Field of Science

Is that an Ebola virus superantigen I see?

ResearchBlogging.orgThe process in which a virus causes disease and dysfunction within its host is termed viral pathogenesis; the study of which is pretty important if we are to fully understand infection, replication and transmission of pathogens as well as to develop effective antivirals and vaccines. Ebola virus (EBOV) is one such deadly virus in which there are currently no approved antivirals nor vaccines and which the study of pathogenesis is therefore ever more important. 

EBOV particle.
First isolated in the late '70s, EBOV now causes significant epidemics occurring with increasing frequency - the latest in early  2009. It is  believed that bats play an important role in the natural replication cycle of these viruses and hence may transmit it to neighboring human and other animal populations. There are currently four 'species' of EBOV recognised which infect humans: Zaire, Sudan, Ivory Coast and Bundibugyo - yet a fifth related virus, EBOV-Reston is known only  to infect non-human primates in captivity and domesticated pigs. These viruses which are mainly found throughout Central and Western Africa cause a hemorrhagic fever in humans which most often or not leads to death; EBOV-Zaire (ZEBOV) is the most deadly of all types resulting in at most 90% of those infected to die; the reasons for such high mortality are not known.

We can begin to build up a picture of ZEBOV infection and pathogenesis using a combination of in vitro studies, animal models and clinical work carried out in humans. In animal models EBOV has been shown to replicate to extremely high levels, induce the abundant secretion of inflammatory signalling molecules, cause massive cell death of lymphocytes and a great deal of tissue destruction eventually leading to multi-organ system failure, toxic shock and death. Work carried out on blood samples collected from both human survivors and non-survivors of EBOV outbreaks have showed that lethal infection is associated with a highly deregulated immune response. Extremely high levels of pro-inflammatory cytokines (cell signalling proteins) were detected as well as low levels of circulating T lymphocytes. Yet there was a surprisingly little anti-viral response seen. This all suggests that the EBOV induces a rapid and strong pro-inflammatory immune response without eliciting effective innate and adaptive antiviral defenses resulting in a lethal outcome. Those people which did not develop this lethal immune reaction survived EBOV infection. But how exactly does EBOV do this?

New evidence has been uncovered suggesting that certain ZEBOV components may act like what are known as 'superantigens' (sAg) which may responsible for this damaging deregulation in immune responses.
Superantigen TCR/MHCII interaction.
As the paper explains:
"SAgs are microbial proteins that bind simultaneously to major histocompatibility complex class II molecules and to the T-cell receptor (TCR) V beta region. This “bridge” skews the T-cell repertoire by amplifying specific T- cell V beta subsets, which then are either rapidly deleted by activated cell death or become anergic."
What this means is that maybe ZEBOV proteins are able to bind to our own immune cells through an abnormal mechanism (TCR AND MHCII) which results in those cells going into overdrive and then being selectively killed by our bodies (in order to prevent a runaway immune response) or those cells becoming immunologically unresponsive (anergic). If EBOV did encode a sAg it may be able to vastly eliminate our adaptive immunity.

Vbeta region mRNA expression levels in ZEBOV infected patients

A major feature mentioned above is the massive levels of cell death in T lymphocyte populations. There are many ways in which EBOV could produce this effect, including up regulation of pro-cell death molecules inside lymphocytes or through an alternative indirect pathway via infection of dendritic cells and macrophages - as it is known EBOV infects these cells. These immune regulatory cells are responsible for controlling the levels of other immune cells produced (they are considered major immunoregulators)- alter their behavior and you alter the number of lymphocytes. The finding the EBOV may encode a superantigen adds to the growing number of ways this virus may inhibit host immune responses.

We can begin to investigate this by looking at the specific types of T cell found within EBOV infected patients - normally you would expect each T cell V region type to found to the same level. sAG activity leads to the loss of specific T cell types without loss of others. Looking at the expression levels of specific V regions of the TCR we can observe whether certain types decrease after being infected with EBOV. This recent report demonstrated just this in infected patients versus non-infected (see above) suggesting that something in EBOV may act as an sAg. This appears to correlate well with a fatal immune response. 

Of course we will have to further verify this finding possibly in animal models or cell culture work but we can begin to ask further questions: does this occur in other EBOV species? What protein is causing the sAg activity? Can we somehow inhibit its activity? And, how is it that some patients come to avoid a sAg response?

Leroy EM, Becquart P, Wauquier N, & Baize S (2011). Evidence for ebola virus superantigen activity. Journal of virology, 85 (8), 4041-2 PMID: 21307193

Wauquier N, Becquart P, Padilla C, Baize S, & Leroy EM (2010). Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. PLoS neglected tropical diseases, 4 (10) PMID: 20957152

On the origins of smallpox - where and when did variola virus emerge?

ResearchBlogging.org2011 may be the year where the last known officially acknowledged stocks of the deadly smallpox virus, variola are destroyed - a virus that claimed over 500 million lives in the 20th century alone. The extensive collection of 'live' virus and DNA stocks totalling over 500 isolates/strains, which are held between the US Centres for Disease Control and the Russian State Research Centre of Virology and Biotechnology may be ordered to be eliminated following World Health Organisation (WHO) recommendations soon to be announced.

Although the impending fate of this pathogen has been covered elsewhere by Vincent Racaniello and Steven Salzberg I have been led to ponder its beginnings, at least in humans: where and when, over the course of human history did variola virus emerge  and have we always suffered from it? What confuses the matter further is that there are two clinical forms of smallpox - major (30% mortality) and minor, including both African and Alastrim minor (<1% mortality)- do these viruses have the same evolutionary history and if so, when and where did they diverge? Luckily, we can now study the origins of infectious diseases through both molecular and historical records.

A depiction of Shapona the west-African Yoruba god of smallpox. Courtesy James Gathany (photo), CDC/ Global Health Odyssey.
Conflicting historical records

It has been very confusing trying to make sense of the historical records of suspected smallpox cases as there are significant gaps in documentation and many conflicting reports. Smallpox-like skin lesions have been observed on Egyptian mummies dating from as far back as 1580 B.C yet there is no mention of the disease at all in the Old or New testaments nor even the Hippocratic texts. There was some mention of a smallpox-like disease in China and India as early as 1500 B.C but the only unmistakable description can be found from the 4th century A.D in China.  Interestingly there was no mention of smallpox in the American continents nor in sub-Saharan Africa prior to European exploration. But as shown in the picture above, smallpox has shaped west-African culture. So, did smallpox originate in Asia and spread to Egypt around 1,500 B.C? Or, is smallpox a relatively recent human disease, emerging around the 4th century A.D in Asia?

Molecular data shed light on variola evolution

A 2007 study using genomic data from the CDC's variola collections - the same ones that may soon be destroyed, added a phylogenetic perspective to the origins of smallpox and how it spread worldwide. Through studying single nucleotide polymorphisms (SNPs) from 47 variola genome isolates from geographically distant areas and collected between the 1940s and '60s they examined the genetic relatedness between isolates and were able to estimate the time since they shared a last common ancestor. They combined this DNA evidence with the above historical records to generate an idea as to where, when and how smallpox originated and spread throughout human populations.

Variola genome phylogeny

Abstract: Human disease likely attributable to variola virus (VARV), the etiologic agent of smallpox, has been reported in human populations for >2,000 years. VARV is unique among orthopoxviruses in that it is an exclusively human pathogen. Because VARV has a large, slowly evolving DNA genome, we were able to construct a robust phylogeny of VARV by analyzing concatenated single nucleotide polymorphisms (SNPs) from genome sequences of 47 VARV isolates with broad geographic distributions. Our results show two primary VARV clades, which likely diverged from an ancestral African rodent-borne variola-like virus either ≈16,000 or ≈68,000 years before present (YBP), depending on which historical records (East Asian or African) are used to calibrate the molecular clock. One primary clade was represented by the Asian VARV major strains, the more clinically severe form of smallpox, which spread from Asia either 400 or 1,600 YBP. Another primary clade included both alastrim minor, a phenotypically mild smallpox described from the American continents, and isolates from West Africa. This clade diverged from an ancestral VARV either 1,400 or 6,300 YBP, and then further diverged into two subclades at least 800 YBP. All of these analyses indicate that the divergence of alastrim and variola major occurred earlier than previously believed.

Hypothesised spread of variola worldwide
When analysed, variola fell into two large monophyletic clades signifying a historical divide in their genetic relatedness. The earliest representative - or most basal - of the variola major smallpox viruses are the Asian isolates. This suggests that major may have originated in Asia followed by geographic radiation across the Old world and into Africa. Using historical records as a means to calibrate variola evolutionary history, their results indicated that smallpox spread from Asia as much as 1,600 years ago which neatly backed up the historical records of 4th Century China. By the time smallpox reached out of East-Asia, the ancient Greek and Roman civilisations were no more - hinting that the reason they didn't observe smallpox was because at that time, in the Mediterranean region there wasn't any variola virus transmission. Despite this, analysis of the second major clade suggested a split 6,300 years ago placing variola well into ancient history. So, is smallpox a very old or relatively recent human pathogen? And, if so, where did it occur? The molecular data also showed that the clinically 'minor' forms of smallpox - African minor and Alastrim minor are very much related to the major viruses; evolutionarily speaking these viruses are thus very smilier.

A rodent origin of smallpox?

We can investigate the origin of smallpox through the molecular characterisation of other poxviruses. Variolataterapox virus) and camelpox viruses and they all are more related to each other than to other poxviruses, such as monkeypox. When their genomes were compared to that of variola, a time since divergence was estimated at between 16,000 and 68,000 years ago. As taterapox and camelpox are primarily found throughout Africa and Asia this suggests a possible origin of variola and the other poxviruses from ancient endemic poxviruses in Africa, possibly from rodents. Upon human infection this virus may have followed us out of Africa entering Asia and spreading across the globe. Or possibly, the virus emerged in rodent populations only to pop up again in Asia thousands of years later.

Although this period is quite a bit before the development of human agriculture and increased population density as is possibly required for such a highly infectious and lethal virus like smallpox to persist, the ancient variola virus might have behaved very differently from the one we know and fear. Sadly, we cannot say for sure exactly how and where variola emerged because we simply do not know a lot about the natural diversity of poxviruses in rodents or other mammal species and until we do, we will not have an accurate answer.

Future Pox?

Monkeypox from bushmeat?
What does this history of smallpox say about its impending eradication and the threat of a future virus emergence? Well, sometime in our ancient past variola virus emerged into prehistoric human populations and the data indicate that this may well have occurred within the African continent or nearby in Asia and it is likely that this same ancestral virus emerged into other mammalian species, such as Camels and Rodents. Smallpox then might have followed us through our journey out of Africa and became endemic in large population centres across the Eurasian landmass.

Although we have now effectively eradicated variola from the human population - and soon seek to destroy its last remaining stocks - might another poxvirus emerge just like it did before? We are now in a situation where the human population has very little immunity to variola and other related poxviruses, a situation which last would have existed prior to the initial emergence of smallpox. This provides ample breeding ground for novel poxviruses to emerge and fill the niche emptied by waning population immunity. Alarmingly, the rate of monkeypox infections - another rodent poxvirus - has been increasing (20X)  in the last 3 decades following cessation of smallpox vaccination. May this, or another related poxvirus, be the new smallpox? Could existing smallpox stocks not be used to study poxvirus/human interactions? May it be premature to destroy them in light of possible future pandemics? Only the WHO can decide later ths year.

Gubser C, & Smith GL (2002). The sequence of camelpox virus shows it is most closely related to variola virus, the cause of smallpox. The Journal of general virology, 83 (Pt 4), 855-72 PMID: 11907336

Li, Y., Carroll, D., Gardner, S., Walsh, M., Vitalis, E., & Damon, I. (2007). From the Cover: On the origin of smallpox: Correlating variola phylogenics with historical smallpox records Proceedings of the National Academy of Sciences, 104 (40), 15787-15792 DOI: 10.1073/pnas.0609268104

Raymond S. Weinstein (2011). Should Remaining Stockpiles of Smallpox Virus (Variola) Be Destroyed? Emerg Infect Dis, 17 (Apr) : 10.3201/eid1704.101865

Rimoin AW, Mulembakani PM, Johnston SC, Lloyd Smith JO, Kisalu NK, Kinkela TL, Blumberg S, Thomassen HA, Pike BL, Fair JN, Wolfe ND, Shongo RL, Graham BS, Formenty P, Okitolonda E, Hensley LE, Meyer H, Wright LL, & Muyembe JJ (2010). Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo. Proceedings of the National Academy of Sciences of the United States of America, 107 (37), 16262-7 PMID: 20805472

Fighting dengue with mosquito semen

Dengue virus, DENV - an important mosquito-borne virus
Arthropods are important vectors in the transmission of a number of animal and human pathogens. A major vector group are the mosquitoes of which there are over 3,000 species. However, during their life cycle some mosquitoes feed on the blood of other animals - creating an excellent chance for the direct transfer of manymicrobial species. From here the bacteria/viruses/parasites can initiate infection of the new host which then, following another blood feed, may transmit the pathogen to an uninfected insect. This particular lifestyle allows for the development of pathogen control strategies aimed at interfering with the vector species. If we remove or inhibit the vector, we may prevent the spread of the pathogens they carry.

 Why dengue?

Mosquito sex
Another group of mosquito-borne pathogens are the closely related - but distinct - dengue viruses (DENV). DENV is commonly responsible for a 'flu-like- illness' in humans but complications may include a potentially fatal hemorrhagic fever. The incidence is mainly constrained to tropical and sub-tropical areas although in recent decades it has spread to other areas where it may cause massive epidemics. The World Health Organisation states that, "Some 2.5 billion people – two fifths of the world's population – are now at risk from dengue. WHO currently estimates there may be 50 million dengue infections worldwide every year." There is currently no commercially licensed vaccine or antivirals available for the treatment of dengue leaving the only option to prevent transmission through control of mosquito populations.

The most important vector species is the predominantly urban species Aedes aegypti - control of which may aid DENV eradication. There are a number of potential strategies that could be employed to reduce the numbers of this species including chemical poisoning, genetic strategies and biological control. A major goal is therefore to inhibit  mosquito reproduction and feeding behaviour yet this requires intimate knowledge of mosquito reproductive biology. Insects communicate via a number of chemical signals, one mode of communication is via the males ejaculate -what happens to be a convenient opportunity to control a females behaviour. A mated female is behaviourally very different to an unmated one and there is evidence suggesting that this change is initiated by the transfer of male-derived signaling proteins during mating. It may then prove to be useful to identify some of these molecules so as to possibly control mosquito behaviour ourselves.

What is so good about male semen?

Sirot et al recently report, using proteomic analysis, the identificantion of a number of proteins, termed seminal fluid proteins (Spfs) transferred from males (with labelled proteins) to females (non-labelled proteins) during mating. Of which some may be responsible for the male control over female post-reproductive behaviour; this they say, lays the groundwork for future studies investigating the molecular mechanisms behind how they work and their potential use in controlling vector populations. However, care must be taken in interpreting these results as this study does not directly look at the biological effects of these proteins and does not prove that they do have any effect on female behaviour.

Labelled insect sperm

So, what do these semen proteins actually do?
Using this approach they identified 145 proteins transferred from males to females, 17 of which were previously unknown to science - 93, they say, could be assigned as potential biologically active proteins. What function do this proteins have? Well, based on the previous annotation in protein databases, they were able to assign each of their proteins a potential function indicating the potential important roles in female behaviour. These proteins are predicted to be involved in their reproductive biology, specifically protein degradation and hormonal signalling.

This work has identified a number of proteins present in the semen of the dengue vector, Aedes aegypti which are transferred from males to females during mating. This may mean they are involved in the control of female behaviour. Although this work did not look at the function of any proteins directly, it does lay the foundations for future studies. Researchers may now focus there investigations on a set of a now verified smaller set of proteins and genes. This  species is also the vector for a number of other viruses such as chikungunya and yellow fever and so any work on this may aid the control of these important diseases.
Gillott C (2003). Male accessory gland secretions: modulators of female reproductive physiology and behavior. Annual review of entomology, 48, 163-84 PMID: 12208817

Sirot, L., Hardstone, M., Helinski, M., Ribeiro, J., Kimura, M., Deewatthanawong, P., Wolfner, M., & Harrington, L. (2011). Towards a Semen Proteome of the Dengue Vector Mosquito: Protein Identification and Potential Functions PLoS Neglected Tropical Diseases, 5 (3) DOI: 10.1371/journal.pntd.0000989

Viruses, vaccination and the inflammasome. Part 1.

ResearchBlogging.orgThe inflammasome

Daily, our immune system deals with multiple microbial threats, including viral, bacterial, fungal and parasitic pathogens that have evolved to evade our defences. One major obstacle to infection is our 'innate' immune system - the one that doesn't include all our B and T cells; has no memory and is generally pretty fast in acting. This set of barriers is made of anatomical, chemical, molecular and cellular obstacles that must be overcome if a pathogen is to successfully set up home in our bodies.

Generic inflammasome
Activation results in caspase-1
recruitment and proteolysis

This system has been studied for decades, yet relatively recently, a novel component was discovered - the inflammasome. On top of bein implicated in protecting against microbial pathogens it has also been shown to play a role in many autoinflammatory diseases, such as inflammatory bowel diseases and vitiligo. It is beginning to emerge as a central component in the regulation of our defences.


Detected in many of our cells, the inflammasome is a multi-protein complex whose assembly is triggered by the detection of what are known as 'pathogen-associated molecular patterns' (PAMPs) - basically something our cells can detect which looks only like bacteria, virus, fungi or parasite. These PAMPS are sensed by cellular proteins known as 'pathogen recognition receptors' - (PRRs)  e.g NALP3, on the inside or outside of the host cell; however, triggering can also result from the detection of chemical 'danger-associated molecular patterns' (DAMPS) compounds, including uric acid and asbestos. PRRs include: double stranded DNA, non-capped RNA and lipopolysacharride found in bacterial cell walls. Triggering of other PRRs results in the activation of many other immune responses, including autophagy, interfon secretion and cell signalling.

A pro-inflammatory signalling molecule

Formation of the inflammasome results in the activation of multiple pathways responsible for co-ordinating our immune response, yet interestingly, there are multiple forms of inflammasomes made up and triggered by different sets of proteins. This initial step of activation has been covered very well before, here. The activated inflammsome goes on to trigger key downstream members of our innate immune system through the recruitment of an important regulatory protease (it cuts up other proteins) - caspase 1, which converts inactive molecules to active, pro-inflammatory ones, such as interleukin-1 beta and interleukin-18. This 'inflammatory cascade' functions to initiate an effective local and systemic immune response through the control of the innate and adaptive immune system; for example, IL-beta is responsible for fever and the recruitment of immune cells to the site of infection, and IL-18 induces the development of key T cell responses.

Not all IL-1beta and IL-18?

Recent studies have shown that not all immune functions of the inflammasome are down purely to the effects of these two mediators; a number of other effectors are implicated in our complicated immune responses. Other responses activated by caspase-1 proteolysis include the better cell survival in the face of bacterial toxins; regulation of cellular metabolism limiting pathogen replication; induction of pyroptosis - a pro-inflammatory form of cell-death much like apoptosis and the secretion of high levels of multifuctional cytokines from the cell.

Inflammatory 'pyroptosis' is looking to be an important mediator in the immune response

All in all, the inflammasomes represent a fast and effective barrier to microbial infection in eukaryotic cells which, following detection of PAMPS and subsequent activation, results in a powerful innate immune response, stimulation of adaptive defences and significant contributions to over-all host defence using a variety of pathways.

Inflammasomes and viruses

As the cell is able to detect pathogens (PRRs and PAMPs) and assemble the inflammasome to regulate the immune response, it is clearly in the best interest of the virus (basically a bag of PAMPs) to evade or somehow counteract its effects through preventing its formation or inhibiting its ability to activate an immune response. We are, however, only beginning to understand the complex relationship viruses have with the inflammasome through investigating how viruses trigger its assembly; how viruses trick the inflammasome into failing to act and how triggering of the inflammasome relates to the particular disease symptoms a virus causes. How does this system specifically detect viruses? What is the response to pathogens? And, what role does this play in host immunity?

Hoffman HM, & Brydges SD (2011). The genetic and molecular basis of inflammasome-mediated disease. The Journal of biological chemistry PMID: 21296874

Kanneganti, T. (2010). Central roles of NLRs and inflammasomes in viral infection Nature Reviews Immunology, 10 (10), 688-698 DOI: 10.1038/nri2851

Lamkanfi M (2011). Emerging inflammasome effector mechanisms. Nature reviews. Immunology, 11 (3), 213-20 PMID: 21350580

Martinon F, Burns K, & Tschopp J (2002). The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Molecular cell, 10 (2), 417-26 PMID: 12191486

Virus of the week: MUMPS VIRUS (MuV)

In order to better understand (and maybe even enjoy - is that the right word?) viruses, I think it is time to meet and greet a couple of them; this is why I am starting a weekly tradition here at Ro6 - "Virus of the week". I will introduce a virus; discuss its importance; highlight the important aspects of its biology and how it infects its hosts.

The first virus shown here is one currently close to my heart: the mumps virus (MuV). As part of my PhD work, I am using this virus to understand its molecular biology and how it causes disease in its host - humans. Not much is known about the basic biology of this unique human pathogen but that is beginning to change.

What is mumps?

Mumps, what used to be a common childhood illness, is characterised by the swelling of the salivary glands (parotitis) following infection yet something not commonly known is that it can also very easily infect the central nervous system with rates nearing 50% of those with mumps (see the NHS info site here). Prior to the introduction of vaccination programs it was one of the biggest causes of non-bacterial meningitis worldwide, although not life-threatening, meningitis and encephalitis constitute serious disease. Also, very importantly, in males it is very common for the testis to swell massively causing great pain and discomfort, possibly leading to reduced fertility. There are also a number of much rarer complications associated with MuV infecton, including infection of the heart muscle; the pancreas and the inner ear which can lead to deafness (Lancet review here). Part of my research is trying to understand why - at the molecular level - MuV causes these symptoms and infects these organs rather than others.

Why is it important?

The mumps virus
 But why is it important to study MuV, especially as we have a good vaccine? Well, despite this highly effective vaccine - that HAS worked very well in the past - mumps is still currently circulating worldwide. A good example is the ongoing Scottish outbreak but well publicised outbreaks across the US and UK also highlight this. The reasons why, despite being vaccinated, MuV can infect a person are currently unknown. If we have a good vaccine and the ability to vaccinate people easily yet can't eradicate the mumps virus, what hope do we have for a virus which is more difficult to immunise? Also, in countries lacking mumps immuisation, mumps can contribute to profound morbidity and mortality; mumps is therefore still a global problem! For WHO figures see here.

Mumps virus molecular biology

Viruses are, at the most basic level, very small packages of nucleic acids and proteins packaged in a protective coating which can either be made of proteins (capsid) or fats (an envelope). The mumps virus comes from a group of viruses that whose genome is made out of RNA - not DNA like you and I have - and strangely, it is also only single-stranded while ours is double-stranded; we say that this RNA is 'negative sense' in that it is complementary to its mRNA molecules. The mumps genes are lined up across this single RNA molecule encoding for proteins involved in cell entry, replication and immune evasion.

Other viruses with single-stranded, negative-sense RNA genomes include many important human and animal pathogens: measles virus, respiratory syncitial virus, ebolavirus and the henipaviruses. More specificaly MuV is a Rubulavirus found within the family Paramyxoviridae. Like other viruses, MuV carries out its entire active lifecycle within the cell and uses its extracellular form (shown above) to infect new cells allowing the virus genome access to the cell cytoplasm where replication and gene expression take place and full-blown infection can begin.

Evolutionary tree of Paramyxovirus relationships - notice mumps virus (MuV), a rubulavirus.

So how does the mumps virus cause mumps?

Just like Influenza, mumps is transmitted through aerosol particles that we breathe in and out which allows the virus access to our respiratory tract - a very nice point of entry of many viruses. MuV is believed to first replicate along our airways in the epithelial cell lining and then is somehow able to spread throughout the body, possibly via infection of your bodies immune cells or maybe just release of virus particles into the bloodstream. Infection of the salivary glands, brain, testis and pancreas follows giving rise to the common symptoms known as mumps. Virus particles are finally released back into your airways allowing the spread between person to person and once your immune response kicks in, the virus infection is cleared up hopefully without any long-term problems.

What does the future hold for mumps research?

A lot of this basic knowledge outlined above on mumps infection has been seen only through studying of other viruses and there is so much more basic mechanisms to find out. The advent of modern molecular biology techniques and protocols has allowed for a renewed interest in studying this basic biology of viruses, including mumps. The ability to alter a virus genome and investigate whether it has biologically changed has facilitated a much better understanding of viral infection, replication and evolution. This has - and is being - applied to the study of mumps, however, there is still much work to be done to catch up with other viruses. Maybe, before we have had a chance to understand mumps biology we will have eradicated indigenous mumps transmission worldwide and it will no longer be important.
Galazka AM, Robertson SE, & Kraigher A (1999). Mumps and mumps vaccine: a global review. Bulletin of the World Health Organization, 77 (1), 3-14 PMID: 10063655

Walker J, Huc S, Sinka K, Tissington A, & Oates K (2011). Ongoing outbreak of mumps infection in Oban, Scotland, November 2010 to January 2011. Euro surveillance : bulletin europeen sur les maladies transmissibles = European communicable disease bulletin, 16 (8) PMID: 21371413

An ecological perspective on bat viruses

Mammals hold a large reservoir of potential emerging viruses
Viruses universally infect the tree of life; all species ever known have most likely acted as hosts to viral pathogens. These species, harbouring many unknown viruses may therefore act as virus ‘reservoirs’ – storing potential emerging viruses that may one day infect humans or other species. This is illustrated by the recent emergences of swine and avian-origin Influenza, SARS-coronavirus and the Henipaviruses. Events just like these have probably contributed multiple viral pathogens to the human species over our evolutionary history, for example: HIV and the measles and mumps viruses.

Being able to predict when and where these events may take place is thus important to global health if we are to prevent further deadly pandemics. We therefore must be able to accurately judge zoonotic risks before they happen. Many processes, such as genetic factors, contact between species and the amount of virus present in the population will affect the emergence of viral pathogens; if we are to track these it may therefore be possible to predict these risks easily.

The European 'greater mouse-eared bat', Myotis myotis

Possibly due to them being relatively close relatives to us, mammals constitute the largest threat in terms of future viral pathogens that we know of. The most abundant mammals are the rodents and bats – making up well over 50% of all known mammal species with their large population sizes and geographic closeness to human populations favouring for the frequent ‘spill-over’ of viruses to us. It is therefore not surprising that many emerging viruses have originated in these species. Bats have gained much attention from the scientific community relating to virus emergence and have been shown to harbour multiple RNA and DNA viruses, although the extent to which each may spread to humans and other species is unknown (See recent metagenomic papers 1 and 2).. Despite the international awareness of bats as virus reservoirs, little work has been carried out investigating both the molecular biology of bat viruses and even the epidemiological and ecological dynamics of viruses within bat populations. If we are to fully understand how best to prevent virus emergence from bats and other species we will have to fully investigate these processes.

Drexler et al(2011) recently investigated the epidemiological dynamics of viruses in a single population of Myotis myotis bats in Germany in order to better understand the role these animals play in virus ecology. 

Bats host noteworthy viral pathogens, including coronaviruses, astroviruses, and adenoviruses. Knowledge on the ecology of reservoir-borne viruses is critical for preventive approaches against zoonotic epidemics. We studied a maternity colony of Myotis myotis bats in the attic of a private house in a suburban neighborhood in Rhineland-Palatinate, Germany, during 2008, 2009, and 2010. One coronavirus, 6 astroviruses, and 1 novel adenovirus were identified and monitored quantitatively. Strong and specific amplification of RNA viruses, but not of DNA viruses, occurred during colony formation and after parturition. The breeding success of the colony was significantly better in 2010 than in 2008, in spite of stronger amplification of coronaviruses and astroviruses in 2010, suggesting that these viruses had little pathogenic influence on bats. However, the general correlation of virus and bat population dynamics suggests that bats control infections similar to other mammals and that they may well experience epidemics of viruses under certain circumstances.

Following the extraction of nucleic acids from bat droppings collected every 3 weeks in May, June and July over three years they were able to build up a generalised picture of how the number and diversity of specific virus genome sequences changed over time and how this may influence the bat population. Using this method, they detected a total of 7 separate viral sequences from a single coronavirus, 6 astroviruses (both RNA viruses) and one adenovirus (DNA). From this, they were able to track their abundance over the 3 months noting whether the amount of a virus increased or decreased over time. Despite there being no evidence that these viruses cause disease in humans or other animals, these may be used as a proxy for other deadly pathogens, including SARS-coronavirus and ebolavirus. A significant increase in bat numbers over the study period indictaed that these viruses had little pathogenic influence on populations.

Virus sequence abundance over the 3 years. A = coronavirus. B = Astrovirus and C = Adenovirus. Notice the cyclical dynamis with A and B yet not C

Two general patterns emerged from these studies:

  • One where abundance initially increased only to decrease soon after and finally, in the last month increasing again – shown with the coronavirus and astroviruses. They attribute these different patterns to fundamental changes within the bat population. The initial increase in virus abundance (coronavirus and astrovirus) is possibly due to the increase in the number of bats living in the colony – as time goes on, the colony expands taking in new bats which are susceptible to virus infection just as is seen in human populations. As the bats become immune to the viruses and begin to give birth to pups of their own the transfer of maternal protective immunity to newborns causes an initial decrease in virus numbers; immunity to the virus is still present and hence abundance decreases. As maternal protection fades over time, the newborns become susceptible to infection, leading to rapid increases in virus abundance. These cyclical dynamics are completely the opposite of what is seen with adenovirus where no changes in abundance were observed.
  • And another where virus abundance did not significantly change over time – seen with the adenovirus - the complete opposite to the corona- and astroviruses. This may demonstrate basic differences in virus transmission, with adenoviruses persisting long-term in hosts and do not therefore rely on a readily susceptible population of hosts. These viruses have mechanisms of evading host immunity meaning that increases or decreases in protection do not lead to direct changes in adenovirus numbers.

This paper illustrates the potential importance that bat populations play in the ecology of viruses within general ecosystems shared with humans. This work, although not focussing on proven human pathogens, allows us to infer general principles of virus dynamics; these bat colonies may be able to signifcantly amplify RNA virus abundance across time, indicating potential periods of increased risk. The ability to accurately predict the chances of virus emergence may allow us to prevent future epidemics of seirous disease. But, the major questions to ask are whether this does accurately predict the behaviour of other viruses and whether even if virus numbers increase, will this even represent a signifcantly greater risk to other species? More work should be carried out to explore the role of not just bats but other animals in the spread of viruses through an entire ecosystem.
Drexler JF, Corman VM, Wegner T, Tateno AF, Zerbinati RM, Gloza-Rausch F, et al. (2011). Amplification of Emerging Viruses in a Bat Colony
Emerg Infect Dis, 17 (3) : 10.3201/eid1703.100526