Posts Tagged ‘Emerging disease’

Crossing the species barrier

Friday, June 20th, 2014

The number of pathogens known to infect humans is ever increasing. Whether such increase reflects improved surveillance and detection or actual emergence of novel pathogens is unclear. Nonetheless, infectious diseases are the second leading cause of human mortality and disability-adjusted life years lost worldwide. On average, three to four new pathogen species are detected in the human population every year. Most of these emerging pathogens originate from nonhuman animal species.

Zoonotic pathogens represent approximately 60% of all known pathogens able to infect humans. Their occurrence in humans relies on the human-animal interface, defined as the continuum of contacts between humans and animals, their environments, or their products. The human-animal interface has existed since the first footsteps of the human species and its hominin ancestors 6–7 million years ago, promoting the prehistoric emergence of now well-established human pathogens. These presumably include pathogens with roles in the origin of chronic diseases, such as human T-lymphotropic viruses and Helicobacter pylori, as well as pathogens causing major crowd diseases, such as the smallpox and measles viruses and Bordetella pertussis. Since prehistory, the human-animal interface has continued to evolve and expand, ever allowing new pathogens to access the human host and cross species barriers.

Crossing the Interspecies Barrier: Opening the Door to Zoonotic Pathogens. (2014) PLoS Pathog 10(6): e1004129. doi:10.1371/journal.ppat.1004129

Crossing the species barrier

In case you forgot – we’re still fighting vCJD

Friday, June 13th, 2014

Prions The first cases of Mad Cow disease in humans (properly called variant Creutzfeld Jakob Disease, vCJD) occurred in the late 1990s as the consequence of eating contaminated beef products. Since then, several cases of secondary infections caused by transfusions with blood from donors who subsequently developed vCJD have been reported, raising ongoing concerns about the safety of blood and blood products. A paper just published describes a new test that uses protein misfolding cyclic amplification (PMCA – like PCR for proteins) which can detect prions in blood samples from humans with vCJD and in animals at early stages of the (asymptomatic) incubation phase.

This test could be used to identify vCJD infected but asymptomatic individuals and/or for screening donated blood for the presence of the vCJD agent. In the UK, 1 out 2000 people could carry the vCJD agent. In the absence of a vCJD screen, the UK like most of the developed countries apply systematic measures aiming at mitigating the blood borne transmission risk of the disease. These measures have a substantial cost and increase the difficulty met by the blood banking system to provide certain blood products.

 

Preclinical Detection of Variant CJD and BSE Prions in Blood. (2014) PLoS Pathog 10(6):e1004202. doi: 10.1371/journal.ppat.1004202
The emergence of variant Creutzfeldt Jakob Disease (vCJD) is considered a likely consequence of human dietary exposure to Bovine Spongiform Encephalopathy (BSE) agent. More recently, secondary vCJD cases were identified in patients transfused with blood products prepared from apparently healthy donors who later went on to develop the disease. As there is no validated assay for detection of vCJD/BSE infected individuals the prevalence of the disease in the population remains uncertain. In that context, the risk of vCJD blood borne transmission is considered as a serious concern by health authorities. In this study, appropriate conditions and substrates for highly efficient and specific in vitro amplification of vCJD/BSE agent using Protein Misfolding Cyclic Amplification (PMCA) were first identified. This showed that whatever the origin (species) of the vCJD/BSE agent, the ovine Q171 PrP substrates provided the best amplification performances. These results indicate that the homology of PrP amino-acid sequence between the seed and the substrate is not the crucial determinant of the vCJD agent propagation in vitro. The ability of this method to detect endogenous vCJD/BSE agent in the blood was then defined. In both sheep and primate models of the disease, the assay enabled the identification of infected individuals in the early preclinical stage of the incubation period. Finally, sample panels that included buffy coat from vCJD affected patients and healthy controls were tested blind. The assay identified three out of the four tested vCJD affected patients and no false positive was observed in 141 healthy controls. The negative results observed in one of the tested vCJD cases concurs with results reported by others using a different vCJD agent blood detection assay and raises the question of the potential absence of prionemia in certain patients.

 

A new drug against MERS?

Friday, May 30th, 2014

MERS virus Before the emergence of the highly pathogenic severe acute respiratory syndrome-associated coronavirus (SARS-CoV) in 2003 only two circulating human coronaviruses (HCoVs), HCoV- 229E and HCoV-OC43 causing relatively mild common cold-like respiratory tract infections, were known, and coronaviruses have not been regarded as significant threat for human health. Now, more than ten years later, the emergence of another highly pathogenic coronavirus of zoonotic origin, the Middle East respiratory syndrome coronavirus (MERS-CoV) points to the need for effective drugs against coronaviruses. Viruses such as coronaviruses that replicate in the host cell cytoplasm have evolved to employ host cell-derived membranes to compartmentalize genome replication and transcription. Specifically for positive-stranded RNA viruses, accumulating knowledge concerning the involvement, rearrangement and requirement of cellular membranes for RNA synthesis specify the establishment of the viral replicase complex at host cell-derived membranes as an evolution- ary conserved and essential step in the early phase of the viral life cycle.

A new paper in PLoS Pathogens describe a small molecule inhibitor of coronavirus replication that specifically targets this membrane-bound RNA replication step and has broad antiviral activity against number of diverse coronaviruses including highly pathogenic SARS-CoV and MERS-CoV. Since resistance mutations appear in an integral membrane-spanning component of the coronavirus replicase complex, and since all positive stranded RNA viruses have very similar membrane-spanning or membrane-associated replicase components implicated in anchoring the viral replication complex to host cell-derived membranes, the data suggests that the membrane-bound replication step of the viral life cycle is a novel, vulnerable, and druggable target for antiviral intervention of a wide range of RNA virus infections.

Of course clinical trials are needed before such drugs could be used, so we’re still years away from this approach being put into practce. Just in time for the next emergent coronavirus maybe?

 

Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus. (2014) PLoS Pathog 10(5): e1004166. doi:10.1371/journal.ppat.1004166
Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS–CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.

 

Briefing: banana disease

Wednesday, April 9th, 2014

Banana disease

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The Role of Archaea in Human Disease

Thursday, January 23rd, 2014

Archaea 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.

 

Role of archaea in human disease. (2013) Front Cell Infect Microbiol. 3:42. doi: 10.3389/fcimb.2013.00042

 

Why mice don’t get MERS

Wednesday, November 13th, 2013

Mouse 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.

 

Emergence of the Middle East Respiratory Syndrome Coronavirus (MERS)

Monday, October 14th, 2013

MERS-CoV Nice summary post from PLOS Pathogens explaining where we’re at with MERS:

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…

Emergence of the Middle East Respiratory Syndrome Coronavirus. (2013) PLoS Pathog 9(9): e1003595. doi:10.1371/journal.ppat.1003595

 

Dengue Vaccines: Not A Reality Just Yet

Monday, October 7th, 2013

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.

Dengue Vaccines

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.

Dengue Vaccines: Strongly Sought but Not a Reality Just Yet. (2013) PLoS Pathog 9(10): e1003551. doi:10.1371/journal.ppat.1003551

 

Fungal killers. Or not.

Monday, September 9th, 2013

Histoplasma capsulatum A couple of nice recent papers about fungi and disease – or not:

 

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.

Fungi Infecting Plants and Animals: Killers, Non-Killers, and Cell Death. (2013) PLoS Pathog 9(8): e1003517. doi:10.1371/journal.ppat.1003517

 

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.