Gut viruses tied to potentially deadly complication of bone marrow transplant

August 1, 2017 by Devika Bansal, University of California, San Francisco
Credit: University of California, San Francisco

A virus hiding quietly in the gut may trigger the onset of a severe complication known as graft-versus-host disease (GvHD) in patients who receive bone marrow transplants, according to a new study led by scientists at UC San Francisco and Saint-Louis Hospital in Paris, France.

GvHD affects up to 60 percent of who undergo bone marrow stem-cell transplants, and kills about half of those affected. After transplants, to prevent a recipient's immune cells from laying siege to unfamiliar donor cells and rejecting them, clinicians often use drugs to suppress the immune response. GvHD is a mirror image of organ rejection, in which in the transplant attack its new host, the patient.

Despite the pervasiveness of this , there isn't yet a clear way of foretelling patients' risk of developing it before they go into surgery. The new study, published online July 31, 2017, in Nature Medicine, unveils a viral biomarker that could allow clinicians to assess patients' risk of an acute form of the disease known as enteric GvHD, which affects the gastrointenstinal system.

The team used a technique known as metagenomic next-generation sequencing (mNGS) – which can rapidly and concurrently sequence genetic material of all organisms present in any biological sample – to catalog microbes in patients' digestive tracts, monitoring the evolving bacterial and viral population throughout the transplantation process.

Although mNGS analyses of bacterial populations, called microbiomes, have been much in the news, fewer studies have focused on "viromes," the term for viral populations.

"Viromes can play an important part in health and disease," said Charles Chiu, MD, PhD, an associate professor of laboratory medicine at UCSF and principal investigator of the study. "Our goal was to understand what impact transplantation has on the gut virome."

In the new work, the researchers scanned stool samples taken from 44 patients before they received a transplant and up to six weeks after, and sequenced all the DNA and RNA in the samples in order to assemble a roster of their microbial passengers.

Using this technique, the researchers identified a number of viruses that flared up in the guts of patients who developed the deadly condition. Of particular note were members of the picobirnavirus (PBV) family: the presence of these viruses before transplantation, even in very small populations, was a reliable sign that a patient would likely develop the disease after a transplant.

"I would've expected herpesviruses or adenoviruses to be the more likely cause of infection," said Chiu. "We wouldn't have picked up picobirnaviruses were it not for the metagenomics approach."

PBVs are a very diverse family of viruses – more diverse than HIV, said Jérôme Le Goff, PhD, associate professor at the University of Paris Diderot and lead author of the new study. "It's very difficult to design a single test to detect all viruses simultaneously," said Le Goff. "So for many years, labs did not have the means to look for PBV." Indeed, each of the 18 patients who tested positive for PBV was carrying a different strain, a diversity that makes it challenging to detect PBVs using a simple lab test.

The team also observed a previously unreported "bloom" of other resident viruses in patients that occurred three to five weeks after they had received transplants. Intriguingly, the onset of GvHD appeared to trigger the late awakening of these covert viruses, laying to rest a longstanding chicken-and-egg debate: which comes first, viral infection or GvHD? The researchers conclude that much of the viral flare they saw is due to reactivation of latent gut infections following transplantation.

Given the potential utility of PBV as a predictive biomarker, Chiu and his team now hope to develop a metagenomics-based test to screen patients before transplantation. "We also saw shifts in the microbiome but those in the virome were more pronounced," said Chiu. "Loss of bacteria colonizing the gut has been thought to predispose patients to GvHD; here we show that shifts in the virome may also play a role in the occurrence of this disease."

Although the new study strongly implicates PBVs in the onset of GvHD, it is too early to tell whether or how these viruses trigger the disease. The team is now enrolling more adult and pediatric patients – both in Paris and at UCSF – to expand their analyses and uncover the mechanism by which the virus modulates the risk of disease. A systematic understanding of the virus's role could ultimately inform whether using antiviral drugs or tweaking the body's immune response would be the best strategy to temper the disease.

"It would be great to have a tool that can be used to assess GvHD risk in these patients before they undergo a transplant," Chiu said, a step that Le Goff said could lead to new therapies. "We hope that in the next few years we will find a way to prevent -associated GvHD," said Le Goff.

Explore further: Researchers develop new strategy to limit side effects of stem cell transplants

More information: Jérôme Legoff et al. The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease, Nature Medicine (2017). DOI: 10.1038/nm.4380

Related Stories

Researchers develop new strategy to limit side effects of stem cell transplants

August 15, 2016
Scientists in Germany have developed a new approach that may prevent leukemia and lymphoma patients from developing graft-versus-host disease (GvHD) after therapeutic bone marrow transplants. The researchers describe the ...

Researchers develop novel treatment to prevent graft-versus-host-disease

January 11, 2017
Graft-versus-host-disease (GVHD) is the leading cause of non-relapse associated death in patients who receive stem cell transplants. In a new study published as the cover story in Science Translational Medicine, Moffitt Cancer ...

Immune cell subset is associated with development of gastrointestinal GVHD after HSCT

May 5, 2016
Gastrointestinal graft vs. host disease (GI-GVHD) is a life threatening complication that can occur after allogeneic hematopoietic cell transplantation, a procedure that is commonly used to treat patients with leukemia. There ...

New test helps guide treatment for bone marrow transplant patients with graft vs. host disease

January 13, 2015
A new test can guide treatment for patients with graft versus host disease (GVHD), an often life-threatening complication of bone marrow and stem cell transplants, according to research from the University of Michigan published ...

Depletion of naive T cells from stem cell grafts limits chronic graft-versus host disease

June 8, 2015
Stem cell transplantation is used to treat hematologic malignancies, such as leukemia. Patients that receive donor cells are at risk of developing graft-versus host disease (GVHD). This potentially fatal complication results ...

Inflammatory bowel disease, bone marrow transplant precision medicine clinical trial opens

May 23, 2017
In an effort to find new strategies to personalize treatment for pediatric patients, Seattle Children's has opened the first clinical trial applying next-generation T-cell receptor (TCR) sequencing and single-cell gene expression ...

Recommended for you

Scientists find malformations and lower survival rates in zebrafish embryos exposed to cannabinoids

July 16, 2018
Exposure to the main chemical components of cannabis has a detrimental effects on developing zebrafish embryos, according to a new study conducted by University of Alberta biologists.

Basic research in fruit flies leads to potential drug for diseases afflicting millions

July 13, 2018
River blindness and elephantiasis are debilitating diseases caused by parasitic worms that infect as many as 150 million people worldwide. They are among the "neglected tropical diseases" for which better treatments are desperately ...

Light based cochlear implant restores hearing in gerbils

July 12, 2018
A team of researchers with members from a variety of institutions across Germany has developed a new type of cochlear implant—one based on light. In their paper published in the journal Science Translational Medicine, the ...

Researchers discover gene that controls bone-to-fat ratio in bone marrow

July 12, 2018
In an unexpected discovery, UCLA researchers have found that a gene previously known to control human metabolism also controls the equilibrium of bone and fat in bone marrow as well as how an adult stem cell expresses its ...

Intensive care patients' muscles unable to use fats for energy

July 12, 2018
The muscles of people in intensive care are less able to use fats for energy, contributing to extensive loss of muscle mass, finds a new study co-led by UCL, King's College London and Guy's and St Thomas' NHS Foundation Trust.

Blood biomarker can help predict disease progression in patients with COPD

July 12, 2018
Some patients with COPD demonstrate signs of accelerated aging. In a new study published in the journal CHEST researchers report that measuring blood telomeres, a marker of aging of cells, can be used to predict future risk ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.