From an international collaborative study, researchers from Harvard Medical School and Macrogen, a Korean biotech company, have discovered that the body’s immune system initially detects the presence of anthrax spores by recognizing RNA molecules that coat the spores’ surface. But this prompts an unfavorable immune response that hinders the body’s fight against anthrax once the spores have germinated into live bacteria, according to the study “TLR sensing of bacterial spore-associated RNA triggers host immune responses with detrimental effects” which will be published on April 11 in The Journal of Experimental Medicine.

Anthrax is caused by the bacterium Bacillus anthracis, which is equipped with several mechanisms that allow it to survive and replicate inside its host. But anthrax usually enters the body in the form of dormant spores that only later germinate into the active, replicating form of the bacterium. It was unclear whether anthrax spores trigger host immune responses and, if so, which components of the spore activate host immune sensors.

The U.S.-Korea research team found that anthrax spores do, in fact, stimulate the host immune system, and that they do so by activating a distinct set of immune sensors that don’t recognize the active, or vegetative, form of Bacillus anthracis. Immune cells called macrophages recognize vegetative Bacillus anthracis using a cell surface receptor protein called TLR2, which binds to lipoprotein molecules in the bacterial cell wall. The team discovered that human macrophages use two different receptors­—TLR7 and TLR8—to recognize RNA molecules embedded in the outermost layer of anthrax spores.

This unexpected recognition mechanism means that anthrax spores provoke a distinct immune response in macrophages. Unlike vegetative cells, anthrax spores stimulate the production of immune signaling molecules called type I interferons. Though these molecules are useful for fighting a variety of different pathogens such as viruses, type I interferons could reduce the immune system’s ability to neutralize Bacillus anthracis after the spores have germinated into the vegetative form of the bacterium. Type I interferons are known, for example, to disrupt the activities of two other immune signaling molecules, IL-1 and IL-17, that help protect the body from anthrax infection.

Accordingly, the researchers found that anthrax spores were more lethal to mice than the vegetative form of the bacterium, but spores lacking the outermost, RNA-containing layer that stimulates type I interferon production were much less deadly. They also discovered that mice deficient in type I interferon signaling were also more resistant to anthrax spores.

“We postulate that Bacillus anthracis has evolved to use spore-associated RNA to activate type I interferon signaling and thereby evade host immunity,” the researchers explain. “Our findings suggest that spore-associated RNA triggers early host responses to anthrax infection, but that type I interferon signaling serves to misguide host immunity and impair the body’s defense against the vegetative form of the bacterium at later stages of infection.”

Crucial to this breakthrough was Macrogen’s state-of-the-art RNA sequencing technology. Their bioinformatics capabilities were also essential for the identification of immunostimulatory RNA molecules that exist only in extremely small amounts in anthrax spores. The spore extracts prepared by the Harvard Medical School researchers were handed over to Macrogen, where RNA was carefully separated based on its size and analyzed by Macrogen’s next-generation-sequencing and bioinformatics platform.

The researchers now plan to investigate whether the spores of other bacterial pathogens use similar strategies to misdirect the host immune response. They also aim to develop new therapeutic agents by engineering anthrax spores and testing their ability to induce type I interferon signaling. Although this signaling pathway was found to wreak havoc in anthrax, it holds promise for beneficial effects in other types of diseases.

Released by Rockefeller University Press 
Journal reference:  10.1084/jem.20161141

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