Shigella and the Shiga toxin

[Introduction]  [Mechanism/Pathogenesis]  [Effects]  [Treatment]  [References/Links]  [Goofy Mouse]

Coutesy of UCS:

Shigella dysenteriae cause a Bacillary dysentery disease.
The bacteria release the Shiga exotoxin that inhibits
protein sythesis by lysing 28S rRNA.


    Shigella belong to the bacterial family, Enterobacteriaciae, and can occur as the four different species:

Shigella dysenteriae
Shigella flexneri
Shigella sonnei
Shigella boydii

    They are gram-negative, citrate negative, H2S negative, lysine decarboxylase negative, non-lactose fermenting, bile salt resistant, facultative anaerobes that are non-motile and posses a capsule (K antigen) and an O antigen.  These bacteria typically effect the higher primates, specifically, humans.

    All four species produce a similar disease, shigellosis, which may vary in intensity, but elicits similar symptions in the host.  Shigella are said to be the major cause of diarrheal disease and infant mortality throughout the developing nations of the world, and cause an estimated 15-20% of pediatric diarrhea in the United States.  The species Shigella sonnei is the most comon cause of the disease, shigellosis in the United States and other developed countries, while Shigella flexneri is the most common cause of shigellosis in underdeveloped nations.  However, the species that causes the most serious symptoms (including dysentery) is Shigella dysenteriae.  This species occurs most frequently in the Eastern Hemisphere.

    Only a small number of cells are required for infection (200), thus shigella are spread easily via a fecal-oral route, or even from direct person-to-person contact.  Their generation time is about 40 minutes, and the incubation period is only 1-7 days, averaging 3 days.  Ingestion of contaminated food or water is also a mode of infection, making proper sewage disposal and water treatment necessary steps for prevention.  Because of its association with crowded or poor living conditions, this bacteria is often spread among people in prisons, daycare centers, mental institutions, nursing homes, and military camps.  Daycare centers prove especially susceptable to shigellosis because of the proportion of people under the age of 10yrs. Secondary transmission of the bacteria can occur, and the organism may be carried by its host for an entire month after convalescence.  Shigella can even be carried by a host for several months by establishing a "chronic carrier condition," similar to other enteric bacterial infections.


                                                                        Fig. 1: Mechanism of entry and dissemination of Shigella in epithelial cells
Shigella invade the villus cells of the large intestine by penetrating the colonic mucosa, but do not invade the blood, or perforate the intestine beyond the epithelium into the lamina propria.  Shigella enter the intestinal mucosa by attaching to, and invading lymphoid cells in Peyer's patches.  These specialized lymphoid cells are called "M cells," and normally transport foreign antigens from the intestine to underlying macrophages.  The bacteria are internalized by the epithelial cells via a process similar to phagocytosis.  This usually occurs with an endosome, but these bacteria have the ability to lyse the phagocytic vacuoles of macrophage cells and replicate in their cytoplasm (Fig 1.).  The bacteria are then spread into adjacent epithelial cells by propulsive movements of actin.  This way, the bacteria avoid antibody-mediated humoral immunity.  Shigella produce Ipa proteins in order to help escape
from the endosome, but also                                   From Parsot and Sansonetti (1996), Fig. 1, p. 27
produce them early on in order                       
to initiate a cascade of cellular
signalization that internalizes the bacteria with endosomes.
    While present in the mucosa, Shigella typically cause an inflammatory response that results in extensive tissue damage.  They release a heat-stabile lipopolysaccharide endotoxin that can cause fever.  The LPS of Gram-negative bacteria contains cell wall antigens (O antigens) that can elicit a variety of inflammatory responses in an animal. This endotoxin is part of the outer membrane of the Shigella cell, and has a low degree of specificity and a low degree of potency.  It has an MW of 10kDa, and does not show enzymatic activity.
 Shigella also use apoptosis in order to intentionally activate the host's inflammatory response.  Subsequent infiltration and diapedisis by leukocytes disrupts the tight-junction of the bowel epithelium, thus allowing a massive invasion by bacteria still in the colon, resulting in a massive invasion and degradation of the intestinal mucosa.


          Shiga Toxin Molecular Structure

    Additionally, a heat-labile exotoxin is released by Shigella dysenteriae that damages the mucosa and villi.  This toxin, Shiga toxin,  has enterotoxic, cytotoxic, and neurotoxic effects. The protein has a MW of 50-1000kDa, diffuses extracellularly, is highly potent and has a high degree of specificity.
    It causes local areas of erosion that give rise to bleeding and heavy mucous secretion.  The toxin also leads to nerve cell damage.
Shiga toxin is composed of A (enzymatic) and B (binding) subunits in a ratio of 1:5.  One component binds to the host cell surface, while the other passes into the cell membrane or cytoplasm before acting.  The B subunit binds host cell glycolipids, while the A1 domain causes inactivation of the 60S ribosomal subunit, leading to cell death from inhibition of protein synthesis.  Part of an A subunit has N-glycosidase activity on a single adenosine residue, lysing the bond between the base and ribose.  This two-domain (A-5B) structure is similar to the Shiga-like toxin of enterohemorrhagic E. Coli (EHEC), but coded by a lysogenic bacteria.


Courtesy of Marie Fasier


    In order to successfully treat a Shigella infection, it is first necessary to eliminate the source of the problem, i.e. clean up the water supply and manage waste effectively.  Likewise, eliminating crowded conditions will also decrease the risk of the bacteria spreading.  The people carrying the disease can be treated with the antibiotics Ciprofloxacin and trimethoprim-sulfamethoxazole in order to reuduce the duration of illness.  Antibiotic resistance is a major problem with Shigella.  If resistance is evident, then ampicillin or cephalosporins are prescribed.  However, the bacteria are self-limiting, and infection will pass with time in otherwise healthy individuals.  Oral vaccines have been developed, but have limited success, as they typically provide immunity from Shigella mutants and E. coli hybrids for only six months to a year.

References/Links content/2000/issue1/4310001a.pdf
Talaro, K.P.; A. Talaro: Foundations in Microbiology, Fourth Edition. (2002) pp. 619.