Closing a critical gap in knowledge, Harvard Medical School scientists have unraveled the immune cascade that fuels tissue damage and disease development in chlamydia infection. The study was published in the journal PNAS.
Physicians have long known that complications of chlamydia are not caused by the bacterium itself but instead arise from inflammation in the reproductive organs. However, up until now, it remained unclear what drives this damaging inflammation.
The current study reveals the precise mechanism behind this phenomenon and identifies the cast of immune cells involved in it. Further, the research shows that the body deals with chlamydia infection via two distinct and separate immune pathways: one driving the clearance of bacteria and one fueling inflammation and tissue damage.
The study findings show that complications of chlamydia infections arise from inflammation that occurs when several types of protective immune cells rush to the reproductive organs after the bacterium invades the body.
Remarkably, the research shows these immune cells are not involved in the clearance of bacteria, but rather that clearance is instead prompted by a different class of protective immune cells.
To understand how the bacterium damages urogenital tissue, the team started out by recreating symptoms that mimic human chlamydia infection in mice. Next, the team analyzed the reproductive tissue of infected mice, using a technique that identifies the presence of various immune cells.
The researchers observed that in the first few days after infection, immune cells known as neutrophils charge up to the urogenital tract and cause inflammation and damage. To determine what happens in the absence of neutrophils, researchers used an antibody specifically designed to target these cells while sparing all others.
Chlamydia-infected mice that lacked neutrophils showed no tissue damage despite harboring the bacterium. The absence of neutrophils had no effect on bacterial levels — an indicator that neutrophils play no role in the clearing of the bacterium.
Further analysis showed that in the later stages of infection, a different set of immune cells make their way to the urogenital tract. Researchers observed dramatically elevated levels of two types of T cells. Known as the body's elite assassins, T cells are "trained" to seek out and destroy pathogens.
In this case, however, researchers identified two distinct subtypes of T cells: general-assignment, bystander T cells that drive inflammation and chlamydia-specific T cells, formed in response to the presence of this particular bacterium.
Previous research had shown that chlamydia-specific T cells are responsible for clearing the infection but up until now, the scientists didn't know whether the Chlamydia-specific T cells might also spark damaging inflammation.
To understand what drives inflammation-inducing cells to infected urogenital tissue, researchers analyzed more than 700 inflammation-promoting and immunity-inducing genes. During infection, these genes release signaling proteins known as chemokines, which call on immune cells to make their way to the site of infection.
Researchers identified a trio of chemokines — CXCL 9,10,11 — that were particularly elevated, compared with all others. These very proteins are also known to play a role in the autoimmune conditions inflammatory bowel disease and rheumatoid arthritis.
In a final step, the researchers used a chemical compound to block the activity of the inflammation-inducing chemokines. Mice treated with the compound had markedly reduced levels of nonspecific, bystander T cells and markedly less inflammation and tissue damage. Notably, the improvement occurred without any effect on bacterial levels.
"Our data suggest that such therapies may also be beneficial in the treatment and prevention of pelvic inflammation following chlamydia infection," said study first author Rebeccah Lijek, who conducted the research as a post-doctoral fellow at Harvard Medical School.