Shigella flexneri



Shigella flexneri, a facultative anaerobe belonging to the family Enterobacteriaceae, is a Gram-negative rod that is the causative agent of diarrhea and dysentery in humans.  Potentially life-threatening, S. flexneri's effects include bacteremia, hemolytic uremic syndrome (HUS) and toxic megacolon (4).   The principle disease of diarrhea and dysentery caused by this pathogen is known as shigellosis.  10-100 organisms are sufficient to cause disease, and transmission is generally from person-to-person by way of fecal-oral (2).  Shigellosis can be characterized as a disease with over 60% incidence in children ages 1-5 (6).

Life cycle

S. flexneri causes infection via bacterial penetration of the mucous membrane in the human colon.  Humans are the only known reservoir to this pathogen (7).  Following invasion of M cells and upon contact with the epithelial cells of the colon, S. flexneri releases Ipa proteins through a type three secretion system.   Once inside the host cell, Ipa proteins activate small GTPases in the Rho family as well as c-src, a protooncogene, leading to cytoskeletal rearrangements.  This alteration to the cytoskeleton allows the bacteria to be macropinocytosed by the host cell.   Once inside the host, the pathogen colonizes the cytoplasm.  IcsA, a bacterial surface protein, activates the host protein N-WASP and, in turn, stimulates actin assembly by host Arp 2/3.  Thus, S. flexneri develops actin-based motility enabling the pathogen to become efficient at cell-to-cell spread and host cell cytoplasmic colonization.   Infected cells become highly proinflammatory and secrete IL-8.  IL-8 attracts neutrophils to the site of infection.  The influx of neutrophils, chemokines and cytokines to the area damages the epithelial layer permeability and, in turn, advocates further S. flexneri invasion (6).   Once initial invasion of S. flexneri occurs, the targeted epithelial cells require 45 minutes to 4 hours to mount an inflammatory response (8).

A diagram outlining S. flexneri's type three secretion system can be viewed at:



A 214-kb virulence plasmid encodes for S. flexneri's entry into human epithelial cells and intra-intercellular movement (6).  Once in contact with the target cell, Ipa proteins (IpaB, IpaC and Ipa D) encode for a specific type III secretion system, thus, enabling entry of the pathogen into the target cell and characterizing S. flexneri with an invasive phenotype (1).   One 30-kb block of the plasmid contains genes at the ipa/mxi-spa locus.  This block is recognized as S. flexneri's main pathogenicity island.  This locus is solely responsible for the genes encoding for epithelial entry of the pathogen by macropinocytosis, activation of neutrophils and programmed macrophage death.   

Epidemiological data

Typically, shigellosis by S. flexneri is considered a third world disease.  Approximately 150 million cases per year of shigellosis are reported in third world countries as compared to about 1.5 million cases per year in developed countries (6).   It accounts for approximately 1 million deaths per year worldwide.  In the United States, 208,368 cases of shigellosis were reported to the Center of Disease Control and Prevention from 1989-2002.   S. flexneri accounted for 18.4% of these cases (4).   Regional variation in incidence is seen in shigellosis by S. flexneri in the United States.  Higher incidence is typically seen in the South and West (2).  California has the highest incidence in the United States with 0.41 cases per 100,000 people in June.   This number can be compared to Connecticut's incidence of 0.03 cases per 100,000 people in the same month of 2001 (3).  
   The highest incidence of S. flexneri infection is seen in children aged 1-4.  In addition, S. flexneri also shows high incidence in the 30-39 age group.  Incidence of S. flexneri infections is considerably more prevalent in homosexual males, HIV positive individuals, AIDS patients and in those who participate in sexual oral-anal contact.   This pathogen typically infects men approximately twice as frequently as it infects women: 2.3 cases/100,000 people for males, 1.2 cases/100,000 people for females.  Once contracted, 20% of S. flexneri infections require hospitalization (2).


Treatment of shigellosis has been complicated by the development of multi-antibiotic resistant strains in high incidence areas (6).  Shigellosis by S. flexneri can be nearly prevented by good hygiene.  In particular, people involved in food preparation and service must be disciplined in proper sanitation techniques and given adequate bathroom facilities (5).   Impoverished countries may not have access to appropriate bathroom facilities to support their populations.  Thus, spread of shigellosis with persist and continue to plague developing countries.

Shigella flexneri featuring LINKS:



1. Bartoleschi, C., M.C. Pardini, C. Scaring, M.C. Martino, C. Pazzani and M.L. Bernardini. 2002.  Selection of Shigella flexneri candidate virulence genes specifically induced in bacteria resident in host cell cytoplasm.  Cellular Microbiology. 4(9): 613-626.

2.  Beletshachew, S., S. Shallow, R. Marcus, S. Segler, D. Soderlund, F.P. Hardnett and T. Van Gilder.  2004.  Trends in Population-Based Active Surveillance for Shigellosis and Demographic Variability in FoodNet Sites, 1996-1999.  Clinical Infectious Diseases.   38: S175-S180.

3.  Gupta, A., C.S. Polyak, R.D. Bishop, J. Sobel and E.D. Mintz.  2004.    Laboratory-Confirmed Shigellosis in the United States, 1989-2002:  Epidemiologic Trends and Patterns.  Center for Infectious Disease.  38: 1372-1377. 

4.  Lew, J.F., D.L. Swerdlow, M.E. Dance, P.M. Griffin, C.A. Bopp, M.J. Gillenwater, T. Mercatante, R.I. Glass.  1991.  An outbreak of shigellosis aboard a cruise ship caused by a multiple-antibiotic-resistant strain of Shigella flexneri.   American Journal of Epidemiology.  134(4): 413-420.

5.  Sansonetti, P.J.  2001.  Microbes and Microbial Toxins:  Paradigms for Microbial-Mucosal Interactions, III. Shigellosis: from symptoms to molecular pathogenesis.  American Physiological Society.  280: G319-G323.

7.  Schaechter, M., N.C. Engleberg, B.I. Eisenstein and G. Medoff.  1999.  Mechanisms of Microbial Disease (3rd edition).  Lippincott Williams and Wilkins.  Philadelphia, PA. (p. 178).

8.  Thierry, P., C. Thibault and P.J. Sansonetti.  2003.  The Invasive Phenotype of Shigella flexneri Directs a Distinct Gene Expression Pattern in the Human Intestinal Epithelial Cell Line Caco-2.  The Journal of Biological Chemistry.   278(36): 33878-33886.