Bacteria—at least some of the ones that make people sick—are like burglars.
“They make a profession of breaking into cells,” says Mary O’Riordan, whose studies of the bacterium Listeria monocytogenes are yielding insights that may apply to other disease-causing microbes such as the ones that cause tuberculosis and malaria. Once inside, these invaders aren’t content to grab valuables and slip out unnoticed; they make themselves at home, snacking on their unwitting hosts’ provisions—even those that are hidden or locked up in special compartments.
In this cellular true crime tale, the hosts that these microbes infect are like vigilant homeowners, complete with security systems, watchdogs and weapons that sometimes keep housebreakers at bay, but other times fail to protect or overreact to false alarms.
O’Riordan, for her part, is a sort of crime scene investigator, trying to understand how bacteria breach normally secure cells and unlock those secret compartments to exploit the nutrients they find inside. Her lab focuses both on the bacterial side of the story and on the host’s surveillance system.
“We study these two different aspects of biology with the idea that the dynamic interface between the host and the pathogen is the key determinant of bacterial disease,” O’Riordan says. Finding ways to either fine-tune the host’s security system or interfere with the invaders’ ability to use the riches they find inside could lead to new approaches to treating infectious diseases.
To that end, O’Riordan’s group has identified genes that give Listeria (a food-borne pathogen that can cause serious illness in pregnant women, newborns and people with weakened immune systems) access to key nutrients in host cells. One particularly desirable nutrient is lipoic acid, which is sold in health food stores as an antioxidant.
“We can walk into a store, buy a pill and take it, but it’s not so easy for Listeria,” says O’Riordan. “The problem for the bacterium is that the host cell sequesters lipoic acid in a special compartment called the mitochondrion, and even inside the mitochondrion, lipoic acid is bound to proteins.” But Listeria, like any good safecracker, is undeterred. It possesses a gene encoding an enzyme, lplA1, that allows the bug to liberate and use host-derived, protein-bound lipoic acid.
Interestingly, Listeria has another, very similar enzyme that doesn’t do the trick, so O’Riordan is examining biochemical differences between the two enzymes to try to figure out exactly how the useful one works. And because other disease-causing microbes, such as the protozoan that causes malaria, have similar enzymes, such understanding could lead to ways of inhibiting a broad range of pathogens.
On the host side of the picture, O’Riordan is trying to understand how cells “know” that virulent bacteria have invaded. Recent results point to a protein called XIAP that serves as a sort of command center for the host’s security system, integrating information from inside and outside the cell and signaling the immune system to ramp up or dampen its response.
Understanding and learning how to inhibit or augment such proteins could not only help combat microbial invaders such as Listeria, but it could also lead to better treatments for autoimmune and inflammatory diseases.
“If someone’s not responding well to an infection, you might be able to boost their response,” says O’Riordan, “but alternatively, if the signaling pathway is being triggered too much, as may occur in Crohn’s disease, you could dial it down.”
Arriving at such understanding may take a little more sleuthing, but O’Riordan is on the case.
