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. 2000 May 29;355(1397):575–586. doi: 10.1098/rstb.2000.0599

The pathogenesis of Shigella flexneri infection: lessons from in vitro and in vivo studies.

D J Philpott 1, J D Edgeworth 1, P J Sansonetti 1
PMCID: PMC1692768  PMID: 10874731

Abstract

Shigella flexneri is a Gram-negative facultatively intracellular pathogen responsible for bacillary dysentery in humans. More than one million deaths occur yearly due to infections with Shigella spp. and the victims are mostly children of the developing world. The pathogenesis of Shigella centres on the ability of this organism to invade the colonic epithelium where it induces severe mucosal inflammation. Much information that we have gained concerning the pathogenesis of Shigella has been derived from the study of in vitro models of infection. Using these techniques, a number of the molecular mechanisms by which Shigella invades epithelial cells and macrophages have been identified. In vivo models of shigellosis have been hampered since humans are the only natural hosts of Shigella. However, experimental infection of macaques as well as the murine lung and rabbit ligated ileal loop models have been important in defining some of the immune and inflammatory components of the disease. In particular, the murine lung model has shed light on the development of systemic and local immune protection against Shigella infection. It would be naive to believe that any one model of Shigella infection could adequately represent the complexity of the disease in humans, and more sophisticated in vivo models are now necessary. These models require the use of human cells and tissue, but at present such models remain in the developmental stage. Ultimately, however, it is with such studies that novel treatments and vaccine candidates for the treatment and prevention of shigellosis will be designed.

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Selected References

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  1. Adam T., Giry M., Boquet P., Sansonetti P. Rho-dependent membrane folding causes Shigella entry into epithelial cells. EMBO J. 1996 Jul 1;15(13):3315–3321. [PMC free article] [PubMed] [Google Scholar]
  2. Beatty W. L., Méresse S., Gounon P., Davoust J., Mounier J., Sansonetti P. J., Gorvel J. P. Trafficking of Shigella lipopolysaccharide in polarized intestinal epithelial cells. J Cell Biol. 1999 May 17;145(4):689–698. doi: 10.1083/jcb.145.4.689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beatty W. L., Sansonetti P. J. Role of lipopolysaccharide in signaling to subepithelial polymorphonuclear leukocytes. Infect Immun. 1997 Nov;65(11):4395–4404. doi: 10.1128/iai.65.11.4395-4404.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bernardini M. L., Mounier J., d'Hauteville H., Coquis-Rondon M., Sansonetti P. J. Identification of icsA, a plasmid locus of Shigella flexneri that governs bacterial intra- and intercellular spread through interaction with F-actin. Proc Natl Acad Sci U S A. 1989 May;86(10):3867–3871. doi: 10.1073/pnas.86.10.3867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blocker A., Gounon P., Larquet E., Niebuhr K., Cabiaux V., Parsot C., Sansonetti P. The tripartite type III secreton of Shigella flexneri inserts IpaB and IpaC into host membranes. J Cell Biol. 1999 Nov 1;147(3):683–693. doi: 10.1083/jcb.147.3.683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bourdet-Sicard R., Rüdiger M., Jockusch B. M., Gounon P., Sansonetti P. J., Nhieu G. T. Binding of the Shigella protein IpaA to vinculin induces F-actin depolymerization. EMBO J. 1999 Nov 1;18(21):5853–5862. doi: 10.1093/emboj/18.21.5853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen Y., Smith M. R., Thirumalai K., Zychlinsky A. A bacterial invasin induces macrophage apoptosis by binding directly to ICE. EMBO J. 1996 Aug 1;15(15):3853–3860. [PMC free article] [PubMed] [Google Scholar]
  8. Clerc P. L., Ryter A., Mounier J., Sansonetti P. J. Plasmid-mediated early killing of eucaryotic cells by Shigella flexneri as studied by infection of J774 macrophages. Infect Immun. 1987 Mar;55(3):521–527. doi: 10.1128/iai.55.3.521-527.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DuPont H. L., Hornick R. B., Dawkins A. T., Snyder M. J., Formal S. B. The response of man to virulent Shigella flexneri 2a. J Infect Dis. 1969 Mar;119(3):296–299. doi: 10.1093/infdis/119.3.296. [DOI] [PubMed] [Google Scholar]
  10. DuPont H. L., Hornick R. B., Snyder M. J., Libonati J. P., Formal S. B., Gangarosa E. J. Immunity in shigellosis. II. Protection induced by oral live vaccine or primary infection. J Infect Dis. 1972 Jan;125(1):12–16. doi: 10.1093/infdis/125.1.12. [DOI] [PubMed] [Google Scholar]
  11. DuPont H. L., Levine M. M., Hornick R. B., Formal S. B. Inoculum size in shigellosis and implications for expected mode of transmission. J Infect Dis. 1989 Jun;159(6):1126–1128. doi: 10.1093/infdis/159.6.1126. [DOI] [PubMed] [Google Scholar]
  12. Fernandez-Prada C. M., Hoover D. L., Tall B. D., Venkatesan M. M. Human monocyte-derived macrophages infected with virulent Shigella flexneri in vitro undergo a rapid cytolytic event similar to oncosis but not apoptosis. Infect Immun. 1997 Apr;65(4):1486–1496. doi: 10.1128/iai.65.4.1486-1496.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ghayur T., Banerjee S., Hugunin M., Butler D., Herzog L., Carter A., Quintal L., Sekut L., Talanian R., Paskind M. Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 1997 Apr 10;386(6625):619–623. doi: 10.1038/386619a0. [DOI] [PubMed] [Google Scholar]
  14. Giannasca P. J., Giannasca K. T., Falk P., Gordon J. I., Neutra M. R. Regional differences in glycoconjugates of intestinal M cells in mice: potential targets for mucosal vaccines. Am J Physiol. 1994 Dec;267(6 Pt 1):G1108–G1121. doi: 10.1152/ajpgi.1994.267.6.G1108. [DOI] [PubMed] [Google Scholar]
  15. Hensel M., Shea J. E., Gleeson C., Jones M. D., Dalton E., Holden D. W. Simultaneous identification of bacterial virulence genes by negative selection. Science. 1995 Jul 21;269(5222):400–403. doi: 10.1126/science.7618105. [DOI] [PubMed] [Google Scholar]
  16. High N., Mounier J., Prévost M. C., Sansonetti P. J. IpaB of Shigella flexneri causes entry into epithelial cells and escape from the phagocytic vacuole. EMBO J. 1992 May;11(5):1991–1999. doi: 10.1002/j.1460-2075.1992.tb05253.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hilbi H., Chen Y., Thirumalai K., Zychlinsky A. The interleukin 1beta-converting enzyme, caspase 1, is activated during Shigella flexneri-induced apoptosis in human monocyte-derived macrophages. Infect Immun. 1997 Dec;65(12):5165–5170. doi: 10.1128/iai.65.12.5165-5170.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hilbi H., Moss J. E., Hersh D., Chen Y., Arondel J., Banerjee S., Flavell R. A., Yuan J., Sansonetti P. J., Zychlinsky A. Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB. J Biol Chem. 1998 Dec 4;273(49):32895–32900. doi: 10.1074/jbc.273.49.32895. [DOI] [PubMed] [Google Scholar]
  19. Hueck C. J. Type III protein secretion systems in bacterial pathogens of animals and plants. Microbiol Mol Biol Rev. 1998 Jun;62(2):379–433. doi: 10.1128/mmbr.62.2.379-433.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Inman L. R., Cantey J. R. Peyer's patch lymphoid follicle epithelial adherence of a rabbit enteropathogenic Escherichia coli (strain RDEC-1). Role of plasmid-mediated pili in initial adherence. J Clin Invest. 1984 Jul;74(1):90–95. doi: 10.1172/JCI111423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Islam D., Bardhan P. K., Lindberg A. A., Christensson B. Shigella infection induces cellular activation of T and B cells and distinct species-related changes in peripheral blood lymphocyte subsets during the course of the disease. Infect Immun. 1995 Aug;63(8):2941–2949. doi: 10.1128/iai.63.8.2941-2949.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Islam D., Veress B., Bardhan P. K., Lindberg A. A., Christensson B. In situ characterization of inflammatory responses in the rectal mucosae of patients with shigellosis. Infect Immun. 1997 Feb;65(2):739–749. doi: 10.1128/iai.65.2.739-749.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Islam D., Wretlind B., Lindberg A. A., Christensson B. Changes in the peripheral blood T-Cell receptor V beta repertoire in vivo and in vitro during shigellosis. Infect Immun. 1996 Apr;64(4):1391–1399. doi: 10.1128/iai.64.4.1391-1399.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Islam M. M., Azad A. K., Bardhan P. K., Raqib R., Islam D. Pathology of shigellosis and its complications. Histopathology. 1994 Jan;24(1):65–71. doi: 10.1111/j.1365-2559.1994.tb01272.x. [DOI] [PubMed] [Google Scholar]
  25. Jepson M. A., Clark M. A., Foster N., Mason C. M., Bennett M. K., Simmons N. L., Hirst B. H. Targeting to intestinal M cells. J Anat. 1996 Dec;189(Pt 3):507–516. [PMC free article] [PubMed] [Google Scholar]
  26. Jung H. C., Eckmann L., Yang S. K., Panja A., Fierer J., Morzycka-Wroblewska E., Kagnoff M. F. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J Clin Invest. 1995 Jan;95(1):55–65. doi: 10.1172/JCI117676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kernéis S., Bogdanova A., Kraehenbuhl J. P., Pringault E. Conversion by Peyer's patch lymphocytes of human enterocytes into M cells that transport bacteria. Science. 1997 Aug 15;277(5328):949–952. doi: 10.1126/science.277.5328.949. [DOI] [PubMed] [Google Scholar]
  28. Khan J., Bittner M. L., Chen Y., Meltzer P. S., Trent J. M. DNA microarray technology: the anticipated impact on the study of human disease. Biochim Biophys Acta. 1999 Mar 25;1423(2):M17–M28. doi: 10.1016/s0304-419x(99)00004-9. [DOI] [PubMed] [Google Scholar]
  29. Kotloff K. L., Winickoff J. P., Ivanoff B., Clemens J. D., Swerdlow D. L., Sansonetti P. J., Adak G. K., Levine M. M. Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull World Health Organ. 1999;77(8):651–666. [PMC free article] [PubMed] [Google Scholar]
  30. Labrec E. H., Schneider H., Magnani T. J., Formal S. B. EPITHELIAL CELL PENETRATION AS AN ESSENTIAL STEP IN THE PATHOGENESIS OF BACILLARY DYSENTERY. J Bacteriol. 1964 Nov;88(5):1503–1518. doi: 10.1128/jb.88.5.1503-1518.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lelouard H., Reggio H., Mangeat P., Neutra M., Montcourrier P. Mucin-related epitopes distinguish M cells and enterocytes in rabbit appendix and Peyer's patches. Infect Immun. 1999 Jan;67(1):357–367. doi: 10.1128/iai.67.1.357-367.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mallett C. P., VanDeVerg L., Collins H. H., Hale T. L. Evaluation of Shigella vaccine safety and efficacy in an intranasally challenged mouse model. Vaccine. 1993;11(2):190–196. doi: 10.1016/0264-410x(93)90016-q. [DOI] [PubMed] [Google Scholar]
  33. Mandic-Mulec I., Weiss J., Zychlinsky A. Shigella flexneri is trapped in polymorphonuclear leukocyte vacuoles and efficiently killed. Infect Immun. 1997 Jan;65(1):110–115. doi: 10.1128/iai.65.1.110-115.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Mathan M. M., Mathan V. I. Morphology of rectal mucosa of patients with shigellosis. Rev Infect Dis. 1991 Mar-Apr;13 (Suppl 4):S314–S318. doi: 10.1093/clinids/13.supplement_4.s314. [DOI] [PubMed] [Google Scholar]
  35. McCormick B. A., Siber A. M., Maurelli A. T. Requirement of the Shigella flexneri virulence plasmid in the ability to induce trafficking of neutrophils across polarized monolayers of the intestinal epithelium. Infect Immun. 1998 Sep;66(9):4237–4243. doi: 10.1128/iai.66.9.4237-4243.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mounier J., Vasselon T., Hellio R., Lesourd M., Sansonetti P. J. Shigella flexneri enters human colonic Caco-2 epithelial cells through the basolateral pole. Infect Immun. 1992 Jan;60(1):237–248. doi: 10.1128/iai.60.1.237-248.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ménard R., Sansonetti P. J., Parsot C. Nonpolar mutagenesis of the ipa genes defines IpaB, IpaC, and IpaD as effectors of Shigella flexneri entry into epithelial cells. J Bacteriol. 1993 Sep;175(18):5899–5906. doi: 10.1128/jb.175.18.5899-5906.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ménard R., Sansonetti P., Parsot C. The secretion of the Shigella flexneri Ipa invasins is activated by epithelial cells and controlled by IpaB and IpaD. EMBO J. 1994 Nov 15;13(22):5293–5302. doi: 10.1002/j.1460-2075.1994.tb06863.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ménard R., Sansonetti P., Parsot C., Vasselon T. Extracellular association and cytoplasmic partitioning of the IpaB and IpaC invasins of S. flexneri. Cell. 1994 Nov 4;79(3):515–525. doi: 10.1016/0092-8674(94)90260-7. [DOI] [PubMed] [Google Scholar]
  40. Neutra M. R., Pringault E., Kraehenbuhl J. P. Antigen sampling across epithelial barriers and induction of mucosal immune responses. Annu Rev Immunol. 1996;14:275–300. doi: 10.1146/annurev.immunol.14.1.275. [DOI] [PubMed] [Google Scholar]
  41. Nonaka T., Kuwae A., Sasakawa C., Imajoh-Ohmi S. Shigella flexneri YSH6000 induces two types of cell death, apoptosis and oncosis, in the differentiated human monoblastic cell line U937. FEMS Microbiol Lett. 1999 May 1;174(1):89–95. doi: 10.1111/j.1574-6968.1999.tb13553.x. [DOI] [PubMed] [Google Scholar]
  42. Oaks E. V., Wingfield M. E., Formal S. B. Plaque formation by virulent Shigella flexneri. Infect Immun. 1985 Apr;48(1):124–129. doi: 10.1128/iai.48.1.124-129.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Owen R. L., Pierce N. F., Apple R. T., Cray W. C., Jr M cell transport of Vibrio cholerae from the intestinal lumen into Peyer's patches: a mechanism for antigen sampling and for microbial transepithelial migration. J Infect Dis. 1986 Jun;153(6):1108–1118. doi: 10.1093/infdis/153.6.1108. [DOI] [PubMed] [Google Scholar]
  44. Perdomo J. J., Gounon P., Sansonetti P. J. Polymorphonuclear leukocyte transmigration promotes invasion of colonic epithelial monolayer by Shigella flexneri. J Clin Invest. 1994 Feb;93(2):633–643. doi: 10.1172/JCI117015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Perdomo O. J., Cavaillon J. M., Huerre M., Ohayon H., Gounon P., Sansonetti P. J. Acute inflammation causes epithelial invasion and mucosal destruction in experimental shigellosis. J Exp Med. 1994 Oct 1;180(4):1307–1319. doi: 10.1084/jem.180.4.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Phalipon A., Kaufmann M., Michetti P., Cavaillon J. M., Huerre M., Sansonetti P., Kraehenbuhl J. P. Monoclonal immunoglobulin A antibody directed against serotype-specific epitope of Shigella flexneri lipopolysaccharide protects against murine experimental shigellosis. J Exp Med. 1995 Sep 1;182(3):769–778. doi: 10.1084/jem.182.3.769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Porcelli S. A., Modlin R. L. The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. Annu Rev Immunol. 1999;17:297–329. doi: 10.1146/annurev.immunol.17.1.297. [DOI] [PubMed] [Google Scholar]
  48. Sansonetti P. J., Arondel J., Cantey J. R., Prévost M. C., Huerre M. Infection of rabbit Peyer's patches by Shigella flexneri: effect of adhesive or invasive bacterial phenotypes on follicle-associated epithelium. Infect Immun. 1996 Jul;64(7):2752–2764. doi: 10.1128/iai.64.7.2752-2764.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Sansonetti P. J., Arondel J., Cavaillon J. M., Huerre M. Role of interleukin-1 in the pathogenesis of experimental shigellosis. J Clin Invest. 1995 Aug;96(2):884–892. doi: 10.1172/JCI118135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Sansonetti P. J., Arondel J., Fontaine A., d'Hauteville H., Bernardini M. L. OmpB (osmo-regulation) and icsA (cell-to-cell spread) mutants of Shigella flexneri: vaccine candidates and probes to study the pathogenesis of shigellosis. Vaccine. 1991 Jun;9(6):416–422. doi: 10.1016/0264-410x(91)90128-s. [DOI] [PubMed] [Google Scholar]
  51. Sansonetti P. J., Arondel J., Huerre M., Harada A., Matsushima K. Interleukin-8 controls bacterial transepithelial translocation at the cost of epithelial destruction in experimental shigellosis. Infect Immun. 1999 Mar;67(3):1471–1480. doi: 10.1128/iai.67.3.1471-1480.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sansonetti P. J., Phalipon A. M cells as ports of entry for enteroinvasive pathogens: mechanisms of interaction, consequences for the disease process. Semin Immunol. 1999 Jun;11(3):193–203. doi: 10.1006/smim.1999.0175. [DOI] [PubMed] [Google Scholar]
  53. Sansonetti P. J., Tran Van Nhieu G., Egile C. Rupture of the intestinal epithelial barrier and mucosal invasion by Shigella flexneri. Clin Infect Dis. 1999 Mar;28(3):466–475. doi: 10.1086/515150. [DOI] [PubMed] [Google Scholar]
  54. Sasakawa C., Kamata K., Sakai T., Makino S., Yamada M., Okada N., Yoshikawa M. Virulence-associated genetic regions comprising 31 kilobases of the 230-kilobase plasmid in Shigella flexneri 2a. J Bacteriol. 1988 Jun;170(6):2480–2484. doi: 10.1128/jb.170.6.2480-2484.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Skoudy A., Nhieu G. T., Mantis N., Arpin M., Mounier J., Gounon P., Sansonetti P. A functional role for ezrin during Shigella flexneri entry into epithelial cells. J Cell Sci. 1999 Jul;112(Pt 13):2059–2068. doi: 10.1242/jcs.112.13.2059. [DOI] [PubMed] [Google Scholar]
  56. Takahashi K., Sasaki T., Mammoto A., Takaishi K., Kameyama T., Tsukita S., Takai Y. Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J Biol Chem. 1997 Sep 12;272(37):23371–23375. doi: 10.1074/jbc.272.37.23371. [DOI] [PubMed] [Google Scholar]
  57. Tran Van Nhieu G., Ben-Ze'ev A., Sansonetti P. J. Modulation of bacterial entry into epithelial cells by association between vinculin and the Shigella IpaA invasin. EMBO J. 1997 May 15;16(10):2717–2729. doi: 10.1093/emboj/16.10.2717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Tran Van Nhieu G., Caron E., Hall A., Sansonetti P. J. IpaC induces actin polymerization and filopodia formation during Shigella entry into epithelial cells. EMBO J. 1999 Jun 15;18(12):3249–3262. doi: 10.1093/emboj/18.12.3249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Vasselon T., Mounier J., Hellio R., Sansonetti P. J. Movement along actin filaments of the perijunctional area and de novo polymerization of cellular actin are required for Shigella flexneri colonization of epithelial Caco-2 cell monolayers. Infect Immun. 1992 Mar;60(3):1031–1040. doi: 10.1128/iai.60.3.1031-1040.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wassef J. S., Keren D. F., Mailloux J. L. Role of M cells in initial antigen uptake and in ulcer formation in the rabbit intestinal loop model of shigellosis. Infect Immun. 1989 Mar;57(3):858–863. doi: 10.1128/iai.57.3.858-863.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Watarai M., Funato S., Sasakawa C. Interaction of Ipa proteins of Shigella flexneri with alpha5beta1 integrin promotes entry of the bacteria into mammalian cells. J Exp Med. 1996 Mar 1;183(3):991–999. doi: 10.1084/jem.183.3.991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Watarai M., Kamata Y., Kozaki S., Sasakawa C. rho, a small GTP-binding protein, is essential for Shigella invasion of epithelial cells. J Exp Med. 1997 Jan 20;185(2):281–292. doi: 10.1084/jem.185.2.281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Way S. S., Borczuk A. C., Dominitz R., Goldberg M. B. An essential role for gamma interferon in innate resistance to Shigella flexneri infection. Infect Immun. 1998 Apr;66(4):1342–1348. doi: 10.1128/iai.66.4.1342-1348.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Way S. S., Borczuk A. C., Goldberg M. B. Adaptive immune response to Shigella flexneri 2a cydC in immunocompetent mice and mice lacking immunoglobulin A. Infect Immun. 1999 Apr;67(4):2001–2004. doi: 10.1128/iai.67.4.2001-2004.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Way S. S., Borczuk A. C., Goldberg M. B. Thymic independence of adaptive immunity to the intracellular pathogen Shigella flexneri serotype 2a. Infect Immun. 1999 Aug;67(8):3970–3979. doi: 10.1128/iai.67.8.3970-3979.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Yan H. C., Juhasz I., Pilewski J., Murphy G. F., Herlyn M., Albelda S. M. Human/severe combined immunodeficient mouse chimeras. An experimental in vivo model system to study the regulation of human endothelial cell-leukocyte adhesion molecules. J Clin Invest. 1993 Mar;91(3):986–996. doi: 10.1172/JCI116320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Zwillich S. H., Duby A. D., Lipsky P. E. T-lymphocyte clones responsive to Shigella flexneri. J Clin Microbiol. 1989 Mar;27(3):417–421. doi: 10.1128/jcm.27.3.417-421.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zychlinsky A., Fitting C., Cavaillon J. M., Sansonetti P. J. Interleukin 1 is released by murine macrophages during apoptosis induced by Shigella flexneri. J Clin Invest. 1994 Sep;94(3):1328–1332. doi: 10.1172/JCI117452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Zychlinsky A., Kenny B., Ménard R., Prévost M. C., Holland I. B., Sansonetti P. J. IpaB mediates macrophage apoptosis induced by Shigella flexneri. Mol Microbiol. 1994 Feb;11(4):619–627. doi: 10.1111/j.1365-2958.1994.tb00341.x. [DOI] [PubMed] [Google Scholar]
  70. Zychlinsky A., Prevost M. C., Sansonetti P. J. Shigella flexneri induces apoptosis in infected macrophages. Nature. 1992 Jul 9;358(6382):167–169. doi: 10.1038/358167a0. [DOI] [PubMed] [Google Scholar]
  71. Zychlinsky A., Thirumalai K., Arondel J., Cantey J. R., Aliprantis A. O., Sansonetti P. J. In vivo apoptosis in Shigella flexneri infections. Infect Immun. 1996 Dec;64(12):5357–5365. doi: 10.1128/iai.64.12.5357-5365.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. van de Verg L. L., Mallett C. P., Collins H. H., Larsen T., Hammack C., Hale T. L. Antibody and cytokine responses in a mouse pulmonary model of Shigella flexneri serotype 2a infection. Infect Immun. 1995 May;63(5):1947–1954. doi: 10.1128/iai.63.5.1947-1954.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

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