Genetic variation shown in patients with severe vascular complications of infection

Major infections such as influenza and bacterial sepsis kill millions of people each year, often resulting fro dangerous complications that impair the body's blood vessels. But the reasons why some patients experience these dramatic responses to infections - and others don't - have been unclear.

Now a research team led by investigators in the Center for Vascular Biology Research (CVBR) at Beth Israel Deaconess Medical Center (BIDMC) has shown that variations in the Tie2 gene, which is expressed on the inner surface of blood vessels, play an important role in patient responses. The new findings, which appear online this week in the Proceedings of the National Academy of Sciences (PNAS), demonstrate that diminished Tie2 levels are associated with potentially devastating responses to infections, while higher Tie2 levels provide protection. This new discovery suggests that Tie2 could be an important target to help clinicians more quickly determine which patients are at highest risk of developing these life-threatening vascular complications following infectious disease.

"The complications arising from sepsis and other infections can appear rapidly and dramatically, leaving patients in absolutely terrible shape," said senior author Samir Parikh, MD, an investigator in BIDMC's CVBR and Division of Nephrology and Associate Professor of Medicine at Harvard Medical School. "Patients might arrive at the hospital feeling generally unwell and within a few hours, can be in critical condition." But, this is not the case for everyone: many other patients arrive at the hospital with the same infectious symptoms, but get no worse and go on to recover fully.

In studying the host response to infections, researchers have for many years focused on the role of the innate immune system. More recently, the focus has broadened to include the role played by the body's vascular system.

"Improperly functioning blood vessels can have lethal consequences," explained Parikh. "For example, when the lungs' small blood vessels become leaky, the lungs fill with water and stop working properly, resulting in an often fatal condition called acute respiratory distress syndrome [ARDS]. No matter what type of infection a patient has initially, if he or she goes on to develop vascular leakage, that patient is in trouble. We wanted to find out if the Tie2 protein played a role in determining whether or not patients experience these devastating vascular complications," said Parikh.

The authors first determined in mouse models of several infections - including the parasitic infection malaria, the viral infection influenza and the bacterial infection sepsis - that all animals had decreased levels of Tie2 compared to baseline levels. Subsequent experiments revealed that reduced Tie2 was indeed setting the stage for vascular leakage and ensuing clinical complications in the animal models.

"," said corresponding author Chandra Ghosh, PhD, a member of the Parikh laboratory at BIDMC. "Interestingly, mice with a single copy of the gene behave normally until they are challenged with infections."