Chronic oral infection with the periodontal disease
pathogen, Porphyromonas gingivalis, not only causes local inflammation of the
gums leading to tooth loss but also is associated with an increased risk of
atherosclerosis. A study published on July 10th in PLOS Pathogens now reveals
how the pathogen evades the immune system to induce inflammation beyond the
oral cavity.
Like other gram-negative bacteria, P. gingivalis has an
outer layer that consists of sugars and lipids. The mammalian immune system has
evolved to recognize parts of this bacterial coating, which then triggers a
multi-pronged immune reaction. As part of the "arms race" between
pathogens and their hosts, several types of gram-negative bacteria, including
P. gingivalis, employ strategies by which they alter their outer coats to avoid
the host immune defense.
Caroline Attardo Genco, from Boston University School of
Medicine, USA, in collaboration with Richard Darveau, at the University of
Washington School of Dentistry, USA, and colleagues focused on the role of a
specific lipid expressed on the outer surface of P. gingivalis, called lipid A,
which is known to interact with a key regulator of the host's immune system
called TLR4. P. gingivalis can produce a number of different lipid A versions,
and the researchers wanted to clarify how these modify the immune response and
contribute to the ability of the pathogen to survive and cause
inflammation—both locally, resulting in oral bone loss, and systemically, in
distant blood vessels.
They constructed genetically modified strains of P.
gingivalis with two distinct lipid A versions. The resulting bacteria produced
either lipid A that activated TLR4 (called "agonist") or lipid A that
interacted with TLR4 but blocked activation ("antagonist"). Utilizing
these strains, they demonstrate that P. gingivalis production of antagonist
lipid A renders the pathogen resistant to host bacterial killing responses.
This facilitates bacterial survival in macrophages, specific immune cells that
normally not only gobble up the bacteria but also "digest" and kill
them.
When the researchers infected atherosclerosis-prone mice
with the P. gingivalis TLR4 antagonist strain, they found that this exacerbates
inflammation in the blood vessels and promotes atherosclerosis. In contrast,
the ability of P. gingivalis to induce local inflammatory bone loss was
independent of lipid A variations, which demonstrates that there are distinct
mechanisms for induction of local versus systemic inflammation.
The researchers conclude, "P. gingivalis modifies its
lipid A structure in order to evade host defenses and establish chronic
infection leading to persistent systemic low-grade inflammation". They go
on to state that "uniquely among gram-negative pathogens, P. gingivalis
evasion of TLR4-mediated host immunity results in progression of inflammation
at a site that is distant from local infection by gaining access to the
vasculature."
