TABLE 1.
Steps in the pathogenic process of shigellosisa
| Step | Stage of infection or related observationd | Probable molecular mechanism | Candidate ORFs in islandsb | S. flexneri products known to be involved |
|---|---|---|---|---|
| 1 | Penetration through mucus gel to epithelial surface | Activities of mucinases, proteases, and hydrolytic and glycolytic enzymes | Secreted or outer membrane enzymes with putative enzyme activity or of unknown function S3126 (Yp), S1990 (Ph), S0734 (Ph), S3187 (Ec), S2105 (Ec), S3191 (Ec), S3197 (Ec) | PicF (S3178) |
| 2 | M cells translocate bacteria across epithelium | Attachment to M cell surface | Adhesins, fimbriae, hypothetical membrane ORFs S0211 (St), S0213-14 (St), S0215 (Sy), S0217 (St), S2105 (Ec), S3341 (Bc), S3194-5 (Ec), S4048 (Ec), S3197 (Ec), S3229 (Ec) | |
| 3 | Phagocytosis by macrophages; secretion of proinflammatory cytokines | Type III secretion system (plasmid)c | ||
| 4 | Induction of macrophage apoptosis | Specificity of toxicity for particular cell types | Secreted protein S1443 (Me) | IpaB (plasmid) |
| 5 | Binding to basolateral surfaces of colonic epithelial cells | Specificity for human colon; epithelial receptor | Adhesins, fimbriae, hypothetical membrane ORFs S0211 (St), S0213-14 (St), S0215 (Sy), S0217 (St), S2105 (Ec), S3341 (Bc), S3194-5 (Ec), S4048 (Ec), S3197 (Ec), S3229 (Ec) | |
| 6 | S. flexneri-induced uptake into epithelial cells by macropinocytosis | Type III secretion system (plasmid), LPS | ||
| 7 | Lysis of vacuole | Lysis of vacuolar membrane | IpaB, IpaH (plasmid) | |
| 8 | Bacterial replication in cytosol | Metabolic pathways utilized in the cytosol | Nutrient transport proteins S3636-42 (Eo) (PTS sor-like operon); S3114-8 (Eo), S1762 (Sy), S3968 (Eo), S4229 (Cj); metabolic enzymes, hpa operon S4643-55 (Ew) | TonB, CydC, VpsAC, Sit/Iuc/Feo |
| 9 | Actin-based motility | VirG/IcsA (plasmid), DksA | ||
| 10 | Intercellular spread | Interaction with cell-cell junction components | Outer membrane proteins S2105 (Ec), S3197 (Ec), S2341 (St) | |
| 11 | Lysis of double-membrane vacuole | Lysis of two membranes: one from inner face the other from outer face | Lytic secreted or outer membrane proteins S1443 (Me), S2105 (Ec), S2341 (St), S3197 (Ec); regulators of gene expression S2953 (Eo), S2956 (Ec), S4473 (St); S3212 (Vi), S1277 (Ec) | VacJ, plasmid type III secretion effectors, including IpaBC, IcsB, IpgC |
| 12 | Disruption of tight junctions by PMN transmigration and S. flexneri enterotoxins | Bacterial factors induce PMN transmigration and disrupt tight junctions | Secretion of proteins in intestinal lumen S3187 (Ec) | Plasmid type III secretion system; Shet1, Shet2, SigA |
| 13 | S. flexneri passing through open tight junctions | S. flexneri tropism for opened tight junctions | Outer membrane proteins S2105 (Ec), S2341 (St), S3197 (Ec) | |
| 14 | Infected cells secrete cytokines; intense acute inflammatory response | Surface lipoproteins, S0227 (Eo), S3870 (Eo), S3130 (Eo, partial) | LPS, Cld (plasmid) | |
| 15 | Innate immunity prevents systemic spread | Lipoproteins responsible for activity; additional antigens? | Surface lipoproteins S0227 (Eo), S3870 (Eo), S3130 (Eo, partial): surface antigens S0211 (St), S0213-14 (St), S0215 (Sy), S0217 (St), S2341 (St), S3194-S3195 (Ec), S3197 (Ec), S3341 (Bc), S4048 (Ec) | LPS, lipoproteins |
| 16 | Adaptive immune response appears to be T-lymphocyte independent | Mechanism of inhibiting T-lymphocyte response | Secreted or surface proteins S1443 (Me), S2105 (Ec), S2341 (St), S3197 (Ec) | |
| 17 | Chromosomal segments enhance virulence | Additional modulating factors | Regulators of virulence plasmid gene expression S1277 (Ec), S2953 (Eo), S2956 (Ec), S3212 (Vi), S4473 (St) | VirR |
Shown is what is known about the infectious stages of bacterial invasion and spread through the colonic mucosa. Known proteins have been characterized experimentally. Unknown processes are those for which some or all of the genetic determinants are not yet identified and the biochemical or physiological mechanisms remain hidden. Candidate island ORFs encoded in the genome sequence were selected on the basis of homology search results and transmembrane domain predictions and are denoted by the unique identifier (S number) assigned in the annotated 2457T GenBank entry. Other factors that influence virulence, such as the ability to survive passage through the stomach, are also poorly understood, but since they are shared with many other species, they are not included here. PMN, polymorphonuclear leukocyte; LPS, lipopolysaccharide.
Species with most similar proteins are in parentheses. Normal letters indicate homologs (i.e., >90% identity over >90% of query and target length). Italic letters indicate matches of <90% but still significant. Bc, Burkholderia cepacia; Cj, Campylobacter; Eo, Escherichia coli O157:H7; Ec, other E. coli pathogens; Ew, E. coli W; Me, Mesorhizobium loti; Sy, S. enterica serovar Typhi; St, S. enterica serovar Typhimurium; Sf, S. flexneri flexneri; Si, Sinorhizobium meliloti; Vi, Vibrio cholerae; Yp, Yersinia pestis.
The type III secretion system includes structural proteins (Mxi and Spa proteins), secreted effector proteins (including IpaBCDA, VirA, MxiC, Spa32, and IpaH), and chaperone proteins.
For steps 15 to 17, these processes, while not sequential steps in infection, are intimately involved in promoting or limiting the progression of infection and are most likely to involve bacterial components yet to be identified.