September 30, 2021 feature
On the trail of a medical mystery: Scientists zero in on elevated MRSA susceptibility after liver transplants
For decades, recipients of liver transplants have been inexplicably vulnerable to MRSA infection after their lifesaving surgeries, but the molecular mechanisms underlying that risk had remained stubbornly mystifying, at least until now.
In the hunt for a culprit at the core of a nagging—and sometimes deadly—susceptibility, a multidisciplinary team of physicians, surgeons and scientists in China and the United States zeroed in on an answer. Their finding holds implications globally because the MRSA risk has been documented among liver transplant patients worldwide.
Patients who receive organ transplants of all kinds must take immune-suppressing drugs to prevent rejection, treatments that also leaves them vulnerable to infections. But as doctors and scientists searched for an answer to a full-blown medical mystery, they soon discovered that taking immune-suppressing medications didn't fully explain the worldwide susceptibility to MRSA infections in liver transplant patients. That conclusion seemed to defy logic.
MRSA is one of the world's biggest drug resistance threats, a bacterial species capable of thwarting multiple antibiotics. Additionally, MRSA—methicillin-resistant Staphylococcus aureus—is a noteworthy cause of nosocomial infections, frequently afflicting patients in hospital settings around the globe.
Yet, the problem among liver transplant patients stood out as especially vexing. About 23% of liver transplant patients develop MRSA infections, according to the World Health Organization. And among these patients an estimated 21% perish within 30 days after transplantation. The reason? MRSA.
Dr. Hao Li from the department of general surgery at Shanghai General Hospital and a team of U.S. investigators found that the problem isn't the result of something that is biologically amiss among transplant recipients. Li and colleagues discovered that the problem exists in the "healthy livers" from donors. Some donor organs invariably—surprisingly—are low in the expression of a gene that leads to the production of a specific protein and the paucity of that protein explains the increased susceptibility to MRSA infection after transplant, Li and colleagues say.
"We found that genetic predisposition to low pannexin 1 expression in donor livers was associated with MRSA infection in human liver transplantation recipients," asserted Li, whose report on the finding is published in Science Translational Medicine.
The Pannexin-1 gene, also known by the shorthand, PANX1, leads to the production of the PANX1 channel protein ubiquitously present in many mammalian tissues. PANX1 was first described in 2000 as part of a family of integral membrane proteins. In addition to PANX1, there are two others: PANX2 and PANX3.
While PANX1 is largely involved in releasing energy to tissues in the form of adenosine triphophate—ATP—it has many other roles, according to research by Dr. Silvia Penuela and colleagues at the University of Western Ontario. They describe PANX1 as having a sweeping array of functions and particularly cite it for its key role in the release of "find-me" signals for apoptotic—dead cell—clearance.
Additionally, Penuela and her collaborators underscore that PANX1's functions are diverse. The channel protein is linked with the propagation of calcium waves in the regulation of vascular tone and also is involved in mucociliary clearance of debris from the lungs. The protein apparently plays a role in taste-bud function and has been shown to act as a tumor suppressor in the brain cancers known as gliomas.
PANX1 channels, nevertheless, can be detrimental, according to Penuela, noting they contribute to cell death and seizures under ischemic or epileptic conditions and even facilitate HIV-1 viral infection. Given the dark side of this channel protein, it comes as no surprise that PANX1 might be a suspect in the unexplained MRSA susceptibility following liver transplantation.
For Li and a large team of researchers throughout Shanghai, as well as Louisiana, Michigan and Pennsylvania, arriving at an explanation for MRSA vulnerability was part laboratory science, part surgical experience and part infectious disease sleuthing. On the whole, the research helped explain why MRSA infections seemed disproportionately to impact liver transplant recipients.
To understand why, the investigators analyzed gene expression patterns in 64 samples from transplant donor livers. They discovered that patients who received livers with low activity of the PANX1 gene were at higher risk of developing MRSA infections.
Experiments involving PANX1 and Il-33-knockout mice (bred as models for liver transplantation studies) revealed that a lack of the PANX1 protein in donor livers stunted the release of the immune-stimulating molecule interleukin-33 (IL-33). This, in turn, lowered the recruitment of immune cells and left the mice vulnerable to colonization by MRSA.
"We found that decreased PANX1 expression in the liver led to reduced release of ATP from hepatocytes, which further reduced the activation of P2X2, an ATP-activating P2X receptor," Li wrote in Science Translational Medicine. "Reduced P2X2 function further decreased the NLRP3-mediated release of IL-33, reducing hepatic recruitment of macrophages and neutrophils."
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