Chlamydia is one of the most common sexually transmitted diseases in Germany. Chlamydia bacteria need host cells to survive and reproduce. They often use mucous membrane cells in the human reproductive and urinary organs for this purpose, effectively “hijacking” the host’s cellular metabolism. These intruders either go undetected or signaling molecules alert the innate immune system of their presence. In the latter case, the body’s own defense system recognizes the bacteria as foreign and provokes an inflammatory response to destroy the bacteria.
The human guanylate-binding protein 1 (GBP1) plays a key role in the defense mechanisms against chlamydia or other pathogens. Researchers already know that this enzyme is not only capable of slowing down the reproduction of the chlamydia bacteria, but can also set off an inflammatory response by turning on certain signaling pathways. Yet exactly how these processes work is still a mystery. Now, a team led by Professor Oliver Daumke at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has learned more about the role of specific metabolites of the enzyme in question. Working with the Max Planck Institute for Infection Biology, the researchers discovered which signaling pathways and protein complexes are activated by the metabolites.
GMP is important for the immune defense
The enzyme being studied – GBP1 – can act as a catalyst to speed up the cleavage of bioactive compounds. “It converts GTP to GMP in two steps through a reaction with water,” Daumke says. “GTP is a widely distributed cellular molecule that serves as a building block of RNA and is required for signaling processes.”
To understand what effect this cleavage has on the cell, Audrey Xavier, a PhD student in Daumke’s lab and the lead author of the study, modified the catalyzing enzyme. The enzyme either no longer functioned or it could only carry out the first step of the cleavage. She then introduced the different variants of the enzyme into human immune cells and infected them with chlamydia. The researcher was only able to measure typical inflammatory responses in those cells where the cleavage was fully possible. “That shows that GMP is crucial for this process,” Xavier says. But GMP does not appear to be responsible for slowing the growth of chlamydia. “Unfortunately, we still don’t exactly know how GBP1 inhibits the growth of the bacteria,” she says.
Blocking the signaling pathway
Xavier was even able to determine which signaling pathway GMP turns on in infected cells. According to the researcher, there are various protein complexes that can provoke an inflammatory response in cells, and the most well-known of these – the NLRP3 inflammasome – is activated when GMP is broken down to uric acid.
She managed to shut down this uric acid signaling pathway with an already approved drug that is normally used to treat gout. This disease is characterized by especially severe inflammatory responses. The research team observed that the agent allopurinol attenuates the inflammatory symptoms in cells infected with chlamydia. “Allopurinol helps reduce inflammation – and possibly also in people who have chlamydia,” Xavier says, adding: “But first clinical trials will need to test whether this might have potential as a supplemental therapy in combination with an antibiotic.”
Xavier, Audrey et al. (2020): „GBP1 coordinates Chlamydia restriction and inflammasome activation through sequential GTP hydrolysis”, Cell Reports, DOI: