MicrobiologyBytes

Biologists have uncovered virus fragments from the same family of the modern Hepatitis B virus locked inside the genomes of songbirds such as the modern-day zebra finch. This article marks the first time that endogenous hepadnaviruses have been found in any organism. An endogenous virus is one that deposits itself or fragments of itself into the chromosome of an organism, allowing it to be passed from generation-to-generation. Previously, most of these known “fossilized” virus sequences have come from retroviruses. These fragments have been sitting in the bird’s genomes for at least 19 million years, far longer than anyone previously thought this family of viruses had been in existence.

The researchers dated the hepadnavirus fragments by locating them in the same spot on the genome of five species of passerine birds and then tracing those species to a common ancestor that lived more than 19 million years ago. This work provides a glimpse into an ancient viral world that we never knew existed. The results are remarkable – hepadnaviruses, and likely many other viruses as well, are far older than we previously thought. Another surprise is that the older versions of the hepadnaviruses are remarkably similar to today’s viruses. This suggests that the slow evolution of the hepadnaviruses observed in birds indicates that the viruses are, in the long run, better adapted to their hosts than what is suggested by study of the disease-causing Hepatitis B viruses. Genomic fossils like these remarkable hepadnaviral fossils have the prospect of completely revising our preconceived notions about the age and evolution of such viruses.

This study also opens new avenues for research that might help predict and prevent human viral pandemics originating in bird species. Given that they were infected in the past, it is legitimate to think that some of these birds may still carry such viruses today. We can use this discovery as a guide to screen targeted groups of bird species for the presence of new circulating Hepatitis B-like viruses.

Genomic Fossils Calibrate the Long-Term Evolution of Hepadnaviruses. (2010) PLoS Biol 8(9): e1000495. doi:10.1371/journal.pbio.1000495
Because most extant viruses mutate rapidly and lack a true fossil record, their deep evolution and long-term substitution rates remain poorly understood. In addition to retroviruses, which rely on chromosomal integration for their replication, many other viruses replicate in the nucleus of their host’s cells and are therefore prone to endogenization, a process that involves integration of viral DNA into the host’s germline genome followed by long-term vertical inheritance. Such endogenous viruses are highly valuable as they provide a molecular fossil record of past viral invasions, which may be used to decipher the origins and long-term evolutionary characteristics of modern pathogenic viruses. Hepadnaviruses (Hepadnaviridae) are a family of small, partially double-stranded DNA viruses that include hepatitis B viruses. Here we report the discovery of endogenous hepadnaviruses in the genome of the zebra finch. We used a combination of cross-species analysis of orthologous insertions, molecular dating, and phylogenetic analyses to demonstrate that hepadnaviruses infiltrated repeatedly the germline genome of passerine birds. We provide evidence that some of the avian hepadnavirus integration events are at least 19 My old, which reveals a much deeper ancestry of Hepadnaviridae than could be inferred based on the coalescence times of modern hepadnaviruses. Furthermore, the remarkable sequence similarity between endogenous and extant avian hepadnaviruses (up to 75% identity) suggests that long-term substitution rates for these viruses are on the order of 10^-8 substitutions per site per year, which is a 1,000-fold slower than short-term rates estimated based on the sequences of circulating hepadnaviruses. Together, these results imply a drastic shift in our understanding of the time scale of hepadnavirus evolution, and suggest that the rapid evolutionary dynamics characterizing modern avian hepadnaviruses do not reflect their mode of evolution on a deep time scale.

Related:

1. Phoenix from the ashes: The 5 million year old virus
2. The Island of Fossil Viruses

According to official estimates, rabies kills 55,000 people each year, primarily in India, Southeast Asia and Africa. However, the death toll is probably much higher; one report estimates that the number of deaths in some areas is possibly 100 times that reported. As rabies cases do not need to be reported to the authorities in many countries, and many people do not seek treatment or are misdiagnosed, obtaining an accurate estimate of the overall prevalence is difficult. Even the official death toll is higher than that for diseases such as human African trypanosomiasis, leishmaniasis and Chagas disease.

As with other diseases that are preventable and treatable, such as pneumonia, it seems unthinkable that rabies still claims so many lives. Successful control of rabies in the United Kingdom and the Americas shows that rabies can be controlled and possibly eliminated. Further research will bring us closer to this goal, but it will require funding agencies and governments to better understand the scope of the problem. Until then, important events like World Rabies Day will remain vital to shed light on this neglected problem.

Biting back against rabies. Nature Reviews Microbiology 8: 676 (October 2010) doi:10.1038/nrmicro2451

Related:

• Transmission and elimination of rabies
• Simplified rabies vaccination
• Pre-exposure and Post-exposure Prevention of rabies

miRNAs are small single-stranded RNA species of approximately 20–24 bases in length that regulate gene expression through post transcriptional mechanisms. Expression of miRNAs is thought to be ubiquitous among multicellular eukaryotes. In addition to eukaryotic miRNAs, more than 100 viral miRNAs have been identified, almost all of which are expressed by herpesviruses. Targets for the majority of viral miRNAs are currently unknown due to the difficulty involved in identifying novel target transcripts. This remains one of the major challenges in elucidating the function of miRNAs. However, recent reports have begun to elucidate the various roles of viral miRNAs. These include blocking apoptosis, immune evasion and regulation of virus replication through targeting of both cellular and virus gene expression.

Regulation of gene expression is as important as the genes themselves in determining the diverse array of living creatures we see in nature. Recently, scientists have discovered a whole new level of gene regulation through the actions of small molecules called microRNAs (miRNAs). It is currently thought that miRNAs regulate gene expression primarily through binding to target sites within the 3′ untranslated region (UTR) of mRNAs. This paper identifies a population of cellular genes that are targeted by a virally-encoded miRNA. Many of the genes are related to cell cycle control, suggesting that the viral miRNA is targeting genes within a related pathway. In contrast to most miRNAs, this miRNA inhibits gene expression through binding to target sites within the 5′ UTRs, suggesting that viral miRNAs may target genes through mechanisms divergent from cellular miRNAs.

A Viral microRNA Down-Regulates Multiple Cell Cycle Genes through mRNA 5′ UTRs. (2010) PLoS Pathog 6(6): e1000967. doi:10.1371/journal.ppat.1000967
Global gene expression data combined with bioinformatic analysis provides strong evidence that mammalian miRNAs mediate repression of gene expression primarily through binding sites within the 3′ untranslated region (UTR). Using RNA induced silencing complex immunoprecipitation (RISC-IP) techniques we have identified multiple cellular targets for a human cytomegalovirus (HCMV) miRNA, miR-US25-1. Strikingly, this miRNA binds target sites primarily within 5′UTRs, mediating significant reduction in gene expression. Intriguingly, many of the genes targeted by miR-US25-1 are associated with cell cycle control, including cyclin E2, BRCC3, EID1, MAPRE2, and CD147, suggesting that miR-US25-1 is targeting genes within a related pathway. Deletion of miR-US25-1 from HCMV results in over expression of cyclin E2 in the context of viral infection. Our studies demonstrate that a viral miRNA mediates translational repression of multiple cellular genes by targeting mRNA 5′UTRs.

Related:

1. Five Questions about Viruses and MicroRNAs
2. Virus-encoded microRNAs in herpesvirus biology
3. MicroRNAs in Picornavirus Infection

The source of persistent HIV in patients on suppressive therapy is debated. Recent studies of treatment intensification have produced varied results: no reduction in low-level plasma viremia indicating the source of persistent viremia is long-lived HIV-infected cells that release HIV when activated and increase in episomal HIV DNA indicating active replication persists in some infected individuals on suppressive therapy. In addition, clonal HIV sequences found in plasma from patients on long-term suppressive therapy are rarely found in CD4 memory T cells. These results indicate that persistent viremia may arise from several different sources. Recent studies emphasize the complexity of HIV latency. Current strategies for HIV eradication focus on compounds that activate viral transcription in memory CD4 T cells by many routes, including inhibiting histone deacetylation and activating nuclear factor kappa B. Several compounds and combinations of these compounds appear to induce the expression of integrated HIV in different latency models. This review focuses on recent advances in HIV research and therapy that seek to eradicate persistent HIV in patients on suppressive therapy.

Many researchers currently investigate the source and dynamics of residual viremia. A well defined latent reservoir of HIV is memory CD4 T cells. However, other cell types such as hematopoietic stem cells and cells of the monocyte/macrophage lineage may also serve as long-term reservoirs of HIV. Several mechanisms appear to play a role in maintaining HIV latency including viral integration sites, chromatin environment, and downregulated transcription factors. Further studies are necessary to better understand the mechanisms that promote HIV latency in vivo. Recent studies shed new light on persistent HIV reservoirs and the mechanisms of latency. These studies highlight an important conclusion: any long-term strategy for HIV eradication must take HIV latency and its implications into account. Importantly, approaches to eradication of latent HIV reservoirs should not lead to new HIV infection as a result of activating latently infected cells or cause global T-cell activation. Although many challenges remain, it is encouraging to note that new research and debate have begun to seriously address HIV eradication and/or remission.

Can HIV infection be eradicated through use of potent antiviral agents? Curr Opin Infect Dis. Sep 16 2010

Related:

• HIV-1 latency and the eradication of long-term virus reservoirs
• HIV “can never be cured”

In a damning indictment of the UK government, Nature says:

The killing fields. Nature 467, 368 (23 September 2010) doi:10.1038/467368a

Related:

• Culling badgers a low priority for curbing cattle tuberculosis (PNAS article)
• Public health and bovine tuberculosis
• Irish badger cull ‘futile’ in controlling bovine tuberculosis
• David Willetts warned over science cuts by universities
• Science is Vital Campaign

After mapping humans’ intricate social networks, Nicholas Christakis and colleague James Fowler began investigating how this information could better our lives. Now, he reveals his hot-off-the-press findings: These networks can be used to detect epidemics earlier than ever, from the spread of innovative ideas to risky behaviors to viruses (like H1N1).

Related:

• Web 2.0 and sexually transmitted infections
• Health Risk Behaviors on MySpace
• You’ve Got Mail

More information about Microbiology at Leicester

High-throughput sequencing is an umbrella term applied to new sequencing technologies that deliver sequence data hundreds or thousands times more cheaply and speedily than traditional approaches. Three competing technologies have achieved widespread uptake: the Roche 454 platform, the Solexa/Illumina platform and Life Technologies SOLiD platform.

Genome sequencing has already transformed the study of microbial pathogens. For the first time, sequencing on a genomic scale now falls within the technical capability of the average university department and within the financial envelope of a modest research grant. Now that bacterial genomes can be sequenced in days or weeks rather than months or years, microbial genomics is at last poised to make a direct impact in clinical diagnostics, epidemiology and infection control. High-throughput sequencing also stands to revolutionise our view of the host response to infection and vaccination.

High-throughput sequencing and clinical microbiology: progress, opportunities and challenges. Curr Opin Microbiol. Sep 13 2010
High-throughput sequencing is sweeping through clinical microbiology, transforming our discipline in its wake. It is already providing an enhanced view of pathogen biology through rapid and inexpensive whole-genome sequencing and more sophisticated applications such as RNA-seq. It also promises to deliver high-resolution genomic epidemiology as the ultimate typing method for bacteria. However, the most revolutionary effect of this ‘disruptive technology’ is likely to be creation of a novel sequence-based, culture-independent diagnostic microbiology that incorporates microbial community profiling, metagenomics and single-cell genomics. We should prepare for the coming ‘technological singularity’ in sequencing, when this technology becomes so fast and so cheap that it threatens to out-compete existing diagnostic and typing methods in microbiology.

Related:

• Structural and functional analysis of virus siRNAs
• Metagenomic Analysis of Human Diarrhoea

Measles is a common infection in children and is spread by the respiratory route, but where did the virus come from? The disease is characterized by a prodromal (initial) illness of fever, coryza, cough, and conjunctivitis followed by appearance of a generalized maculopapular rash. Measles virus (MeV) infects approximately 30 million people annually, with a mortality of 197,000, mainly in developing countries. In the prevaccine era, more than 90% of 15-year-old children had a history of measles. Measles remains a major cause of mortality in children, particularly in areas with inadequate vaccination and medical care.

MeV infection can confer lifelong immunity, and there is no animal reservoir or evidence of latent or common persistent infection except for a rare condition called subacute sclerosing panencephalitis (SSPE). Therefore, maintenance of MeV in a population requires constant supply of susceptible individuals. If the population is too small to establish continuous transmission, the virus can be eliminated. Mathematical analysis shows that an immunologically-naïve population of 250,000-500,000 is needed to maintain MeV. This is approximately the population of the earliest urban civilizations in ancient Middle Eastern river valleys around 3000-2500 BCE. Historically, the first scientific description of measles-like syndrome was provided by Abu Becr, known as Rhazes, in the 9th century. However, smallpox was accurately described by Galen in the 2nd second century whereas measles was not. Epidemics identified as measles were recorded in the 11th and 12th centuries.

MeV is a member of the genus Morbillivirus, which belongs to the family Paramyxoviridae. In addition to MeV, Morbillivirus includes dolphin and porpoise morbillivirus, canine distemper virus, phocid distemper virus, peste des petits ruminants virus, and rinderpest virus (RPV). Genetically and antigenetically, MeV is most closely related to RPV, which is a pathogen of cattle. MeV is assumed to have evolved in an environment where cattle and humans lived in close proximity. MeV probably evolved after commencement of livestock farming in the early centers of civilization in the Middle East. The speculation agrees with the mathematical analysis mentioned above.

Molecular clock analysis can estimate the age of ancestors in evolutionary history by phylogenetic patterns. The basic approach to estimating molecular dates is to measure the genetic distance between species and use a calibration rate (the number of genetic changes expected per unit time) to convert the genetic distance to time. Pomeroy et al. showed that “Time to the Most Recent Common Ancestor” of the current MeV circulating worldwide is recent, i.e., within the last century (around 1943). Nevertheless, the time when MeV was introduced to human populations has not been investigated. In this study, the researchers performed molecular clock analysis on MeV to determine the time of divergence from RPV, suggesting that MeV emerged in humans in the 11th to 12th centuries.

Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries. Virology Journal 2010, (7):52 doi:10.1186/1743-422X-7-52
Measles, caused by measles virus (MeV), is a common infection in children. MeV is a member of the genus Morbillivirus and is most closely related to rinderpest virus (RPV), which is a pathogen of cattle. MeV is thought to have evolved in an environment where cattle and humans lived in close proximity. Understanding the evolutionary history of MeV could answer questions related to divergence times of MeV and RPV. We investigated divergence times using relaxed clock Bayesian phylogenetics. Our estimates reveal that MeV had an evolutionary rate of 6.0 – 6.5×10^-4 substitutions/site/year. It was concluded that the divergence time of the most recent common ancestor of current MeV was the early 20th century. And, divergence between MeV and RPV occurred around the 11th to 12th centuries. The result was unexpected because emergence of MeV was previously considered to have occurred in the prehistoric age. MeV may have originated from virus of non-human species and caused emerging infectious diseases around the 11th to 12th centuries. In such cases, investigating measles would give important information about the course of emerging infectious diseases.

Related:

• Emerging and re-emerging infectious diseases
• Measles vaccination and SSPE