Shigellosis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-In-Chief: Yazan Daaboul; Serge Korjian

Overview

A small inoculum of Shigella (10 to 200 organisms) is sufficient to cause shigellosis. Shigella is commonly spread by the fecal-oral route in regions of poor sanitation (foodborne or waterborne transmission). Shigella first invades the epithelial cells of the large intestine by using M cells as entry ports for transcytosis. Shigella then invades macrophages and induces cellular apoptosis, which results in inflammation, generation of proinflammatory cytokines, and recruitment of polymorphonuclear neutrophils (PMNs). Following transcytosis and macrophage apoptosis, Shigella avoids extracellular exposure and spreads intercellularly using actin polymerization processes (rocket propulsion). As PMN invade the site of active inflammation, the integrity of the intestinal epithelial barrier is lost, and adsorption of fluids and nutrients is impaired, resulting in clinical manifestations of shigellosis (e.g. diarrhea). On gross pathology, hyperemia with development of ulcers and edema are typical findings. On microscopic pathology, infiltration of PMN and inflammatory pseudomembranes are characteristic features.

Pathophysiology

Transmission

  • A small inoculum of Shigella (10 to 200 organisms) is sufficient to cause shigellosis.[1]
  • Shigella is commonly spread by the fecal-oral route in regions with poor sanitation.[1][2]
  • Exposure to contaminated food (e.g. vegetables or meat) or water (drinking or swimming in untreated water) is associated with shigellosis. Contaminated food and water may have a normal appearance and smell.
  • Epidemics may be foodborne or waterborne.[1]
  • Shigella can also be transmitted by flies and sexual contact.[2]

Cellular Pathogenesis

The small inoculum may be attributed to the following features of the organism:

  • Shigella contains acid resistance systems that enable the organism to survive the acidic environment in the stomach.[3]
  • Shigella can downregulate the expression of antibacterial proteins released by the host (human) intestinal mucosa.[4]

Phase 1:Transcytosis Using M Cells As Entry Ports

Shigella migrates to the large intestine, where it causes infection via invasion of the epithelial barrier of the large intestine. Initially, Shigella uses M cells from the basolateral side of the intestinal epithelium as entry port.[5] M cells are specialized cells that sample the gut lumen for pathogenic antigens and delivers these antigens to mucosal lymphoid tissue to activate an adequate immune response.[6] Shigella is transcytosed across the epithelial layer of the intestinal M cells.

Phase 2:Uptake by Macrophages

Phase 3: Release from Apoptotic Macrophages

  • Following apoptosis and inflammation, Shigella is released from the macrophages.[10]
  • Invasion of the intestinal epithelium continues from the basolateral side, and the bacteria further spreads to adjacent epithelial cells and avoids extracellular exposure by using intercellular actin polymerization processes (rocket propulsion).[11]

Phase 4: Infiltration of Polymorphonuclear Neutrophils

  • As Shigella infiltrates the epithelial cells, activation of nuclear factor kappa-B (NF-KB) by Shigella generates IL-8, which in turn mediates the recruitment of polymorphonuclear neutrophils (PMN) to the site of inflammation.[12]
  • PMN destroy the integrity of the intestinal epithelial barrier and allow more Shigella organisms to directly and more easily invade the intestinal epithelium. The loss of the intestinal epithelial cells results in impaired adsorption of other nutrients and fluids and leads to clinical manifestations of shigellosis (diarrhea).[2]
  • Shigella enterotoxin 1 (ShET1) and enterotoxin 2 (ShET2) are synthesized during the inflammatory process and are thought to account, at least in part, for fluid secretion that results in shigellosis-associated diarrhea.[13]
  • Other Shigella toxins, such as Shigella dysenteriae serotype 1 toxin, results in cytotoxicity and development of vascular lesions at the level of the colon, the kidneys, and the central nervous system. The cytotoxic activity of the toxin is thought to cause shigella-associated complications, such as hemolytic uremic syndrome (HUS).[14]

Ultimately, more PMNs are recruited and Shigella organisms are killed.

Gross Pathology

On gross pathology, shigellosis is typically associated with acute-onset diffuse fibrinous exudative inflammation in the colon and/or the rectum. The following histopathological features may be observed:

Microscopic Pathology

On microscopic histopathological analysis, the following findings may be observed from samples of the colon, rectum, and occasionally the distal ileum:

The following video demonstrates the microscopic pathological features of shigellosis:

References

  1. 1.0 1.1 1.2 DuPont HL, Levine MM, Hornick RB, Formal SB (1989). "Inoculum size in shigellosis and implications for expected mode of transmission". J Infect Dis. 159 (6): 1126–8. PMID 2656880.
  2. 2.0 2.1 2.2 Schroeder GN, Hilbi H (2008). "Molecular pathogenesis of Shigella spp.: controlling host cell signaling, invasion, and death by type III secretion". Clin Microbiol Rev. 21 (1): 134–56. doi:10.1128/CMR.00032-07. PMC 2223840. PMID 18202440.
  3. Gorden J, Small PL (1993). "Acid resistance in enteric bacteria". Infect Immun. 61 (1): 364–7. PMC 302732. PMID 8418063.
  4. Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B; et al. (2001). "Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator". Nat Med. 7 (2): 180–5. doi:10.1038/84627. PMID 11175848.
  5. Wassef JS, Keren DF, Mailloux JL (1989). "Role of M cells in initial antigen uptake and in ulcer formation in the rabbit intestinal loop model of shigellosis". Infect Immun. 57 (3): 858–63. PMC 313189. PMID 2645214.
  6. Man AL, Prieto-Garcia ME, Nicoletti C (2004). "Improving M cell mediated transport across mucosal barriers: do certain bacteria hold the keys?". Immunology. 113 (1): 15–22. doi:10.1111/j.1365-2567.2004.01964.x. PMC 1782554. PMID 15312131.
  7. Zychlinsky A, Prevost MC, Sansonetti PJ (1992). "Shigella flexneri induces apoptosis in infected macrophages". Nature. 358 (6382): 167–9. doi:10.1038/358167a0. PMID 1614548.
  8. Zychlinsky A, Fitting C, Cavaillon JM, Sansonetti PJ (1994). "Interleukin 1 is released by murine macrophages during apoptosis induced by Shigella flexneri". J Clin Invest. 94 (3): 1328–32. doi:10.1172/JCI117452. PMC 295219. PMID 8083373.
  9. Sansonetti PJ, Phalipon A, Arondel J, Thirumalai K, Banerjee S, Akira S; et al. (2000). "Caspase-1 activation of IL-1beta and IL-18 are essential for Shigella flexneri-induced inflammation". Immunity. 12 (5): 581–90. PMID 10843390.
  10. Sansonetti PJ, Ryter A, Clerc P, Maurelli AT, Mounier J (1986). "Multiplication of Shigella flexneri within HeLa cells: lysis of the phagocytic vacuole and plasmid-mediated contact hemolysis". Infect Immun. 51 (2): 461–9. PMC 262354. PMID 3510976.
  11. Bernardini ML, Mounier J, d'Hauteville H, Coquis-Rondon M, Sansonetti PJ (1989). "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. 86 (10): 3867–71. PMC 287242. PMID 2542950.
  12. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jéhanno M, Viala J; et al. (2003). "Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan". Science. 300 (5625): 1584–7. doi:10.1126/science.1084677. PMID 12791997.
  13. Fasano A, Noriega FR, Liao FM, Wang W, Levine MM (1997). "Effect of shigella enterotoxin 1 (ShET1) on rabbit intestine in vitro and in vivo". Gut. 40 (4): 505–11. PMC 1027126. PMID 9176079.
  14. Cherla RP, Lee SY, Tesh VL (2003). "Shiga toxins and apoptosis". FEMS Microbiol Lett. 228 (2): 159–66. PMID 14638419.


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