TABLE 1.

Steps in the pathogenic process of shigellosisa

StepStage of infection or related observationdProbable molecular mechanismCandidate ORFs in islandsbS. flexneri products known to be involved
1Penetration through mucus gel to epithelial surfaceActivities of mucinases, proteases, and hydrolytic and glycolytic enzymesSecreted 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)
2M cells translocate bacteria across epitheliumAttachment to M cell surfaceAdhesins, 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)
3Phagocytosis by macrophages; secretion of proinflammatory cytokinesType III secretion system (plasmid)c
4Induction of macrophage apoptosisSpecificity of toxicity for particular cell typesSecreted protein S1443 (Me)IpaB (plasmid)
5Binding to basolateral surfaces of colonic epithelial cellsSpecificity for human colon; epithelial receptorAdhesins, 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 macropinocytosisType III secretion system (plasmid), LPS
7Lysis of vacuoleLysis of vacuolar membraneIpaB, IpaH (plasmid)
8Bacterial replication in cytosolMetabolic pathways utilized in the cytosolNutrient 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
9Actin-based motilityVirG/IcsA (plasmid), DksA
10Intercellular spreadInteraction with cell-cell junction componentsOuter membrane proteins S2105 (Ec), S3197 (Ec), S2341 (St)
11Lysis of double-membrane vacuoleLysis of two membranes: one from inner face the other from outer faceLytic 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
12Disruption of tight junctions by PMN transmigration and S. flexneri enterotoxinsBacterial factors induce PMN transmigration and disrupt tight junctionsSecretion 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 junctionsOuter membrane proteins S2105 (Ec), S2341 (St), S3197 (Ec)
14Infected cells secrete cytokines; intense acute inflammatory responseSurface lipoproteins, S0227 (Eo), S3870 (Eo), S3130 (Eo, partial)LPS, Cld (plasmid)
15Innate immunity prevents systemic spreadLipoproteins 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
16Adaptive immune response appears to be T-lymphocyte independentMechanism of inhibiting T-lymphocyte responseSecreted or surface proteins S1443 (Me), S2105 (Ec), S2341 (St), S3197 (Ec)
17Chromosomal segments enhance virulenceAdditional modulating factorsRegulators of virulence plasmid gene expression S1277 (Ec), S2953 (Eo), S2956 (Ec), S3212 (Vi), S4473 (St)VirR
  • a 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.

  • b 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.

  • c 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.

  • d 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.