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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: http://www.grad.ucl.ac.uk/comp/2003/jointposter/gallery/index.pht?entryID=29
Virulence:
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).
Prevention:
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:
References:
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.
4. 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.
5. 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.
6. 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.
