̽��ֱ�� of Cambridge - herpes

Meet the hominin species that gave us genital herpes

fpjl2 — Sun, 01 Oct 2017 23:06:35 +0000

Two herpes simplex viruses infect primates from unknown evolutionary depths. In modern humans these manifest as cold sores (HSV1) and genital herpes (HSV2).

Unlike HSV1, however, the earliest proto-humans did not take HSV2 with them when our ancient lineage split from chimpanzee precursors around 7 million years ago. Humanity dodged the genital herpes bullet – almost.

Somewhere between 3 and 1.4 million years ago, HSV2 jumped the species barrier from African apes back into human ancestors – probably through an intermediate hominin species. Hominin is the zoological ‘tribe’ to which our species belongs.

Now, a team of scientists from Cambridge and Oxford Brookes universities believe they may have identified the culprit: Paranthropus boisei, a heavyset bipedal hominin with a smallish brain and dish-like face.

In a study published today in the journal Virus Evolution, they suggest that P.boisei most likely contracted HSV2 through scavenging ancestral chimp meat where savannah met forest – the infection seeping in via bites or open sores.

Hominins with HSV1 may have been initially protected from HSV2, which also occupied the mouth. That is until HSV2 “adapted to a different mucosal niche” say the scientists. A niche located in the genitals.

Close contact between P.boisei and our ancestor Homo erectus would have been fairly common around sources of water, such as Kenya’s Lake Turkana. This provided the opportunity for HSV2 to boomerang into our bloodline.

̽��ֱ��appearance of Homo erectus around 2 million years ago was accompanied by evidence of hunting and butchery. Once again, consuming “infected material” would have transmitted the virus – only this time it was P.boisei being devoured.

“Herpes infect everything from humans to coral, with each species having its own specific set of viruses,” said senior author Dr Charlotte Houldcroft, a virologist from Cambridge’s Department of Archaeology.

“For these viruses to jump species barriers they need a lucky genetic mutation combined with significant fluid exchange. In the case of early hominins, this means through consumption or intercourse – or possibly both.”

“By modelling the available data, from fossil records to viral genetics, we believe that Paranthropus boisei was the species in the right place at the right time to both contract HSV2 from ancestral chimpanzees, and transmit it to our earliest ancestors, probably Homo erectus.”

When researchers from ̽��ֱ�� of California, San Diego, published findings suggesting HSV2 had jumped between hominin species, Houldcroft became curious.

While discussing genital herpes over dinner at Kings College, Cambridge, with fellow academic Dr Krishna Kumar, an idea formed. Kumar, an engineer who uses Bayesian network modelling to predict city-scale infrastructure requirements, suggested applying his techniques to the question of ancient HSV2.

Houldcroft and her collaborator Dr Simon Underdown, a human evolution researcher from Oxford Brookes, collated data ranging from fossil finds to herpes DNA and ancient African climates. Using Kumar’s model, the team generated HSV2 transmission probabilities for the mosaic of hominin species that roamed Africa during “deep time”.

“Climate fluctuations over millennia caused forests and lakes to expand and contract,” said Underdown. “Layering climate data with fossil locations helped us determine the species most likely to come into contact with ancestral chimpanzees in the forests, as well as other hominins at water sources.”

Some promising leads turned out to be dead ends. Australopithecus afarensis had the highest probability of proximity to ancestral chimps, but geography also ruled it out of transmitting to human ancestors.

Ultimately, the researchers discovered the key player in all the scenarios with higher probabilities to be Paranthropus boisei. A genetic fit virally who was found in the right places to be the herpes intermediary, with Homo erectus – and eventually us – the unfortunate recipients.

“Once HSV2 gains entry to a species it stays, easily transferred from mother to baby, as well as through blood, saliva and sex,” said Houldcroft.

“HSV2 is ideally suited to low density populations. ̽��ֱ��genital herpes virus would have crept across Africa the way it creeps down nerve endings in our sex organs – slowly but surely.”

̽��ֱ��team believe their methodology can be used to unravel the transmission mysteries of other ancient diseases – such as human pubic lice, also introduced via an intermediate hominin from ancestral gorillas over 3 million years ago.

New research uses innovative data modelling to predict which species acted as an intermediary between our ancestors and those of chimpanzees to carry HSV2 – the genital herpes virus – across the species barrier.

Herpes infect everything from humans to coral, with each species having its own specific set of viruses

Charlotte Houldcroft

Left: a cast of a P.boisei skull used for teaching at Cambridge ̽��ֱ��. Right: a figure from the data analysis in the study.

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Time of day influences our susceptibility to infection, study finds

cjb250 — Mon, 15 Aug 2016 19:00:21 +0000

When a virus enters our body, it hijacks the machinery and resources in our cells to help it replicate and spread throughout the body. However, the resources on offer fluctuate throughout the day, partly in response to our circadian rhythms – in effect, our body clock. Circadian rhythms control many aspects of our physiology and bodily functions – from our sleep patterns to body temperature, and from our immune systems to the release of hormones. These cycles are controlled by a number of genes, including Bmal1 and Clock.

To test whether our circadian rhythms affect susceptibility to, or progression of, infection, researchers at the Wellcome Trust-Medical Research Council Institute of Metabolic Science, ̽��ֱ�� of Cambridge, compared normal ‘wild type’ mice infected with herpes virus at different times of the day, measuring levels of virus infection and spread. ̽��ֱ��mice lived in a controlled environment where 12 hours were in daylight and 12 hours were dark.

̽��ֱ��researchers found that virus replication in those mice infected at the very start of the day – equivalent to sunrise, when these nocturnal animals start their resting phase – was ten times greater than in mice infected ten hours into the day, when they are transitioning to their active phase. When the researchers repeated the experiment in mice lacking Bmal1, they found high levels of virus replication regardless of the time of infection.

“ ̽��ֱ��time of day of infection can have a major influence on how susceptible we are to the disease, or at least on the viral replication, meaning that infection at the wrong time of day could cause a much more severe acute infection,” explains Professor Akhilesh Reddy, the study’s senior author. “This is consistent with recent studies which have shown that the time of day that the influenza vaccine is administered can influence how effectively it works.”

In addition, the researchers found similar time-of-day variation in virus replication in individual cell cultures, without influence from our immune system. Abolishing cellular circadian rhythms increased both herpes and influenza A virus infection, a dissimilar type of virus – known as an RNA virus – that infects and replicates in a very different way to herpes.

Dr Rachel Edgar, the first author, adds: “Each cell in the body has a biological clock that allows them to keep track of time and anticipate daily changes in our environment. Our results suggest that the clock in every cell determines how successfully a virus replicates. When we disrupted the body clock in either cells or mice, we found that the timing of infection no longer mattered – viral replication was always high. This indicates that shift workers, who work some nights and rest some nights and so have a disrupted body clock, will be more susceptible to viral diseases. If so, then they could be prime candidates for receiving the annual flu vaccines.”

As well as its daily cycle of activity, Bmal1 also undergoes seasonal variation, being less active in the winter months and increasing in summer. ̽��ֱ��researchers speculate that this may help explain why diseases such as influenza are more likely to spread through populations during winter.

Using cell cultures, the researchers also found that herpes viruses manipulate the molecular ‘clockwork’ that controls our circadian rhythms, helping the viruses to progress. This is not the first time that pathogens have been seen to ‘game’ our body clocks: the malaria parasite, for example, is known to synchronise its replication cycle with the host’s circadian rhythm, producing a more successful infection.

“Given that our body clocks appear to play a role in defending us from invading pathogens, their molecular machinery may offer a new, universal drug target to help fight infection,” adds Professor Reddy.

̽��ֱ��research was mostly funded by the Wellcome Trust and the European Research Council.

Reference
Edgar, RS et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. PNAS; e-pub 15 Aug 2016; DOI: 10.1073/pnas.1601895113

We are more susceptible to infection at certain times of the day as our body clock affects the ability of viruses to replicate and spread between cells, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��findings, published today in the Proceedings of the National Academy of Sciences, may help explain why shift workers, whose body clocks are routinely disrupted, are more prone to health problems, including infections and chronic disease.

̽��ֱ��time of day of infection can have a major influence on how susceptible we are to the disease, or at least on the viral replication, meaning that infection at the wrong time of day could cause a much more severe acute infection

Akhilesh Reddy

Alexandra Bilham

Clock

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Herpes virus hijackers

cjb250 — Fri, 22 May 2015 10:20:22 +0000

̽��ֱ��common cold sore, caused by herpes simplex virus 1 (HSV-1), is relatively harmless to most people, but for others it can cause life-threatening disease. In intensive care units, for example, the virus commonly leads to severe lung infections. Even in healthy people, in rare cases it can spontaneously cause inflammation of the brain, which can lead to irreversible brain damage.

̽��ֱ��genetic material of the virus consists of DNA, like in humans. As soon as HSV-1 has penetrated human cells, it smuggles its DNA into the cell nucleus, where the molecular machinery is located that is used to read the genetic information contained in the DNA and to transcribe it into RNA molecules. This RNA then determines which proteins are produced by the cell.

In the cell nucleus, the virus takes full control of this machinery within a few hours of infection. It uses it to produce its own proteins and produce new virus particles on a massive scale. Formation of the cellular proteins soon becomes almost an irrelevance. In the end, the host cell dies off and thousands of new viruses are released that again infect other cells.

Professor Lars Dölken from the Department of Medicine at the ̽��ֱ�� of Cambridge and the Institut für Virologie, Würzburg, Germany, together with the bioinformatics team at LMU Munich, led by Professor Caroline Friedel have looked in greater detail at the process of infection. Today in the journal Nature Communications, they report using cell cultures to see how HSV-1 infects human connective tissue cells (fibroblasts) and examine what happens with all the RNA molecules in the cells during the process. ̽��ֱ��researchers used fibroblasts as this enabled them to look at what the virus does with the cell rather than how the innate immune system responds to the virus.

Just three to four hours after the virus enters the cells it does something quite unexpected. Usually, the process of transcribing DNA into RNA stops when it reaches the end of the genes being transcribed. But in this case, the human cell DNA continued to be transcribed for tens-of-thousands of nucleotides – the A, C, G and Ts of DNA – and often across several neighbouring genes. This creates masses of unusable RNA products that can no longer properly translate into proteins.

“It’s like someone transcribing a short story, but instead of stopping at ‘ ̽��ֱ��End’, they carry on and transcribe all the copyright and publication details and ISBN numbers at the beginning and end of the book,” explains Professor Dölken. “This produces lots of meaningless, confusing and useless information.”

Interestingly, the viral DNA is accurately transcribed throughout infection. By interfering with the transcription processes in our own cellular genes, the virus is acting to benefit itself – it causes the cell to shut itself off, preventing the immune system from attacking the virus. It also increases the synthesis of viral proteins and thus aids the production of new virus particles.

This newly discovered mechanism can give the impression that the virus also activates a large number of genes in the cell, but this is actually not the case and may have led previous studies to incorrectly interpret experimental data. According to the findings, hundreds of cellular genes seemingly activated by the viruses are not translated into proteins at all.

“Unlike previous studies which only studied single genes, we also found no indication that the virus generally impedes the processing of RNA in the cell nucleus, known as splicing,” says Dölken. “Instead, it causes unusual splicing events, many of which have never before been observed.”

̽��ֱ��research team from Cambridge, Würzburg and Munich set a milestone in methodology with this work: With a single experimental approach it is possible to record all the changes that occur when transcribing and processing RNA as well as their impact on protein production.

Reference
Rutkowski, AJ. Wide-spread disruption of host transcription termination in HSV-1 infection. Nature Communications; 20 May 2015.

̽��ֱ��virus responsible for the common cold sore hijacks the machinery within our cells, causing them to break down and help shield the virus from our immune system, researchers from the ̽��ֱ�� of Cambridge and colleagues in Germany have discovered.

It’s like someone transcribing a short story, but instead of stopping at ‘ ̽��ֱ��End’, they carry on and transcribe all the copyright and publication details and ISBN numbers

Lars Dölken

Metju12

cold sore

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