To watch a video interview with Dr. Jorge Galán, click here.
Among the most common causes of food-borne illness, the bacterium Salmonella enterica serovar Typhimurium is a continual source of public health concern in the developed and developing world, infecting millions and killing thousands of people every year.
Like many other infectious bacteria, S. enterica serovar Typhimurium transfers proteins into its target cells using the bacterial type III protein secretion system (T3SS). “The T3SS is a remarkable device that is central to how Salmonella causes disease,” explained Professor Jorge Galán, Lucille P. Markey Professor of Microbial Patho¬genesis and chair of the Section of Microbial Pathogenesis at Yale.
The T3SS can be thought of as a “nanosyringe” through which Salmonella injects proteins into its target. A needle complex, anchored to the bacterial cell, serves as a passage for bacterial proteins targeted to the mammalian cell. These bacterial proteins, termed effectors, interfere with the machinery of the mammalian cell and thus allow the bacterium to penetrate or otherwise use its target for its own benefit. At the tip of the needle complex, proteins called translocases ensure delivery of the effector proteins through the eukaryotic cell membrane.
The T3SS also determines the order in which the proteins are delivered into the mammalian cell. This order of delivery is essential to the bacterium’s ability to manipulate its target. The Galán lab has recently discovered a sorting platform that is responsible for this ordering process. “The idea of the necessity of an order was probably more of a theoretical concept, but our discovery of the sorting platform has added more evidence that indeed, you need to have an order,” explained Galán. “But the main focus is not just to prove that there is an order but rather how that sorting takes place.”
This sorting process is related to how the proteins are guarded inside the bacterial cell. Each protein that is to be injected into the target cell has a customized chaperone that binds to it inside the bacterium. “We’ve known for a while that the chaperones are necessary for the protein to be targeted for secretion,” said Galán. “Now we know that these chaperones mediate the process of bringing these proteins to the platform. Our proposed model is that the affinity of each chaperone for the platform provides the priority in the sorting of the proteins for secretion.”
The proteins that make up the sorting platform discovered in the Galán lab could serve as targets for pharmaceutical compounds. Unlike most of the antimicrobials in use today, these new drugs would cripple, rather than kill, the pathogen. In this way, these antimicrobials would give the immune system an opportunity to eliminate the pathogens. However, because they cripple rather than kill their bacterial targets, these drugs would impose less selective pressure on the bacteria, thus reducing the likelihood of the bacteria developing antimicrobial resistance.
Furthermore, because they specifically target a structure that functions in the pathogen’s infection mechanism, the antimicrobials would cripple the pathogenic bacteria without killing the “good” bacterial florae in our bodies, such as the gut flora that plays an important role in human digestion of certain nutrients. Given the success of the T3SS, it is not surprising that this structure is found in a large variety of bacteria. Thus, antimicrobial drugs targeting the sorting platform could potentially be used against many other pathogens.
Meanwhile, Galán’s lab continues to attempt to understand how Salmonella causes disease: “We are trying to build this sorting platform from the components from the ground up in a test tube so that we can truly understand how it works.”