̽��ֱ�� of Cambridge - Cambridge Immunology Network

Likelihood of severe and ‘long’ COVID may be established very early on following infection

cjb250 — Mon, 18 Jan 2021 12:39:36 +0000

Among the key findings, which have not yet been peer-reviewed, are:

Individuals who have asymptomatic or mild disease show a robust immune response early on during infection.
Patients requiring admission to hospital have impaired immune responses and systemic inflammation (that is, chronic inflammation that may affect several organs) from the time of symptom onset.
Persistent abnormalities in immune cells and a change in the body’s inflammatory response may contribute to ‘long COVID’.

̽��ֱ��immune response associated with COVID-19 is complex. Most people who get infected by SARS-CoV-2 mount a successful antiviral response, resulting in few if any symptoms. In a minority of patients, however, there is evidence that the immune system over-reacts, leading to a flood of immune cells (a ‘cytokine storm’) and to chronic inflammation and damage to multiple organs, often resulting in death.

To better understand the relationship between the immune response and COVID-19 symptoms, scientists at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, have been recruiting individuals who test positive for SARS-CoV-2 to the COVID-19 cohort of the NIHR BioResource. These individuals range from asymptomatic healthcare workers in whom the virus was detected on routine screening, through to patients requiring assisted ventilation. ̽��ֱ��team take blood samples from patients over several months, as well as continuing to measure their symptoms.

In research published today, the team analysed samples from 207 COVID-19 patients with a range of disease severities taken at regular interviews over three months following the onset of symptoms. They compared the samples against those taken from 45 healthy controls.

Because of the urgent need to share information relating to the pandemic, the researchers have published their report on MedRXiv. It has not yet been peer-reviewed.

Professor Ken Smith, senior co-author and Director of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), said: “ ̽��ֱ��NIHR BioResource has allowed us to address two important questions regarding SARS-CoV-2. Firstly, how does the very early immune response in patients who recovered from disease with few or no symptoms, compare with those who experienced severe disease? And secondly, for those patients who experience severe disease, how rapidly does their immune system recover and how might this relate to ‘long COVID’?”

Listen to Professor Ken Smith discuss the findings with the Naked Scientists

̽��ֱ��team found evidence of an early, robust adaptive immune response in those infected individuals whose disease was asymptomatic or mildly symptomatic. An adaptive immune response is where the immune system identifies an infection and then produces T cells, B cells and antibodies specific to the virus to fight back. These individuals produced the immune components in larger numbers than patients with more severe COVID-19 managed, and within the first week of infection – after which these numbers rapidly returned to normal. There was no evidence in these individuals of systemic inflammation that can lead to damage in multiple organs.

In patients requiring admission to hospital, the early adaptive immune response was delayed, and profound abnormalities in a number of white cell subsets were present. Also present in the first blood sample taken from these patients was evidence of increased inflammation, something not seen in those with asymptomatic or mild disease. This suggests that an abnormal inflammatory component to the immune response is present even around the time of diagnosis in individuals who progress to severe disease.

̽��ֱ��team found that key molecular signatures produced in response to inflammation were present in patients admitted to hospital. They say that these signatures could potentially be used to predict the severity of a patient’s disease, as well as correlating with their risk of COVID-19 associated death.

Dr Paul Lyons, senior co-author, also from CITIID, said: “Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms. This finding could have major implications as to how the disease needs to be managed, as it suggests we need to begin treatment to stop the immune system causing damage very early on, and perhaps even pre-emptively in high risk groups screened and diagnosed before symptoms develop.”

̽��ֱ��researchers found no evidence of a relationship between viral load and progression to inflammatory disease. However, once inflammatory disease was established, viral load was associated with subsequent outcome.

̽��ֱ��study also provides clues to the biology underlying cases of ‘long COVID’ – where patients report experiencing symptoms of the disease, including fatigue, for several months after infection, even when they no longer test positive for SARS-CoV-2.

̽��ֱ��team found that profound alterations in many immune cell types often persisted for weeks or even months after SARS-CoV-2 infection, and these problems resolved themselves very differently depending on the type of immune cell. Some recover as systemic inflammation itself resolves, while others recover even in the face of persistent systemic inflammation. However, some cell populations remain markedly abnormal, or show only limited recovery, even after systemic inflammation has resolved and patients have been discharged from hospital.

Dr Laura Bergamaschi, the study’s first author, said: “It’s these populations of immune cells that still show abnormalities even when everything else seems to have resolved itself that might be of importance in long COVID. For some cell types, it may be that they are just slow to regenerate, but for others, including some types of T and B cells, it appears something is continuing to drive their activity. ̽��ֱ��more we understand about this, the more likely we will be able to better treat patients whose lives continue to be blighted by the after-effects of COVID-19.”

Professor John Bradley, Chief Investigator of the NIHR BioResource, said: “ ̽��ֱ��NIHR BioResource is a unique resource made possible by the strong links that exist in the UK between doctors and scientists in the NHS and at our universities. It’s because of collaborations such as this that we have learnt so much in such a short time about SARS-CoV-2.”

̽��ֱ��research was supported by CVC Capital Partners, the Evelyn Trust, UK Research & Innovation COVID Immunology Consortium, Addenbrooke’s Charitable Trust, the NIHR Cambridge Biomedical Research Centre and Wellcome.

Reference
Bergamaschi, L et al. Early immune pathology and persistent dysregulation characterise severe COVID-19. MedRXiV; 15 Jan 2021; DOI: 10.1101/2021.01.11.20248765

New research provides important insights into the role played by the immune system in preventing – and in some cases increasing the severity of – COVID-19 symptoms in patients. It also finds clues to why some people experience ‘long COVID’.

Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms

Paul Lyons

NIH Image Gallery

SARS-CoV-2 virus particles are shown emerging from the surface of cells cultured in the lab

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Gut research identifies key cellular changes associated with childhood-onset Crohn’s Disease

jg533 — Mon, 07 Dec 2020 16:00:00 +0000

̽��ֱ��results are an important step towards better management and treatment of this devastating condition.

̽��ֱ��research from the ̽��ֱ�� of Cambridge and the Wellcome Sanger Institute is part of the global Human Cell Atlas initiative to map every cell type in the human body. ̽��ֱ��findings reveal intricate cellular mechanisms of how the gut develops.

Crohn’s Disease is a type of Inflammatory Bowel Disease affecting around one in every 650 people in the UK. Incidence has increased dramatically in recent decades, especially in children - who can suffer very aggressive symptoms including abdominal pain, diarrhoea and fatigue. This lifelong condition can have major life implications; the cause is not understood, treatments often don’t work, and there is no cure.

“Crohn’s Disease can be particularly aggressive and more treatment-resistant in children, so there’s a real need to understand the condition when it affects them and perhaps come up with childhood-specific treatments,” said Dr Matthias Zilbauer in the Department of Paediatrics at the ̽��ֱ�� of Cambridge and honorary consultant in paediatric gastroenterology at Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, who led the study.

̽��ֱ��researchers used a cutting-edge technology called single-cell RNA sequencing to look at gene expression in individual cells of the developing human gut, six to ten weeks after conception. They focused on the inner lining of the gut, called the intestinal epithelium, and found that the cells there divide constantly at this early stage, guided by messages from other cell types. This allows the gut to grow and form the structures needed for good gut function later in life.

Tissues from the guts of children with Crohn’s Disease, aged between four and twelve, were also analysed. ̽��ֱ��study revealed that some of the cellular pathways active in the epithelium of the foetal gut appear to be reactivated in Crohn’s Disease. These pathways were not active in healthy children of a similar age. ̽��ֱ��results are published today in the journal Developmental Cell.

“Our results indicate there might be a reprogramming of specific gut cell functions in Crohn’s Disease. We don’t know whether this is the cause of the disease or a consequence of it, but either way it is an exciting step in helping us to better understand the condition,” said Zilbauer.

̽��ֱ��findings shed light on fundamental molecular mechanisms of human gut development. ̽��ֱ��team also found that lab-grown ‘mini-guts’ undergo similar individual cellular changes to those inside a developing foetus. This implies that lab-grown models are a powerful and accurate tool for future research into very early gut development and associated diseases.

“This study is part of the international Human Cell Atlas effort to create a ‘Google map’ of the entire human body. With single-cell RNA sequencing we can look at any tissue and identify the individual cell types it’s made up of, the function of those cells, and even identify new cell types,” said Dr Sarah Teichmann at the Wellcome Sanger Institute, and co-chair of the Human Cell Atlas Organising Committee, whose expertise enabled analysis of the huge amount of data generated by this technique.

She added: “A complex tissue like the gut contains different cell types, and these ‘talk’ to each other - the function of one cell affects the function of another. That’s particularly important in the early stages of gut development, and something we can interrogate using computational analyses of single cell RNA sequencing data.”

While the study focused specifically on the dynamics of intestinal epithelial cells, it generated information on around 90,000 primary human intestinal cells of all types. ̽��ֱ��researchers have made this data openly available at www.gutcellatlas.org, creating a valuable resource for further research and drug discovery targeted at childhood Crohn’s Disease.

“From my own experience we’re diagnosing Crohn’s Disease in younger and younger children, some even under the age of five – it’s very much an emerging disease. It’s a really nasty, lifelong condition, and when children are diagnosed, the whole family is affected,” said Zilbauer.

He added: “We are determined to advance our knowledge in this area, and hopefully improve the lives of these children in the future.”

This research was supported by the Medical Research Council, Wellcome, and the Great Ormond Street Hospital Children’s Charity, Sparks. Addenbrooke’s Hospital in Cambridge is a specialist centre for the investigation and treatment of Inflammatory Bowel Disease in children, serving the east of England.

Reference
Elmentaite, R. & Ross, A. et al: ‘Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease.’ Developmental Cell, December 2020. DOI: 10.1016/j.devcel.2020.11.010

Scientists have tracked the very early stages of human foetal gut development in incredible detail, and found specific cell functions that appear to be reactivated in the gut of children with Crohn’s Disease.

Our results indicate there might be a reprogramming of specific gut cell functions in Crohn’s Disease

Matthias Zilbauer

Kenny Roberts and Sophie Pritchard, Wellcome Sanger Institute

Emerging intestinal villi with stem cells (green) supporting their growth

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Tackling COVID-19: Professor Gordon Dougan

jg533 — Thu, 16 Jul 2020 07:00:29 +0000

This article is part of a series in which we speak to some of the many Cambridge researchers tackling COVID-19. For other articles about our latest COVID-19-related research, click here.

I run a lab in the Jeffrey Cheah Biomedical Centre (JCBC) on the Cambridge Biomedical Campus, where we study antibiotic resistance and infections. We work closely with Cambridge ̽��ֱ�� Hospitals (CUH), applying genomics to analyse clinical samples. I’m also a strategic advisor to Wellcome, and until recently was spending two days a week at its headquarters in London. I’m now spending all my working time in the JCBC, continuing to work remotely for Wellcome. I’ve worked throughout the lockdown.

My team was involved in setting up COVID-19 testing for healthcare workers, and establishing a containment level 3 facility (designed to safely handle infectious diseases) for this. It was hard work, but I believe it made a major impact on reducing COVID in the hospital and department so it has been very rewarding. ̽��ֱ��group is now slowly stepping back from testing and returning to our normal work.

I also helped establish the COVID-19 Genomics UK (COG-UK) Consortium for sequencing the virus, together with the Principal Investigator Sharon Peacock. I did a lot of the organisational work, including setting up the grant with the ̽��ֱ��. This was all done at very short notice. Ian Goodfellow is head of sequencing for Cambridge COG-UK, and has been great at linking with the hospital. We also helped out with the Intensive Care Unit at the peak of the pandemic, looking for secondary infections and antibiotic resistance.

My lab works on the molecular mechanisms involved in infection and resistance to treatments. We use simple models of infection, mostly based around high throughput genomic assays and models based on human stem cells. I also have global connections for my work on typhoid - multiple field sites around the world managed partly through joint funding with the International Vaccine Institute from Gates, EU, and Wellcome. We run projects working on maximising the amount of useful data returned on the analysis of samples, both on these sites and within the Cambridge hospital system.

I’ve been working on epidemics all my life, so in some ways I’ve just carried on as normal. I have always been very careful about things like social distancing and hand-washing when traveling in epidemic areas, so this is quite natural for me and my team. I think it’s now a psychological battle to get back to normality. In many parts of the world people still live on a daily basis with diseases like cholera, typhoid and malaria.

̽��ֱ��UK infrastructure was absolutely not ready for COVID-19. We need to learn to adapt and be ready for the next epidemic, because if we carry on the way we are there will be another one and it could be a lot worse, for example by affecting children - who are largely spared by COVID-19.

̽��ֱ��research community’s response to COVID-19 could have been better. Obviously the lockdown has meant that it’s very difficult to find people to get anything done. Some people have stepped up and been excellent; others have struggled. We need to learn from this: the multiple levels of administration within organisations need to be simplified. Ironically during the pandemic we were more or less left to get on with things and I’m sure that helped us.

We need a much better local infrastructure both within hospitals and the community. For example, track and test cannot be invented during an epidemic; it has to be in place already. ̽��ֱ��clinicians, scientists and management within CUH have been fantastic in my opinion, but we need the infrastructure to match. We now have excellent facilities coming online in the JCBC but we need more. We need to re-establish health clinics in the community, and get GPs out of their offices and back out there (this is absolutely not a criticism of GPs, I am sure they would agree!).

When the pandemic is over I’m looking forward to going on holiday and having a meal out with my wife…..and watching Scunthorpe United.

Gordon Dougan FRS is an expert on vaccines and genomics whose distinguished career has included contribution to the development of several vaccines. He is a Professor at the Cambridge Institute for Therapeutic Immunology & Infectious Disease (CITIID) in the Department of Medicine, and is involved in the new Wolfson Interdisciplinary Research Hub in Global Health. He recently wrote a blog on How we lost our collective memory of epidemics.

How you can support Cambridge’s COVID-19 research

“In many parts of the world people still live with the daily threat of diseases like cholera, typhoid, and malaria. In reality COVID is just another infection,” says Professor Gordon Dougan.

Professor Gordon Dougan

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Crohn’s disease risk and prognosis determined by different genes, study finds

cjb250 — Mon, 09 Jan 2017 16:00:07 +0000

Crohn’s disease is one of a number of chronic ‘complex’ diseases for which there is no single gene that causes the disease. In fact, to date around 170 common genetic variants have been identified that each increase the risk of an individual developing the disease. ̽��ֱ��conventional wisdom has been that there exists a ‘tipping point’: if someone has enough of these genes, they become very likely to develop the disease – and the more of the variants they carry, the more the severe the disease will then be.

However, in a study published today in Nature Genetics, a team of researchers led by the ̽��ֱ�� of Cambridge has shown that this is not the case: genetic variants that affect the progression, or prognosis, of a disease operate independently of those that increase the likelihood of developing the disease in the first place.

“Genetic studies have been very successful at identifying genetic risk factors for Crohn’s disease, but have told us virtually nothing about why one person will get only mild disease while someone else might need surgery to treat their condition,” says Dr James Lee from the Department of Medicine at Cambridge. “We do know, though, that family members who have the disease often tend to see it progress in a similar way. This suggested to us that genetics was likely to be involved in prognosis.”

̽��ֱ��researchers looked at the genomes – the entire genetic makeup – of more than 2,700 individuals, who were selected because they had either had experienced particularly mild or particularly aggressive Crohn’s disease. By comparing these patients’ DNA, the researchers found four genetic variants that influenced the severity of a patient’s condition. Strikingly, none of these genes have been shown to affect the risk of developing the disease.

̽��ֱ��team then looked at all the known genetic risk variants for Crohn’s and found that none of these influenced the severity of disease.

“This shows us that the genetic architecture of disease outcome is very different to that of disease risk,” adds Professor Ken Smith, Head of the Department of Medicine. “In other words, the biological pathways driving disease progression may be very different to those that initiate the disease itself. This was quite unexpected. Past work has focussed on discovering genes underlying disease initiation, and our work suggests these may no longer be relevant by the time a patient sees the doctor. We may have to consider directing new therapies to quite different pathways in order to treat established disease”

One of the genetic variants discovered by the team was in a gene called FOXO3. This gene is involved in modulating the release of the cytokine TNFα – cytokines are proteins released into the blood by immune cells in response to infection or, in the case of conditions such as Crohn’s, to the body erroneously attacking itself. This FOXO3-TNFα pathway is also known to affect the severity of rheumatoid arthritis, another auto-inflammatory disease.

Another of the variants was close to the gene IGFBP1, which is known to play a role in the immune system. This genetic region, too, has previously been linked to rheumatoid arthritis, in a study looking at the presence of a particular antibody in patients – presence of this antibody is associated with more severe disease.

̽��ֱ��third genetic variant was in the MHC region, which is responsible for determining how our immune cells respond to invading organisms. This region has been implicated in a number of auto-immune diseases, including Crohn’s, but the genetic variant that alters Crohn’s disease risk is different to the one that affects prognosis. ̽��ֱ��variant the team identified, which was associated with a milder course of Crohn’s disease, was shown to affect multiple genes in this region, and result in a state that is known to cause weaker immune responses.

̽��ֱ��final variant occurred in the gene XACT, about which very little is known; however, in adults this gene appears to be mainly active in cells in the intestine – the organ affected by Crohn’s disease.

“This discovery has shown us a new way of looking at disease and opens up potential new treatment options, which could substantially ease the burden of Crohn’s disease,” says Dr Lee. “What’s more, we have evidence that some of these prognosis genes will be shared with other diseases, and as such this approach could be used to improve treatment in a number of conditions.”

̽��ֱ��study has been welcomed by Crohn's and Colitis UK, who helped fund the study. "This is an exciting breakthrough which offers new hope for people who suffer every day from Crohn's and Colitis,” says Dr Wendy Edwards, Research Manager at Crohn’s and Colitis UK. “ ̽��ֱ��research sheds new light on why some people with inflammatory bowel disease experience more severe symptoms than others, which has been little understood until now."

As well as its implications for Crohn’s and other diseases, the approach taken by the researchers has suggested that there is value in re-examining previous genetic studies. Around a third of the genomes of Crohn’s disease patients analysed in this study had been collected for a previous study in 2007. By dividing the patients into groups categorised by disease severity, the researchers were able ask new questions – and gain new insights – from the old data.

̽��ֱ��research was mainly funded by Wellcome, NIHR Cambridge Biomedical Research Centre, Crohn’s and Colitis UK and the Evelyn Trust.

Reference
Lee, JC, Biasci, D, et al. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nature Genetics; 9 Jan 2017; DOI: 10.1038/ng.3755

Researchers have identified a series of genetic variants that affect the severity of Crohn’s disease, an inflammatory bowel disease – but surprisingly, none of these variants appear to be related to an individual’s risk of developing the condition in the first place.

Genetic studies have been very successful at identifying genetic risk factors for Crohn’s disease, but have told us virtually nothing about why one person will get only mild disease while someone else might need surgery to treat their condition

James Lee

Charles Clegg

DNA

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FAMIN or feast? Newly-discovered mechanism influences how immune cells ‘eat’ invading bacteria

cjb250 — Mon, 01 Aug 2016 15:00:31 +0000

To date, researchers have identified hundreds of genetic variants that increase or decrease the risk of developing diseases from cancer and diabetes to tuberculosis and mental health disorders. However, for the majority of such genes, scientists do not yet know how the variants contribute to disease – indeed, scientists do not even understand how many of the genes function.

One such gene is C13orf31, found on chromosome 13. Scientists have previously shown that variants of the gene in which a single nucleotide – the A, C, G and T of DNA – differs are associated with risk for the infectious disease leprosy, and for the chronic inflammatory diseases Crohn’s disease and a form of childhood arthritis known as systemic juvenile idiopathic arthritis.

In a study published today in the journal Nature Immunology and led by the ̽��ֱ�� of Cambridge, researchers studied how this gene works and have identified a new mechanism that drives energy metabolism in our immune cells. Immune cells help fight infection, but in some cases attack our own bodies, causing inflammatory disease.

Using mice in which the mouse equivalent of the C13orf31 gene had been altered, the team showed that the gene produces a protein that acts as a central regulator of the core metabolic functions in a specialist immune cell known as a macrophage (Greek for ‘big eater’). These cells are so named for their ability to ‘eat’ invading organisms, breaking them down and preventing the infection from spreading. ̽��ֱ��protein, which the researchers named FAMIN (Fatty Acid Metabolic Immune Nexus), determines how much energy is available to the macrophages.

̽��ֱ��researchers used a gene-editing tool known as CRISPR/Cas9, which acts like a biological ‘cut and paste’ tool, to edit a single nucleotide in the risk genes within the mouse’s genome to show that even a tiny change to our genetic makeup could have a profound effect, making the mice more susceptible to sepsis (blood poisoning). This showed that FAMIN influences the cell’s ability to perform its normal function, controlling its capacity to kill bacteria and release molecules known as ‘mediators’ that trigger an inflammatory response, a key part of fighting infection and repairing damage in the body.

Professor Arthur Kaser from the Department of Medicine at the ̽��ֱ�� of Cambridge, who led the research, says: “By taking a disease risk gene whose role was completely unknown and studying its function down to the level of a single nucleotide, we’ve discovered an entirely new and important mechanism that affects our immune system’s ability to carry out its role as the body’s defence mechanism.”

Dr Zaeem Cader, the study’s first author, adds: “Although it’s too early to say how this discovery might influence new treatments, genetics can provide invaluable insights that might help in identifying potential drug targets for so-called precision medicines, tailored to an individual’s genetic make-up.”

̽��ֱ��research was largely funded by the European Research Council and the Wellcome Trust, with support from National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

Reference
Cader, MZ et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nature Immunology; 1 Aug 2016; DOI: 10.1038/ni.3532

A new mechanism that affects how our immune cells perform – and hence their ability to prevent disease – has been discovered by an international team of researchers led by Cambridge scientists.

By taking a disease risk gene whose role was completely unknown and studying its function down to the level of a single nucleotide, we’ve discovered an entirely new and important mechanism that affects our immune system’s ability to carry out its role as the body’s defence mechanism

Arthur Kaser

Mário Tomé

Pacman

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Cambridge partners with India to fight multidrug resistant TB

Anonymous — Fri, 13 Feb 2015 16:30:42 +0000

̽��ֱ��Cambridge-Chennai Centre Partnership on Antimicrobial Resistant Tuberculosis will bring together a multidisciplinary team of international researchers, and will be led by Professor Sharon Peacock and Dr Soumya Swaminathan. ̽��ֱ��team, including Professors Lalita Ramakrishnan, Ken Smith, Tom Blundell and Andres Floto, will focus on developing new diagnostic tools and treatments to address the sharp rise in cases of multidrug resistant tuberculosis (TB).

This will include research into:

the use of emerging sequence-based diagnostics to improve the accuracy of individual patient treatment for drug resistant TB
predicting the impact of genetic mutations on drug resistance based on modelling of bacterial genome data
the development of an in-depth understanding of bacterial genes associated with so-called ‘drug-tolerance’, where the drug’s ability to kill the bacteria gradually weakens
novel approaches to treatment of TB based on enhancing the body’s immune system to enable it to fight infection.

̽��ֱ��partnership will generate a rich and lasting clinical and genomic dataset for studying TB, and the transfer of scientific training and technology will foster future international collaborative projects.

“I am delighted that Cambridge has been given the opportunity to work on a disease of global importance through the development of this partnership,” said Professor Sharon Peacock. “Chennai was the site for many of the early MRC-funded TB treatment trials, and the chance to explore new therapies and diagnostics to improve patient outcome through the use of state-of-the-art technologies represents an exciting opportunity.”

̽��ֱ��funding is part of a landmark collaboration between the MRC and the Government of India DBT. Nearly £3.5million will be invested by the UK, through the MRC and the Newton Fund, a new initiative intended to strengthen research and innovation partnerships between the UK and emerging knowledge economies, with matched funding provided by DBT.

Prof K. VijayRaghavan, Secretary, Department of Biotechnology added: “ ̽��ֱ��Department of Biotechnology, Government of India is delighted to partner with the MRC in creating research centres which will address vexing challenges in medicine through quality science and collaboration. India is committed to working with the best in the world, for India and for the world. We are acutely aware that the fruits of our partnership can mean better lives for the most- needy everywhere and are committed to make the collaboration succeed.”

̽��ֱ�� ̽��ֱ�� of Cambridge has been awarded £2 million from the UK Medical Research Council and the Government of India’s Department for Biotechnology to develop a partnership with the National Institute for Research in Tuberculosis (NIRT) in Chennai.

I am delighted that Cambridge has been given the opportunity to work on a disease of global importance through the development of this partnership

Sharon Peacock

CDC/ Melissa Brower

This illustration depicts a three-dimensional (3D) computer-generated image of a cluster of rod-shaped drug-resistant Mycobacterium tuberculosis bacteria, the pathogen responsible for causing the disease tuberculosis (TB). ̽��ֱ��artistic recreation was base

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Scientists discover genetic disease which causes recurrent respiratory infections

sj387 — Fri, 18 Oct 2013 08:36:28 +0000

Cambridge scientists have discovered a rare genetic disease which predisposes patients to severe respiratory infections and lung damage. Because the scientists also identified how the genetic mutation affects the immune system, they are hopeful that new drugs that are currently undergoing clinical trials to treat leukaemia may also be effective in helping individuals with this debilitating disease.

For the study, led by the ̽��ֱ�� of Cambridge in collaboration with the Babraham Institute and the MRC Laboratory for Molecular Biology, the researchers first examined genetic information from individuals who suffer from immunodeficiency and are predisposed to infections. From this group, the scientists identified a unique genetic mutation in 17 patients that suffer from severe respiratory infections and rapidly develop lung damage.

̽��ֱ��researchers, who were primarily funded by the Wellcome Trust, MRC, BBSRC and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, found that the mutation increases activity of an enzyme called Phosphoinositide 3-Kinase δ (PI3Kδ). ̽��ֱ��enzyme is present in immune cells and regulates their function. However, constantly activated PI3Kδ impairs work of these immune cells, preventing them from responding efficiently to infection and providing long-lasting protection. Consequently, patients with this mutation have severe and recurrent infections.

“Patients with this mutation have a defect in the immune cells, so their protection from infections is weak and inefficient,” said Sergey Nejentsev, Wellcome Trust Senior Research Fellow from the ̽��ֱ�� of Cambridge who led the research. “We called this newly identified disease Activated PI3K- δ Syndrome (APDS) after the enzyme in the immune system that is affected by the genetic mutation.”

̽��ֱ��researchers believe that it may be possible to treat APDS in future. There are currently drugs in clinical trials for leukaemia that were designed specifically to inhibit the PI3Kδ enzyme. ̽��ֱ��researchers have already shown that these drugs reduce activity of the mutant protein.

Alison Condliffe, joint senior author on the paper from the ̽��ֱ�� of Cambridge, said: “We are very excited by the prospect of using these drugs to help patients with APDS. We believe that they may be able to restore functions of immune cells, thereby reducing infections and preventing lung damage.”

Although the prevalence of the disease is not yet known, the scientists believe that it is relatively frequent compared to other immunodeficiencies and may underpin immunodeficiencies and chronic lung disorders in a substantial fraction of patients.

“It is very important that doctors consider a possibility of APDS in their patients,” said Dr Nejentsev. “A simple genetic test can tell if the patient has the mutation or not. We believe that now many more APDS patients will be identified all over the world.”

̽��ֱ��research was published by Science Express (the electronic publication of selected Science papers).

Discovery could lead to new treatments for this genetic disorder.

We believe that now many more APDS patients will be identified all over the world

Sergey Nejentsev

Chikumaya

X-ray photo of a chest

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