Bleeding, not inflammation, is major cause of early lung infection death

August 27, 2007

Researchers believe they have discovered why a bacterial lung infection is so lethal in the early stages, and it's not what medical authorities had thought, according to research published August 23 in the journal Immunity. The study reveals for the first time that a toxin released by bacteria causes severe bleeding in the lungs by patients with pneumococcal pneumonia. It is the bleeding, the authors argue, not inflammation as once thought, which makes the infections deadly. The same study also reveals why antibiotics often fail to help prevent early death.

Also called pneumococcus, the bacteria Streptococcus pneumoniae infects the upper respiratory tracts of the elderly and young children mostly. There are 500,000 cases of pneumococcal pneumonia annually in the United States, with about 40,000 of them fatal, according to the Centers of Disease Control and Prevention. Those numbers would be worse in children younger than 2 years if not for the 2000 introduction of the pneumococcal vaccine (Prevnar), according to one report. The picture remains far more serious outside of the United States, however, where pneumococcal infections take the lives of at least one million children each year, according to the World Health Organization

"Our finding provides a better understanding of what makes a major global bacterial infection deadly, and marks the beginning of realistic efforts to save lives worldwide," said Jian-Dong Li, M.D., Ph.D., professor of Microbiology & Immunology at the University of Rochester Medical Center and an author on the Immunity paper. "The power of understanding this mechanism is that it not only suggests how better to treat this disease, but also that we should think twice about whether standard drug treatments are doing more harm than good," said Li, also senior and corresponding author on the paper.

A Medical Mystery

Recognizing molecules as "self," versus foreign invaders to be labeled for destruction, is a central responsibility of the human immune system. Vaccines are mixtures, made of parts of many bacterial strains in this case, designed to help the immune system recognize and remember an invader without causing a full-scale infection. The hope is that when the real disease comes along, the immune system will be primed to combat it. Complicating matters, children under two, the elderly and those with HIV have weaker immune systems than a typical healthy adult. Thus, they cannot mount as strong an immune response to a vaccine that would later protect them against the actual infection. Even worse, bacteria can thwart the protection afforded by vaccines by reproducing and evolving so quickly that they become unrecognizable to both vaccine and immune system. For all these reasons, new, more effective ways to treat these infections are major thrust of research efforts worldwide.

"Pneumococcal infection is characterized by fluid build-up in the lungs, and breathing difficulty is the reason that most infections become lethal early on," said Jae Hyang Lim, Ph.D., DVM, instructor in Microbiology & Immunology at the Medical Center and first author on the paper. "The medical establishment had for years believed that the breathing difficulty was brought on by inflammation: the swelling and fluid build-up caused as immune system proteins rushed to the lungs to fight the infection. A medical mystery emerged, however, when our studies revealed that such inflammation was actually lower during the early time period when most people died."

The newly published study reveals for the first time that a toxin released by S. pneumoniae causes severe bleeding in the lungs. Normally, competing regulatory pathways maintain a balance between the competing tendencies of blood to either become thinner (more likely to leak bleed out of vessels) or thicker (more likely form blood clots that choke off blood flow through blood vessels). Blood clots can represent either a dangerous blockage of blood flow, or a protective mechanism that prevents unchecked bleeding, all depending on a careful balance.

Specifically, the ability of blood to clot is increased by one regulatory pathway of reactions that end with the activation of a protein called plasminogen activator 1 (PAI-1). Against the pro-clotting influence of PAI-1 is balanced the action of another protein, cylindromatosis (CYLD), which blocks the clotting pathway just enough to keep blood flowing under normal circumstances. What Li and colleagues found is that the S. pneumoniae bacteria release a protein called pneumolysin, which causes an overproduction of CYLD, which increases the permeability of the lung's blood vessels and causes them to leak blood. They also found that pneumolysin directly increases the permeability of the lung's blood vessels, which causes yet more bleeding. Furthermore, antibiotic drugs kill bacteria by cutting them open, which releases of even more pneumolysin.

Li's team found for the first time that too much CYLD inhibits a signaling molecule (p38 kinase), which leads to reduced expression of PAI-1 expression in lung. To prove the point further, Li's team genetically engineered mice that do not have CYLD, and found that very few die of S. pnuemoniae infection.

"The most immediate implication of this work is that we could make purified, recombinant PAI-1 and inject it directly into the lungs of these patients, and it would have a benefit," Li said. "The next step will be to design a small molecule, a protein fragment, that can mimic PAI-1, which would be easier to deliver in the lungs, more effective and have fewer side effects. It would be even better if we could design an aerosol form, so you could just spray it into the air around these patients and their bleeding would stop."
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University of Rochester Medical Center

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