Various gram-negative animal and plant pathogens use a novel, sec-independent protein secretion system as a basic virulence mechanism. It is becoming increasingly clear that these so-called type III secretion systems inject (translocate) proteins into the cytosol of eukaryotic cells, where the translocated proteins facilitate bacterial pathogenesis by specifically interfering with host cell signal transduction and other cellular processes. Accordingly, some type III secretion systems are activated by bacterial contact with host cell surfaces. Individual type III secretion systems direct the secretion and translocation of a variety of unrelated proteins, which account for species-specific pathogenesis phenotypes. In contrast to the secreted virulence factors, most of the 15 to 20 membrane-associated proteins which constitute the type III secretion apparatus are conserved among different pathogens. Most of the inner membrane components of the type III secretion apparatus show additional homologies to flagellar biosynthetic proteins, while a conserved outer membrane factor is similar to secretins from type II and other secretion pathways. Structurally conserved chaperones which specifically bind to individual secreted proteins play an important role in type III protein secretion, apparently by preventing premature interactions of the secreted factors with other proteins. The genes encoding type III secretion systems are clustered, and various pieces of evidence suggest that these systems have been acquired by horizontal genetic transfer during evolution. Expression of type III secretion systems is coordinately regulated in response to host environmental stimuli by networks of transcription factors. This review comprises a comparison of the structure, function, regulation, and impact on host cells of the type III secretion systems in the animal pathogens Yersinia spp., Pseudomonas aeruginosa, Shigella flexneri, Salmonella typhimurium, enteropathogenic Escherichia coli, and Chlamydia spp. and the plant pathogens Pseudomonas syringae, Erwinia spp., Ralstonia solanacearum, Xanthomonas campestris, and Rhizobium spp.

/pdf/type-iii-protein-secretion-systems-in-bacterial-pathogens-of-4iowv8mqxc.pdf

Type III Protein Secretion Systems in Bacterial Pathogens of Animals and Plants

Bacterial pathogens employ a number of genetic strategies to cause infection and, occasionally, disease in their hosts. Many of these virulence factors and their regulatory elements can be divided into a smaller number of groups based on the conservation of similar mechanisms. These common themes are found throughout bacterial virulence factors. For example, there are only a few general types of toxins, despite a large number of host targets. Similarly, there are only a few conserved ways to build the bacterial pilus and nonpilus adhesins used by pathogens to adhere to host substrates. Bacterial entry into host cells (invasion) is a complex mechanism. However, several common invasion themes exist in diverse microorganisms. Similarly, once inside a host cell, pathogens have a limited number of ways to ensure their survival, whether remaining within a host vacuole or by escaping into the cytoplasm. Avoidance of the host immune defenses is key to the success of a pathogen. Several common themes again are employed, including antigenic variation, camouflage by binding host molecules, and enzymatic degradation of host immune components. Most virulence factors are found on the bacterial surface or secreted into their immediate environment, yet virulence factors operate through a relatively small number of microbial secretion systems. The expression of bacterial pathogenicity is dependent upon complex regulatory circuits. However, pathogens use only a small number of biochemical families to express distinct functional factors at the appropriate time that causes infection. Finally, virulence factors maintained on mobile genetic elements and pathogenicity islands ensure that new strains of pathogens evolve constantly. Comprehension of these common themes in microbial pathogenicity is critical to the understanding and study of bacterial virulence mechanisms and to the development of new "anti-virulence" agents, which are so desperately needed to replace antibiotics.

/pdf/common-themes-in-microbial-pathogenicity-revisited-5g424sp8ag.pdf

Common themes in microbial pathogenicity revisited.

Several Gram-negative pathogenic bacteria have evolved a complex protein secretion system termed type III to deliver bacterial effector proteins into host cells that then modulate host cellular functions. These bacterial devices are present in both plant and animal pathogenic bacteria and are evolutionarily related to the flagellar apparatus. Although type III secretion systems are substantially conserved, the effector molecules they deliver are unique for each bacterial species. Understanding the biology of these devices may allow the development of novel prevention and therapeutic approaches for several infectious diseases.

https://science.sciencemag.org/content/sci/284/5418/1322.full.pdf

Type III Secretion Machines: Bacterial Devices for Protein Delivery into Host Cells

Escherichia coli O157:H7 is a major food-borne infectious pathogen that causes diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Here we report the complete chromosome sequence of an O157:H7 strain isolated from the Sakai outbreak, and the results of genomic comparison with a benign laboratory strain, K-12 MG1655. The chromosome is 5.5 Mb in size, 859 Kb larger than that of K-12. We identified a 4.1-Mb sequence highly conserved between the two strains, which may represent the fundamental backbone of the E. coli chromosome. The remaining 1.4-Mb sequence comprises of O157:H7-specific sequences, most of which are horizontally transferred foreign DNAs. The predominant roles of bacteriophages in the emergence of O157:H7 is evident by the presence of 24 prophages and prophage-like elements that occupy more than half of the O157:H7-specific sequences. The O157:H7 chromosome encodes 1632 proteins and 20 tRNAs that are not present in K-12. Among these, at least 131 proteins are assumed to have virulence-related functions. Genome-wide codon usage analysis suggested that the O157:H7-specific tRNAs are involved in the efficient expression of the strain-specific genes. A complete set of the genes specific to O157:H7 presented here sheds new insight into the pathogenicity and the physiology of O157:H7, and will open a way to fully understand the molecular mechanisms underlying the O157:H7 infection.

/pdf/complete-genome-sequence-of-enterohemorrhagic-eschelichia-29rnleib4r.pdf

Complete Genome Sequence of Enterohemorrhagic Eschelichia coli O157:H7 and Genomic Comparison with a Laboratory Strain K-12

Salmonella enterica serovar Typhimurium invades host macrophages and induces a unique caspase-1-dependent pathway of cell death termed pyroptosis, which is activated during bacterial infection in vivo. We demonstrate DNA cleavage during pyroptosis results from caspase-1-stimulated nuclease activity. Although poly(ADP-ribose) polymerase (PARP) activation by fragmented DNA depletes cellular ATP to cause lysis during oncosis, the rapid lysis characteristic of Salmonella-infected macrophages does not require PARP activity or DNA fragmentation. Membrane pores between 1.1 and 2.4 nm in diameter form during pyroptosis of host cells and cause swelling and osmotic lysis. Pore formation requires host cell actin cytoskeleton rearrangements and caspase-1 activity, as well as the bacterial type III secretion system (TTSS); however, insertion of functional TTSS translocons into the host membrane is not sufficient to directly evoke pore formation. Concurrent with pore formation, inflammatory cytokines are released from infected macrophages. This mechanism of caspase-1-mediated cell death provides additional experimental evidence supporting pyroptosis as a novel pathway of inflammatory programmed cell death.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1462-5822.2006.00751.x

Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages.

The ability of Salmonella typhimurium to interact with host cells is largely dependent on the function of a type III protein-secretion system encoded at centisome 63 of its chromosome. We have shown here that two targets of this protein-secretion system, SipB and SipC, are translocated into cultured intestinal Henle-407 cells. Translocation required the function of the type III secretion apparatus, as an S. typhimurium strain carrying a mutation in invA, which encodes an essential component of this system, failed to translocate the Sip proteins. Null mutations in the genes encoding SipB, SipC or SipD, prevented protein translocation, indicating that these proteins are involved in the translocation process. In contrast, mutations in sipA and sptP, which also encode secreted proteins, did not interfere with the translocation of SipC, indicating that only a subset of targets of the type III secretion system act as translocases. Externally or internally localized bacteria could direct protein translocation into Henle-407 cells as this process occurred in the presence of cytochalasin D at a concentration that prevented bacterial entry, or in the presence of gentamicin added shortly after bacterial internalization at a concentration that killed extracellular Salmonella. These results indicate that protein translocation into host cells may be a universal function of all type III secretion systems.

The invasion-associated type III system of Salmonella typhimurium directs the translocation of Sip proteins into the host cell.

The invasion-associated type-III protein secretion system in Salmonella--a review.

Summary
We have carried out a functional analysis of invl and invJ, two Saimonella typhimurium genes required for this organism to gain access So cultured mammalian cells. These genes are located immediately downstream of invC, a previously identified gene also required for bacterial invasion. Non-polar mutations in either of these genes rendered S. typhimurium severely defective for entry into cultured epithelial cells, although these mutations did not affect the ability of these organisms to attach to those cells. Nucleotide sequence analysis revealed that the invl and invJ genes encode proteins with molecular weights of 18077 and 36415, respectively. Polypeptides of similar sizes were observed when these genes were expressed in a bacteriophage T7 RNA polymerase-based expression system. Comparison of the predicted sequences of Invl and InvJ with translated sequences in the existing databases indicated that these proteins are Identical to the previously identified S. typhimurium SpaM and SpaN proteins. Further analysis of these sequences revealed regions of homology between Invl and the N-terminus of lpaB of Shigella spp. and between InvJ and EaeB of enteropathogenic Escherichia coli. Localization studies by immunoblot analysis indicated that InvJ is secreted to the culture supernatant, a surprising finding since this protein also lacks a typical signal sequence. Mutations in invG and inyC, two members of the Salmonella inv locus, effectively prevented the transport of InvJ to the culture supernatant. Thus, InvJ is the first identified target of the protein secretion apparatus encoded in the inv locus and therefore a candidate to have effector functions related to bacterial entry.

Functional analysis of the Salmonella typhimurium invasion genes invl and invJ and identification of a target of the protein secretion apparatus encoded in the inv locus

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The invasion-associated type III system of Salmonella typhimurium directs the translocation of Sip proteins into the host cell.

The invasion-associated type-III protein secretion system in Salmonella--a review.

Functional analysis of the Salmonella typhimurium invasion genes invl and invJ and identification of a target of the protein secretion apparatus encoded in the inv locus