The Type III Secretion System
The protein Type III Secretion System (T3SS) is a supramolecular, organic nanomachine that injects bacterial virulence proteins into eukaryotic cells to modulate their physiology for the benefit of the pathogen. It underlies the virulence of numerous medically relevant organisms, such as those causing plague (Yersinia pestis), food poisoning and typhoid (Salmonella, E. coli, Shigella), opportunistic infections (Pseudomonas aeruginosa), sexually transmitted diseases (Chlamydia) as well as plant diseases caused by numerous phytopathogenic bacteria (e.g., Erwinia, Ralstonia, Rhizobium and Xanthomonas). Diseases caused by these organisms have been historically devastating (e.g, plague, typhoid) and also represent significant medical concerns today. Diarrheal disease from Salmonella alone account for a hundred million infections a year and hundreds of thousands of deaths. Other organisms such as pathogenic E. coli, Pseudomonas, and Chlamydia are medically significant pathogens, especially in the immuno-compromised, and as they acquire antibiotic resistance. Even plague, as it gains antibiotic resistance, could become a re-emergent disease, and its weaponization makes it a threat of a different, yet important, class.
Nearly one billion years ago, according to bioinformatic reconstructions, bacteria were in possession of genes highly homologous to the modern virulence associated T3SS. The genes for this protein secretion system have found their way, through pathogenicity islands and large plasmids, to a wide variety of Gram-negative pathogens of animals and plants, and also function in phytosymbiotic relationships. The known virulence substrates for these systems currently number in the several hundred, modulating host biochemical functions such as cytoskeletal structure, programmed cell death, cell cycle progression, endocytic trafficking, and gene expression.
The secretion machinery itself is highly conserved, consisting of more than twenty proteins, many showing homology to flagellar export genes. A conceptual division can be made between the so-called basal body of the apparatus and the core transmembrane proteins. The basal body may be thought of as the “syringe” body, the channel or tunnel that provides a solid structural framework for the secretion machinery to use for translocation, through which substrates travel. Protruding from the outer membrane at the “top” of the basal body is a long filamentous structure composed of a single protein. This “needle” is in some pathogens surrounded also by a polymerized sheath.
Believed to assemble underneath the basal body within the inner membrane, are a set of proteins that are the most highly conserved in all of T3SS, strongly so even between the pathogenic and flagellar systems. These proteins include an ATPase, and a set of more than five integral membrane proteins that are absolutely critical to the functioning of the system. Outside of a few soluble domains of two of these proteins, structure-function information is extremely scarce. For the integral membrane domains, there is very little biochemical, and no structural information at all.
Sample Project 1: Type III Secretion System Chaperones
Sample Project 2: Type III Secretion System Protein InvA