Viral study suggests an approach that may decrease kidney damage in transplant patients

May 29, 2019

BIRMINGHAM, Ala. - While studying one of the smallest DNA viruses known, Sunnie Thompson, Ph.D., may have found a new way to help prevent kidney damage following organ transplant.

The University of Alabama at Birmingham researcher studies BK polyomavirus, a major source of kidney damage and rejection in transplant recipients. Nearly all humans silently harbor polyomaviruses in their bodies; but when transplant recipients receive drugs to suppress their immune system to prevent graft rejection, the virus can reactivate, resulting in damage to the kidney.

No FDA-approved therapy exists to combat BK polyomavirus. Thompson, an associate professor in the UAB Department of Microbiology, says that, if their findings can be verified in human patients, they may have discovered a new way to reduce BK polyomavirus levels in transplant patients without reducing the immunosuppressing drugs that are needed to prevent transplant rejection.

Thompson's findings came through basic research on the virus, now published as a featured article in the Journal of Virology.

With only seven genes, the polyomavirus must commandeer the host cell's DNA replication machinery in order to produce new viruses. To do this, the virus forces host cells to start replicating to subvert the cell's proteins into making copies of the virus. Viral replication activates a response to DNA damage; but it was unclear why this was important for viral replication, so Thompson's laboratory set out to understand how activation of the DNA damage response helped the virus.

The DNA damage response involves two major proteins called ATM and ATR that are recruited to sites of DNA damage. Activation of this response leads to DNA repair, arrest of cell replication while the DNA is being repaired, or cell death if the DNA damage is too severe. Thompson and her colleagues inhibited ATM or ATR in infected cells, which revealed that the virus activated the DNA damage response in order to arrest the cell cycle. This kept the cell's proteins available to continue to replicate the virus.

When ATR was inhibited in cells infected with BK polyomavirus, infected cells began to divide while they were still making DNA. This led to severe DNA damage and decreased viral production.

The role for ATM was different. ATM was needed for the virus to start host DNA replication. ATM also prevented the cell from entering mitosis, though only after DNA replication was completed, resulting in reduced viral production, but with no DNA damage.

Importantly, these inhibitors did not alter the cell cycle or increase DNA damage in uninfected cells. Only BK polyomavirus-infected cells treated with these inhibitors had increased cell division, which reduced viral titers. Since these inhibitors are already in clinical trials as cancer drugs, this may provide an opportunity to use them to reduce BK polyomavirus levels in kidney transplant patients with active BK polyomavirus infections. The current standard of care is to reduce the drugs that suppress the immune system, which increases the chances of transplant rejection.
-end-
Thompson's co-authors for the study, "BK polyomavirus activates the DNA damage response to prolong S phase," are Joshua L. Justice, Ph.D., and Jason M. Needham, UAB Department of Microbiology. Justice is now a postdoctoral fellow at Princeton University.

Support came from National Institutes of Health grant AI123162. Justice was supported by NIH training program grant GM008111.

University of Alabama at Birmingham

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.