Chemical Sabotage
How a stubborn respiratory pathogen can lead to hardening of the arteries.
When most harmful bacteria enter your body, the infected cells release specific chemicals—an SOS answered by white blood cells called monocytes, the body's first responders. When they pass from the bloodstream into infected tissue, the monocytes transform themselves into cells called macrophages. Macrophages—whose name is Greek for "big eaters"—stretch to engulf invading pathogens and destroy them with toxic-chemical-producing enzymes.
But as they're ingested by macrophages, some pathogens fight back. When Chlamydia pneumoniae—a respiratory pathogen that causes pneumonia and bronchitis—encounters macrophages, it assumes a chronic form, changing itself into a stubborn variant that infects the infection-fighters. C. pneumoniae is of particular concern because of its connection to atherosclerosis, a clogging, narrowing, and hardening of the body's arteries that can lead to stroke or heart attack, as well as eye and kidney problems.
The disease is usually attributed to heredity or risk factors such as high blood cholesterol, high blood pressure, smoking, diabetes, obesity, and lack of physical activity.
The medical community has gradually come to accept C. pneumoniae as a cause of atherosclerosis. But exactly how a respiratory pathogen is linked to hardening of the arteries remained a mystery, until UWM Assistant Professor of Health Sciences Anthony Azenabor provided unique biochemical insights into the mechanisms involved in the process.
C. pneumoniae survives inside macrophages through chemical sabotage, Azenabor has discovered. The pathogen releases signals that render macrophages' toxic-chemical-producing enzymes ineffective as "killing molecules." It hijacks their intracellular cholesterol, which macrophages need to stretch and move effectively. And C. pneumoniae causes macrophages to take on extracellular cholesterol and lipids that they can't use.
As these Chlamydia-infected cells take on more and more cholesterol, they become immobile foam cells. They multiply and accumulate in blood vessel walls, forming lesions that are the precursors of atherosclerosis.
The usual forms of Chlamydia—for example, those infecting epithelial cells—are normally treated successfully with antibiotics. But antibiotics are often ineffective against Chlamydiae in macrophage or in their chronic forms.
Azenabor—who teaches courses including Medical Parasitology and Mycology and Clinical Immunology—discovered that when C. pneumoniae attaches to macrophages, it initiates a pattern of calcium ion movement into macrophages that disturbs the production of toxic radicals that would normally kill microbes.
"Interestingly, this process contributes to Chlamydia chronicity," the Nigerian-born Azenabor explains. "We then decided, let's control that aspect of it. We regulated the movement of calcium and succeeded in preventing the circumstances that led to onset of chronicity." In laboratory samples, Azenabor employed agents known as calcium channel blockers during C. pneumoniae infection. "We found out that by this method of blocking these channels, we can render C. pneumoniae non-chronic and more susceptible to antibiotic killing effect." Azenabor has a patent for this process of altering the chronic course of the organism.
But recently, Azenabor and his team discovered a drug that kills C. pneumoniae outright. He can't discuss details of this brand-new technology, disclosing only that he applied for a patent in March, and has submitted his findings for publication to the journal Medical Microbiology and Immunology.
Studying effects of estrogen on macrophages
In his laboratory, Azenabor is also studying the effects of estrogen on macrophages. He cites the gender disparity in the onset of some autoimmune diseases such as multiple sclerosis, as well as age disparity in women in terms of susceptibility to such diseases.
"Why all these differences?" he says. "Without a specific disease in mind, we studied how estrogen impacts macrophage physiology."
"The research going on in my lab now is addressing such areas as, the mechanisms involved in the observed possible role of estrogen in protection against cardio vascular diseases."
This work hasn't resulted in any great discoveries, but such basic research has more modest goals. "We are beginning to understand better how it works," Azenabor says.
Recognition
In 2003 Azenabor was recognized for his Chlamydia work with a coveted Shaw Scientist Award. This program, which is supported by the James D. Shaw and Dorothy Shaw Fund within the Greater Milwaukee Foundation, is used to advance research in the fields of biochemistry, biological science and cancer research at UWM and UW-Madison.
Almost three years after being awarded the $200,000 grant—an unrestricted award which is dispensed over five years—Azenabor still is in awe of Dorothy Shaw, who chose to use the bequest from her late husband to fund these awards.
"At the point when she begins to realize she will be passing away," Azenabor says, "she was still able to reflect and say this money should be used for the development of science for the benefit of humanity, especially those sciences that are addressing diseases in a way that human beings will come to understand them better."