons, and as a result I have a student currently doing a final year project with me on this topic – not chucking buckets of MERS-CoV around in the laboratory, but trying to figure out where this virus came from and what it is likely to do next. Both of these are interesting questions.
There has been a lot published about the origins of MERS-CoV recently. Only this week came the news that a camel in Saudi Arabia has tested positive for the virus. But which came first – the virus or the camel? Almost certainly the camel – there’s no reason to suppose that camels are the original source of the outbreak. MERS is almost certainly a zoonotic infection – arising in animals and transmitted to humans – but which animals? The closest relatives to MERS-CoV have been found in bats, and those viruses are pretty similar to the virus currently causing human deaths. However, these bat viruses have only been identified by nucleotide sequences and have never been isolated as live viruses from either bats or the environment, so the animal reservoir of MERS-CoV has still not been identified (Emergence of the Middle East Respiratory Syndrome Coronavirus. (2013) PLoS Pathog 9(9): e1003595. doi:10.1371/journal.ppat.1003595).
If we don’t know where MERS came from, we should all be interested in the question of what it is likely to do next. Since September 2012, there have been over 150 laboratory-confirmed cases of infection with MERS-CoV – not that many on a global scale. That’s because the virus is only weakly infectious in humans. As long as this remains the case we are OK, but if at some point it decides it likes being in humans and wants more of the same, then we’re in trouble. What are the odds of that happening? Right now, we simply don’t know. And that’s why I’m interested in MERS.
To answer the question of what MERS will do next, we need a lot more knowledge than we have right now. One of the key pieces of information is exactly how MERS-CoV gets inside a host cell, and specifically, why it finds it difficult to infect human cells. It was recently shown that the receptor MERS-CoV needs to infect cells is dipeptidyl peptidase 4, a cell surface protein which cleaves dipeptides from hormones and chemokines after a proline amino acid residue, regulating their bioactivity (Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. (2013) Nature 495, 251-254). Dipeptidyl peptidase 4 is similar to other known coronavirus receptors, but the use of these peptidases as receptors by coronaviruses could be more related to their abundance on epithelial and endothelial tissues – the primary tissues involved in coronavirus infection – rather than any inherent properties of the protein.
That’s where a new paper in the Journal of General Virology comes in. It’s difficult to study lethal viruses in humans, so like it or not animal models of infection still have their place in these life-threatening outbreaks. The study of SARS-CoV pathogenesis progressed rapidly due to the development of a mouse adapted variant of SARS-CoV that produced lethal lung disease in mice similar to SARS in humans. But MERS-CoV doesn’t like growing in mice and it turns out that this is because mice have low levels of dipeptidyl peptidase 4 mRNA in their lungs (Wild type and innate immune deficient mice are not susceptible to the Middle East Respiratory Syndrome Coronavirus. J Gen Virol. 06 Nov 2013 doi: 10.1099/vir.0.060640-0). Good news for the mice, but also of great interest when thinking about how the pathogenesis of MERS is shaped in humans. Most viruses are not able to switch from one receptro to another easily, so drugs which interfere with the binding of the virus to this protein or antibodies which block attachment could be the best way to treat MERS until we have a vaccine which is able to stop people becoming infected. And the search for those drugs and antibodies is going on right now.
It began routinely enough. A patient with severe respiratory disease at the Dr. Soliman Fakeeh Hospital in Jeddah, Saudi Arabia was getting worse and no one knew why. A sample of sputum was sent to Dr. Ali Mohamed Zaki to identify the culprit, as he had identified these diseases many times before. However, this time would be different. The sample showed no positive hits on any of the virus assays he normally used. He contacted Dr. Ron Fouchier, at Erasmus Medical College in Rotterdam, Netherlands, to see if he could be of help. Dr. Zaki’s initial idea was that the virus was a paramyxovirus, and Dr Fouchier had recently published a Pan-paramyxovirus polymerase chain reaction (PCR) assay. In Dr. Fouchier’s lab, the virus was identified as a novel coronavirus, one that had never been seen before…
Dengue virus (DV) infections cause undisputedly the most important arthropod-borne viral disease in terms of worldwide prevalence, human suffering, and cost. Worldwide DV infection prevalence in 2010 was between 284 to 528 million cases. Approximately 84% of these cases come from Asia and the Americas, where the cost for emerging economies can be as high as 580 million dollars per year. The need for an efficient vaccine against DV is extreme.
Vaccination has been the most desired strategy for controlling the spread of DV. Neutralizing antibodies directed against mosquito-borne flavivirus envelopes can prevent the development of infectious disease. This has been beautifully illustrated by the development of successful vaccines against other related mosquito-borne flaviviruses with similar structure, specifically the attenuated strain 17D vaccine against yellow fever virus (YFV) and the attenuated strain 14-14-2 against Japanese encephalitis virus (JEV), both obtained by serial passage in cell culture.
Why then has the development of a DV vaccine proven so challenging? Natural DV infection triggers a robust, neutralizing immunity that provides an apparently life-long protection against the infecting DV serotype and a short-lived (months) cross-protection against heterologous DV serotypes. Interestingly, the humoral response to DV not only mediates protection though viral neutralization, but also seems to play a major role in the development of more severe forms of dengue disease. Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) cases are often associated with secondary DV infections with a heterologous DV serotype.
There are two main windows of opportunity to build upon toward realizing efficient vaccination for DV. First, a clinically relevant animal model for dengue infection and vaccine development is lacking. Rhesus monkeys do not show clinical signs of infection after a wild-type DV challenge; instead the intensity and length of viremia serves as a proxy to infer protection. Second, rigorous correlates of protection have not been established for DV. The best available indicator of immunogenicity is the titration of neutralizing antibodies, however titration of plaque reduction neutralization antibodies has not been promoted to a bona fide correlate of protection because of ambiguous results pertaining to the protective titer. Testing the protection efficiency of tetravalent vaccine candidates in volunteers may answer both questions. Results from the first human DV challenge experiments have been recently published and demonstrate the viability of this approach.
Pathogens are often described by the nature of their relationship with their hosts. At one extreme are species that are entirely dependent on their host to complete their life cycle (often called obligate parasites). At the other are opportunistic species, which live as saprobes on dead organic matter, but can also invade living organisms (often called facultative pathogens). In between lies an array of combinations ranging in their degree of host dependency and ability to cause disease.
Another way to categorize pathogens is according to their pathogenic lifestyle and disease characteristics. In this case, different terminology is used for plant and animal pathogens: plant-attacking fungi are usually categorized according to the way they feed on the host, e.g., biotrophic or necrotrophic pathogens. Fungi that cause disease in animals are usually described according to the type of disease they cause, e.g., superficial or invasive mycoses. Therefore, we tend to think about fungal pathogens of plants and animals in different terms and treat them separately. Yet fungi attacking animals or plants are actually closely related. Moreover, close examination of animal and plant pathosystems reveals that fungal pathogens in both groups share similar infection strategies and sometimes even cause similar symptoms (although similarity in symptoms doesn’t necessarily indicate similar mechanism). For example, pH-lowering molecules, such as oxalic acid, are virulence factors against plant, animal, and insect hosts. This warrants revisiting the terminology and the way in which we think about fungal pathogens of animals and plants.
And on to:
The yeast Candida albicans is well known as the most common agent of symptomatic fungal disease, but its more typical role is as a permanent resident of the healthy gastrointestinal microbiome. Longitudinal molecular typing studies indicate that disseminated C. albicans infections originate from individuals’ own commensal strains, and the transition to virulence is generally thought to reflect impaired host immunity. Nevertheless, the ability of this commensal pathogen to thrive in radically different host niches speaks to the existence of functional specializations for commensalism and disease. To investigate the C. albicans commensal lifestyle, researchers developed a mouse model of stable gastrointestinal candidiasis in which the animals remain healthy, despite persistent infection with high titers of yeast. Using this model, they found that a C. albicans mutant lacking the Efg1 transcriptional regulator had enhanced commensalism, such that mutant cells strongly outcompeted wild-type cells in mixed infections.
Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism. (2013) Nature Genetics 45, 1088–1091. doi:10.1038/ng.2710
Among ∼5,000,000 fungal species, C. albicans is exceptional in its lifelong association with humans, either within the gastrointestinal microbiome or as an invasive pathogen. Opportunistic infections are generally ascribed to defective host immunity but may require specific microbial programs. Here we report that exposure of C. albicans to the mammalian gut triggers a developmental switch, driven by the Wor1 transcription factor, to a commensal cell type. Wor1 expression was previously observed only in rare genetic backgrounds, where it controls a white-opaque switch in mating. We show that passage of wild-type cells through the mouse gastrointestinal tract triggers WOR1 expression and a novel phenotypic switch. The resulting GUT (gastrointestinally induced transition) cells differ morphologically and functionally from previously defined cell types, including opaque cells, and express a transcriptome that is optimized for the digestive tract. The white-GUT switch illuminates how a microorganism can use distinct genetic programs to transition between commensalism and invasive pathogenesis.
Historically, new viruses were discovered when they popped up and did something nasty of humans, their animals, or occasionally, to plants. But for the last few decades, most new viruses have been discovered as a result of people going looking for them. Awareness of emerging human pathogens as public health threats has grown rapidly since HIV was identified in the 1980s. Annual references to “emerging disease” in the medical literature have risen a hundred-fold, from 11 in 1993 to 313 in 2012; a similar search of popular print media uncovered two references in 1993 and 241 in 2012. Does this really mean there are lots more emerging viruses these days, or is there another explanation? A new paper in PNAS looks a some of the factors behind this increase.
By one estimate, 335 “emergent events” occurred during 1940–2004. If the definition is limited to only newly recognized causes of human disease, viruses now predominate. Of the six classes of agents causing disease (prions, viruses, bacteria, fungi, protozoa, and helminths), viruses comprised 67% of the 87 pathogens discovered during 1980–2005, a period that saw the first descriptions of HIV, severe acute respiratory syndrome, hepatitis C, and Nipah viruses. Nearly 85% of these emergent viruses had single-stranded RNA (ssRNA) genomes. In an analysis of 188 viruses first found to cause human disease between 1900 and 2005, the rate at which new viruses were identified in humans appeared to quicken between 1950 and 1970 but then to slow. To examine if changes in approach or methods might account for the change in pace, the authors compiled a list of the viruses found to cause human illness from 1897, when the first virus infecting vertebrates (foot-and-mouth disease virus) was discovered, through 2010 – take a look at the list, your favourite virus is likely to be on there! Not surprisingly, when people go looking for viruses, they find them.
There are some interesting gems in this data. West Nile virus, first discovered in Uganda in 1937, rapidly spread across the United States after its introduction in 1999; in 2012 it produced severe neuroinvasive disease in about 3,000 Americans, which has been estimated to represent only about 1% of infections. The unprecedented 2004–2009 pandemic of chikungunya virus, also first described in East Africa in 1957, infected at least 2 million people in the Indian Ocean region. This analysis implies that not only has the emergence of arboviruses in the tropics been underestimated over the last 40 years but that the discovery of nonarboviruses has lagged as well because of the lack of systematic searching. The development of faster, more sensitive methods for virus identification will continue to be important in discovering new pathogens, but strategy, support, and commitment for looking in the right places in the right ways will be critical to their most effective use.
Search strategy has influenced the discovery rate of human viruses (2013) PNAS USA 05 August doi: 10.1073/pnas.1307243110
A widely held concern is that the pace of infectious disease emergence has been increasing. We have analyzed the rate of discovery of pathogenic viruses, the preeminent source of newly discovered causes of human disease, from 1897 through 2010. The rate was highest during 1950-1969, after which it moderated. This general picture masks two distinct trends: for arthropod-borne viruses, which comprised 39% of pathogenic viruses, the discovery rate peaked at three per year during 1960-1969, but subsequently fell nearly to zero by 1980; however, the rate of discovery of nonarboviruses remained stable at about two per year from 1950 through 2010. The period of highest arbovirus discovery coincided with a comprehensive program supported by The Rockefeller Foundation of isolating viruses from humans, animals, and arthropod vectors at field stations in Latin America, Africa, and India. The productivity of this strategy illustrates the importance of location, approach, long-term commitment, and sponsorship in the discovery of emerging pathogens.
Babesiosis is an emerging zoonosis caused by protozoan parasites of the genus Babesia. In many ways, the organism is similar to the parasites which cause malaria. Although most clinical cases have been reported on the USA, species of Babesia capable of causing disease occur worldwide. In humans, babesiosis causes a broad range of symptoms, broad, ranging from clinically silent infections with no outward signs of infection to intense malaria-like episodes resulting occasionally in death. When present, symptoms typically are nonspecific (fever, headache, and muscle pains).
Babesiosis has long been recognized as an economically important disease of cattle and is transmitted to humans by ticks which feed on cattle asnd then subsequently on a human host. But there are approximately 5 million people who receive blood donations in the USA each year, and the transmission of babesiosis is increasing – it’s not always possible to tell if a blood donor is infected as many have no symptoms. There are currently no good laboratory tests which are cost-effective to use for screening blood donations, so presently a questionnaire is used to try to screen out the highest risk donors.
There are drugs avavilable which treat this infection, although there are also signs that drug resistance may be emerging. You’ll be hearing more about Babesia over the next few years.
Novel viruses belonging to a genus called cycloviruses within the Circoviridae family have been detected in patients with severe neurological disease on two continents. In papers published independently this week, researchers report the discovery of agents called cycloviruses in Vietnam and in Malawi. The studies suggest that the viruses – one of which also widely circulates in animals in Vietnam – could be involved in brain inflammation and paraplegia, but further studies are needed to confirm a causative link.