A team of scientists, part of the international effort to curb further spread of the Ebola virus in Sierra Leone, has released its first dataset of the virus’ genetic structure online. The dataset will allow the global scientific community to monitor the pathogen’s evolution in real-time and conduct research that can lead to more effective strategies against further outbreaks.

The team of British scientists, funded by the Wellcome Trust, is using semi-conductor next-generation sequencing technology developed by Thermo Fisher Scientific to generate data in a lab facilitated by Public Health England and International Medical Corps. The genetic analysis is being made freely available to the scientific community.

Since the first reported case in March 2014, the Ebola outbreak has claimed nearly 11,000 lives in West African countries. Professor Ian Goodfellow, Head of Virology at the University of Cambridge, travelled to Sierra Leone in December last year and then again in March this year to help set up a new diagnostics centre attached to an Ebola Treatment Centre in one of the country’s worst affected parts. He returned a third time, together with his postdoc Dr Armando Arias, to study the virus at a molecular level using the sequencing technology.

“Sequencing the genome of a virus can tell us a lot about how it spreads and changes as it passes from person to person. While this information is invaluable to researchers, the rapid sharing of data does not always occur,” said Professor Paul Kellam at the Wellcome Trust Sanger Institute, who is leading the team to map the genomic data captured by Professof Goodfellow and colleagues. “It used to take months to process samples that had to be brought back to labs in the UK for analysis. Having sequencing capabilities on the ground helps generate data in a matter of days or at the longest weeks, which should have a profound impact on how the Ebola virus is researched and inevitably addressed on a global scale.”

Rapid sequencing enables epidemiologists to decipher the source of individual strains, and helps eliminate the need to rely upon Ebola patients to tell them how and where they contracted the virus, as different strains can be tracked as they are transmitted from person to person.

“Only by understanding the Ebola virus and other pathogens, which cause so much suffering in countries like Sierra Leone, can we take meaningful steps to protect communities from future outbreaks,” said Goodfellow. “My hope is that this technology will be used by the next generation of Sierra Leonean scientists and researchers to help provide a sustainable research and surveillance system in the future.” University of Cambridge

​Cancer’s ability to grow unchecked is often attributed to cancer stem cells, a small fraction of cancer cells that have the capacity to grow and multiply indefinitely. How cancer stem cells retain this property while the bulk of a tumour’s cells do not remains largely unknown. Using human tumour samples and mouse models, researchers at University of California, San Diego School of Medicine and Moores Cancer Center discovered that cancer stem cell properties are determined by epigenetic changes — chemical modifications cells use to control which genes are turned on or off.
The study reports that an enzyme known as Lysine-Specific Demethylase 1 (LSD1) turns off genes required to maintain cancer stem cell properties in glioblastoma, a highly aggressive form of brain cancer. This epigenetic activity helps explain how glioblastoma can resist treatment. What’s more, drugs that modify LSD1 levels could provide a new approach to treating glioblastoma.

The researchers first noticed that genetically identical glioblastoma cells isolated from patients differed in their tumourigenicity, or capacity to form tumours, when transplanted to mouse models. This observation suggested that epigenetics, rather than genetics (DNA sequence), determines tumourigenicity in glioblastoma cancer stem cells.

“One of the most striking findings in our study is that there are dynamic and reversible transitions between tumorigenic and non-tumorigenic states in glioblastoma that are determined by epigenetic regulation,” said senior author Clark Chen, MD, PhD, associate professor of neurosurgery and vice-chair of research and academic development at UC San Diego School of Medicine.
Probing further, Chen’s team discovered that the epigenetic factor determining whether or not glioblastoma cells can proliferate indefinitely as cancer stem cells is their relative abundance of LSD1. LSD1 removes chemical tags known as methyl groups from DNA, turning off a number of genes required for maintaining cancer stem cell properties, including MYC, SOX2, OLIG2 and POU3F2.

“This plasticity represents a mechanism by which glioblastoma develops resistance to therapy,” Chen said. “For instance, glioblastomas can escape the killing effects of a drug targeting MYC by simply shutting it off epigenetically and turning it on after the drug is no longer present. Ultimately, strategies addressing this dynamic interplay will be needed for effective glioblastoma therapy.”
Chen and one of the study’s first authors, Jie Li, PhD, note that the epigenetic changes driving glioblastoma are similar to those that take place during normal human development.
“Though most cells in our bodies contain identical DNA sequences, epigenetic changes help make a liver cell different from a brain cell,” said Li, an assistant project scientist in Chen’s lab. “Our results indicate that the same programming processes determine whether a cancer cell can grow indefinitely or not.” University of California – San Diego Health

Massachusetts General Hospital (MGH) investigators have identified an inflammatory molecule that appears to play an essential role in the autoimmune disorder systemic lupus erythematosus, commonly known as lupus.  In their report, the researchers describe finding that a protein that regulates certain cells in the innate immune system – the body’s first line of defence against infection – activates a molecular pathway known to be associated with lupus and that the protein’s activity is required for the development of lupus symptoms in a mouse model of the disease.

“This study is the first demonstration that the receptor TREML4 amplifies the cellular responses transmitted through the TLR7 receptor and that a lack of such amplification prevents the inflammatory overactivation underlying lupus,” says Terry Means, PhD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Rheumatology, Allergy, and Immunology.  “Our preliminary results suggest that TREML4-regulated signalling through TLR7 may be a potential drug target to limit inflammation and the development of autoimmunity.”

Lupus is an autoimmune disorder characterized by periodic inflammation of joints, connective tissues and organs including heart, lungs, kidneys and brain.  TLR7 is one of a family of receptors present on innate immune cells like macrophages that have been linked to chronic inflammation and autoimmunity.   Animal studies have suggested that overactivation of TLR7 plays a role in lupus, and a gene variant that increases expression of the receptor has been associated with increased lupus risk in human patients.  The current study was designed to identify genes for other molecules required for TLR7-mediated immune cell activation.

The MGH-based team conducted an RNA-interference-based genome-scale screen of mouse macrophages, selectively knocking down the expression of around 8,000 genes, and found that TREML4 – one of a family of receptors found on granulocytes and monocytes – amplifies the response of innate immune cells to activation via TLR7.  Immune cells from mice lacking TREML4 showed a weakened response to TLR7 activation. When a strain of mice genetically destined to develop a form of TLR7-dependent lupus was crossbred with a strain in which TREML4 expression was suppressed, offspring lacking TREML4 were protected from the development of lupus-associated kidney failure and had significantly lower blood levels of inflammatory factors and autoantibodies than did mice expressing TREML4. 

Means notes that identifying the potential role of TREML4 in human lupus may lead to the development of drugs that could prevent or reduce the development or progression of lupus and another autoimmune disorder called Sjögren’s syndrome, which also appears to involve TLR7 overactivation.  Future studies are needed to better define the molecular mechanism behind TREML4-induced amplification of TLR7 signaling and to clarify beneficial reactions controlled by TREML4 – for example, the immune response to influenza virus, which the current study found was inhibited by TREML4 deficiency. Massachusetts General Hospital

Scientists at St. Jude Children’s Research Hospital have discovered how an immune system protein, called AIM2 (Absent in Melanoma 2), plays a role in determining the aggressiveness of colon cancer. They found that AIM2 deficiency causes uncontrolled proliferation of intestinal cells. Surprisingly, they also discovered that AIM2 influences the microbiota—the population of gut bacteria—apparently fostering the proliferation of “good” bacteria that can protect against colon cancer.

The team, led by Thirumala-Devi Kanneganti, Ph.D., a member of the St. Jude Department of Immunology said that the findings could have important applications for prevention, prognosis and treatment.

“Since reduced AIM2 activity in colorectal cancer patients is associated with poor survival, it might be useful to detect the level of AIM2 expression in polyps taken from colonoscopy and use this as one of the biomarkers for prognosis,” Kanneganti said.

Kanneganti and her team believe that it might be possible to prevent the disease or reduce its risk by treating susceptible people to increase AIM2 activity and give them healthy donor bacteria. “In people who already have colorectal cancer, therapies that boost the expression of AIM2, such as interferons, might reduce tumour progression. Also, transferring healthy microbiota or a group of ‘good’ bacteria to patients with colorectal cancer at the early stage of disease may prolong survival,” Kanneganti said.

Cancer researchers had known that mutations in AIM2 were frequently found in patients with colorectal cancers. And a study by other researchers had found that more than half of small bowel tumours had AIM2 mutations.

However, AIM2’s established function in the cell was not in the machinery of cancer, said one of the paper’s first authors Si Ming Man, Ph.D., a postdoctoral fellow in Kanneganti’s laboratory. Rather, he said, AIM2 was known to work in the immune system to detect invading bacteria and viruses and help “alert” the immune system to battle them.

“When we found that the intestine expressed high levels of AIM2, we hypothesized that this gene may also play a role in regulating gut health,” Man said. “This was how we became interested in AIM2 and colorectal cancer.”

In their experiments with mice, the scientists used chemicals to trigger the process mimicking the development of colorectal cancer. They found that the mice showed drastically reduced AIM2 function, confirming the finding in humans with the cancer. They also found that mice genetically altered to have reduced AIM2 function, when treated with the chemicals, showed significantly more tumours than normal mice.

The scientists’ studies also showed that AIM2 played a role independent of its immune role, in suppressing abnormal expansion of intestinal stem cell populations. Conversely, malfunction of AIM2 unleashes abnormal stem cell proliferation. Stem cells are immature cells that differentiate into adult cells such as intestinal cells. These cells continuously proliferate to replace old and dying cells in the intestine.

“Many previous studies have indicated that AIM2 contributes to the immune system by acting as a pathogen sensor,” Man said. “However, our work is the first to identify AIM2’s role in controlling proliferation of intestinal stem cells. This work is truly exciting to us because we have found a new role for AIM2 in regulating colorectal cancer, and it does so by inhibiting excessive proliferation of stem cells in the large intestine.” The researchers also pinpointed the specific cellular machinery regulated by AIM2.

They decided to explore whether AIM2’s protective role might involve gut bacteria, based on studies from Kanneganti’s lab and others indicating that microbial sensors similar to AIM2 contributed to healthy gut microbiota. Indeed, the comparison of gut bacteria in normal and AIM2-deficient mice showed a different “microbial landscape” in the two types of mice.

To test whether gut bacteria might influence the progression of colon cancer, the researchers housed normal and AIM2-deficient mice together, to enable the exchange of gut bacteria. The scientists found a striking reduction in colon tumors in the AIM2-deficient mice and an increase in tumors in the normal mice.

“What this might suggest is that transfer of some of the ‘good’ microbiota from wild-type mice to replace the ‘bad’ microbiota from mice lacking AIM2 offers increased protection against colorectal cancer,” Man said. “We believe that this finding has important clinical relevance because we can potentially prevent or decelerate the progression of colorectal cancer in humans, especially in those who have mutations in the AIM2 gene, by simply giving them ‘good’ microbiota.”

“We have only scratched the surface of the role of AIM2 in controlling stem cell proliferation and the maintenance of a healthy gut microbiota,” Kanneganti said. “How exactly AIM2 does both of these functions is an exciting research area to pursue.” St Jude Children’s Research Hospital