Most of us don’t really pay attention to the bacteria that inhabits our mouth. These bacteria become a problem if there is a chronic infection in the form of periodontisis which causes a disruption to our immune system.
A study by University of Pennsylvania researchers shows that the bacteria responsible for many cases of periodontiitis manipulates the immune system in two ways.
The researchers in this study investigated how bacteria evaded killing without shutting off inflammation which they need to obtain their food.
The research published in the journal Cell Host & Microbe reveals the mechanism of manipulation by specifying that Porphyromonas gingivalis (periodontal bacteria) blocks the killing mechanism of immune cells while preserving the ability of the cells to cause inflammation. The end result is bone loss and inflammation that characterizes chronic periodontitis. The breakdown products produced as a result of inflammation actually feed the dysfunctional microbial community producing a vicious cycle of reinforcement of inflammation and microbial disturbance.
“Scientists are beginning to suspect that keystone pathogens might be playing a role in irritable bowel disease, colon cancer and other inflammatory diseases,” George Hajishengallis, a professor in the Penn School of Dental Medicine’s Department of Microbiology, said. “They’re bugs that can’t mediate the disease on their own; they need other, normally non-pathogenic bacteria to cause the inflammation.”
The research focus was on neutrophils, which shoulder the bulk of responsibility of responding to periodontal insults. Based prior research they examined the role of two protein receptors: C5aR and Toll-like receptor-2, or TLR2. When mice were inoculated with P. Ginivalis, they found that animals that lacked either of these receptors as well as animals that were treated with drugs that blocked these receptors had lower levels of bacteria than untreated, normal mice. Blocking either of these receptors on human neutrophils in culture also significantly enhanced the cells’ ability to kill the bacteria. Microscopy revealed that P. gingivalis causes TLR2 and C5aR to physically come together.
“These findings suggest that there is some crosstalk between TLR2 and C5aR,” Hajishengallis said. “Without either one, the bacteria weren’t as effective at colonizing the gums.”
Further experiments identified additional elements of how P. gingivalis operates to subvert the immune system. They found that the TLR2-C5aR crosstalk leads to degradation of the protein MyD88, which normally helps clear infection. And in a separate pathway from MyD88, they discovered that P. gingivalis activates the enzyme PI3K through C5aR-TLR2 crosstalk, promoting inflammation and inhibiting neutrophils’ ability to phagocytose, or “eat,” invading bacteria. Inhibiting the activity of either PI3K or a molecule that acted upstream of PI3K called Mal restored the neutrophils’ ability to clear P. gingivalis from the gums.
“P. gingivalis uses this connection between C5aR and TLR2 to disarm and dissociate the MyD88 pathway, which normally protects the host from infection, from the proinflammatory and immune-evasive pathway mediated by Mal and PI3K,” Hajishengallis said.
Tomoki Maekawa, Jennifer L. Krauss, Toshiharu Abe, Ravi Jotwani, Martha Triantafilou, Kathy Triantafilou, Ahmed Hashim, Shifra Hoch, Michael A. Curtis, Gabriel Nussbaum, John D. Lambris, George Hajishengallis. Porphyromonas gingivalis Manipulates Complement and TLR Signaling to Uncouple Bacterial Clearance from Inflammation and Promote Dysbiosis. Cell Host & Microbe, 2014; 15 (6): 768 DOI: 10.1016/j.chom.2014.05.012