INTRODUCTION — Shigella species are a common cause of bacterial diarrhea worldwide, especially in resource-limited countries. Shigella organisms can survive transit through the stomach since they are less susceptible to acid than other bacteria; for this reason, as few as 10 to 100 organisms can cause disease [1]. Ingested bacteria pass into the small intestine where they multiply; large numbers of bacteria then pass into the colon, where they enter the colonic cells. Given its relatively low infectious dose, Shigella transmission can occur via direct person-to-person spread, as well as via contaminated food and water. Humans are the only natural reservoir for disease.
The epidemiology, microbiology and pathogenesis of Shigella infections will be reviewed here. The clinical manifestations, diagnosis, and treatment are discussed separately. (See "Shigella infection: Clinical manifestations and diagnosis" and "Shigella infection: Treatment and prevention in adults".)
EPIDEMIOLOGY — Bacterial dysentery due to Shigella species is a major cause of morbidity and mortality. One hundred eighty-eight million cases of Shigella diarrhea or dysentery occur annually worldwide, with 164,000 associated deaths [2]. Among children under the age of five years in low and middle income countries, Shigella species are the most common cause of dysentery and the second most common cause of diarrhea overall [3]. Shigella transmission can occur through direct person-to-person spread or from contaminated food and water. The minimal infectious dose can be transmitted directly from contaminated fingers, since intermediate bacterial replication is not required to achieve the low infectious dose.
●In resource-rich countries, most cases are transmitted by fecal-oral spread from people with symptomatic infection. Outbreaks in the United States occur predominantly in institutions such as day care centers, and less commonly by common source contamination of food or drinking water. Outbreaks have also been associated with untreated recreational water [4]; in a review of untreated recreational water outbreaks in the United States between 2000 and 2014, 14 of the 90 outbreaks with confirmed etiology (15 percent) were caused by Shigella [5]. Outbreaks among men who have sex with men, particularly with drug-resistant isolates are increasingly reported [6].
●In resource-limited countries, both fecal-oral spread and contamination of common food and water supplies are important mechanisms of transmission.
United States — In the United States, the incidence of Shigella infection has decreased substantially over the years (by 57 percent since 1996) [7]. In 2019, the average incidence of confirmed shigellosis in the United States was 4.8 cases per 100,000 population, about three to four times less frequent than Campylobacter or Salmonella infection [8]. In the United States, shigellosis predominantly affects children; in 2010, the incidence among children aged <4 years was 16.4 cases per 100,000 population, and the incidence among children aged 5 to 9 years was 11.7 cases per 100,000 population [9]. Experts estimate that the reported number of cases underestimates the true number of cases by 5- to 100-fold [10,11].
The incidence of Shigella infection is associated with poverty (with an incidence rate ratio of 3.6) and crowded living conditions (incidence rate ratio 1.8) [12]. It is also higher among both Black and Hispanic persons (7.2 and 5.6, respectively, per 100,000 population) than among non-Hispanic white or Asian persons (2.6 and 1.1, respectively, per 100,000 population) [12].
In the United States, Shigella cases occur most commonly from June to October, with fewer cases occurring December to February [11].
Most cases of shigellosis in the United States are caused by Shigella sonnei (>75 percent), with Shigella flexneri the next most frequent isolate [13,14]. Shigella dysenteriae 1 (the Shiga bacillus) was the most common isolate both in Europe and the United States in the early 1900s but is now rare. In the United States, S. dysenteriae 1 infection is generally limited to imported cases from Mexico and Central America [15] or from laboratory contamination [16].
Transmission in institutions — Shigellosis in the United States is most common in day care centers and areas with crowded living conditions such as urban centers or residential institutions [17,18]. Day care center outbreaks can be particularly difficult to control; strict hand washing guidelines must be followed, and infected children must be excluded from the facility until they have recovered. Children who attend day care centers frequently introduce the infection to their families or caregivers and serve as index cases in urban outbreaks [19]. The secondary attack rate for family members or caregivers in the same household as the index case is 20 percent and is highest when the index case is between one and four years old [20].
Foodborne transmission — Foodborne outbreaks are well described. Fecal contamination can occur during cultivation; raw vegetables are the most common mode of foodborne transmission implicated in outbreaks [21].
Updated information on outbreaks may be found on websites maintained by the United States Centers for Disease Control and Prevention and the US Food and Drug Administration.
Sexual transmission in MSM — Outbreaks of shigellosis have occurred among men who have sex with men (MSM) [6,22-24]. In a study of MSM with gastroenteritis, 31 percent of the 151 episodes in which a pathogen was identified in stool involved Shigella [25]. In resource-rich settings, a high percentage of domestically-acquired Shigella infection and intercontinental transmissions, particularly of azithromycin-resistant isolates, has been associated with MSM [24,26-28]. (See "Shigella infection: Treatment and prevention in adults", section on 'Antimicrobial resistance'.)
Resource-limited settings — In sub-Saharan Africa and south Asia, Shigella is the most common cause of moderate to severe diarrhea among children younger than five years old [3]. Increasingly widespread use of molecular diagnostics has increased the sensitivity of Shigella diagnostics, notably in resource-limited settings [29]. Inadequate sewage disposal is associated with high rates of Shigella transmission. A study conducted among children in the Peruvian Amazon noted an incidence of 0.34 episodes of Shigella diarrhea per year among children <6 years of age [30].
In many resource-limited countries, S. flexneri is the predominant species; S. sonnei is the second most prevalent [31]. However, S. sonnei has become the most common isolate in Vietnam [32,33], raising the likelihood that it will become the predominant species in parts or all of Southeast Asia.
Breast feeding appears to confer significant protection against shigellosis and should be encouraged as a preventive measure [34].
MICROBIOLOGY — Shigella are nonmotile, facultatively anaerobic, gram-negative rods. They are members of the family Enterobacteriaceae, genus Shigella. There are four species of Shigella: S. dysenteriae (serogroup A), S. flexneri (serogroup B), Shigella boydii (serogroup C), and S. sonnei (serogroup D). Groups A, B, and C cannot be distinguished biochemically; S. sonnei can be differentiated from the other serogroups by the expression of ornithine decarboxylase.
Stool culture — Shigella is cultured by techniques that are routine for the handling of stool in most clinical microbiology laboratories. Initial inoculation should be on more than one low selectivity medium, such as MacConkey or eosin methylene blue. Colonies that appear suspicious on low selectivity media are usually subcultured onto highly selective media such as SS (Salmonella-Shigella), XLD (xylose-lysine-deoxycholate), HE (hektoen enteric), or deoxycholate citrate agar (picture 1).
All the above media contain lactose, as well as a color indicator. Shigella do not ferment lactose (they are lactose non-fermenters). At 24 hours, lactose-negative colonies are picked and inoculated onto triple sugar iron agar or lysine iron agar slants (picture 2). Shigella colonies give an alkaline slant, acid at the bottom, and no gas or hydrogen sulfide production. In the setting of possible exposure to S. dysenteriae 1 (eg, travel to an endemic area such as Southeast Asia or the Indian subcontinent), the use of more than one selective medium is warranted [35].
Suspicious colonies can be further tested for motility and certain biochemical characteristics. Shigella are non-flagellated and are therefore non-motile. In addition, Shigella are indole positive, urea and oxidase negative, and ferment glucose (picture 3A-B).
Further classification can be pursued including identification of serogroup and serotype, although these are rarely important to clinical management, and these studies are not performed in most clinical laboratories (picture 4). Serotype is determined by the structure of the repeating oligosaccharide that constitutes the O-antigen of the lipopolysaccharide layer of the bacterial envelope. In addition, a variety of deoxyribonucleic acid (DNA) probes of plasmid-encoded virulence determinants and ELISA of virulence proteins are available for use in the detection of Shigella.
Molecular diagnostics — A variety of molecular diagnostics techniques, including US Food and Drug Administration-approved multiplex molecular panels, are used in the diagnosis of Shigella in stool. Polymerase chain reaction has been used to detect Shigella-specific DNA sequences, frequently a group of Shigella-specific genes known as invasion plasmid antigen H (ipaH), which enables the detection of as few as 10 to 100 S. flexneri organisms (as compared with 10(6) organisms detected by routine culture) [36,37]. These molecular assays are becoming increasingly available in clinical laboratories [29,38].
PATHOGENESIS — The inoculum required for the development of clinical disease is quite low. Clinical disease was observed in 39 percent of volunteer subjects who received an inoculum of 100 S. flexneri organisms or 200 S. dysenteriae 1 organisms [39]. The minimum infectious inoculum for Salmonella in normal subjects is at least two orders of magnitude higher than for Shigella [40].
Colonic entry — The pathogenesis of Shigella involves invasion of colonic mucosal cells and induction of an intense inflammatory response, leading to the death of epithelial and immune cells and the formation of colonic mucosal ulcerations and abscesses. Shigella infection of mammalian cells involves entry of bacteria by induced macropinocytosis, escape from the macropinocytic vacuole, multiplication and spread within the cytoplasm, and direct passage into adjacent cells by way of finger-like protrusions of the cell membrane [41,42]. Shigella is among the few pathogens capable of penetrating mammalian cells, lysing the phagocytic vacuole and surviving in the cell cytoplasm; other such organisms include enteroinvasive Escherichia coli and Listeria monocytogenes. Shigella infection is generally limited to the intestinal mucosa. Although bacteremia due to Shigella is rare [43,44], human immunodeficiency virus (HIV) is a major risk factor; in a 10-year study of 11,000 Shigella infections in Georgia, more than half of the 72 bacteremia cases occurred in individuals with HIV [45]. S. flexneri was more likely to cause bacteremia than S. sonnei, although whether this was a secondary effect of the greater prevalence of S. flexneri than S. sonnei among individuals with HIV was not explored.
In the colonic mucosa, Shigella enters both colonic enterocytes and specialized epithelial cells (M cells) that overlie mucosal lymphoid follicles. Entry via the M cells is thought to be an important route of entry in clinical infection as suggested by examination of rectal biopsies from humans infected with Shigella, in which lesions were frequently located over lymphoid follicles [46].
Macropinocytosis and cytoskeletal signaling — Colonic enterocytes do not normally take up microorganisms; Shigella triggers its entry by a process involving bacterium-induced macropinocytosis [41,47]. Shigella enter enterocytes most efficiently via the cell's basolateral surfaces [48] and can gain access to these surfaces from the tissue underlying the M cell, directly from an infected M cell [49], or directly from the intestinal lumen following disruption of enterocyte cell-cell junctions, induced by the transmigration of polymorphonuclear leukocytes across the epithelium [50], by Shigella-induced redistribution of cell junction proteins [51], or at sites of normal extrusion of enterocytes at the tips of villi [52].
Many alterations to host cells that are triggered by Shigella infection are specifically induced by Shigella effector proteins that are injected into the cytoplasm of host cells by a bacterial secretion system known as type 3 secretion [53,54]. Shigella-induced macropinocytosis occurs through extensive rearrangements of the host cell cytoskeleton that cause formation of large extensions of the host cell membrane, in which the bacteria become engulfed [47]. Shigella induces this process by delivering type 3 effector proteins that activate host cytoskeletal signaling pathways into the host cell.
Both the proteins that are delivered into host cells and the proteins that constitute the type 3 secretion apparatus are encoded on a large virulence plasmid carried by all virulent strains of Shigella. Homologs of these proteins exist in several other enteric gram-negative pathogens, including Salmonella typhimurium, Yersinia pestis, and enteropathogenic E. coli [53]. In Shigella, the genes that encode the effector proteins and the secretion apparatus are expressed at 37ºC (normal body temperature), but not at cooler temperatures such as those outside the human host [55], and are induced by oxygen at the surface of colonic cells [56].
Soon after uptake by induced phagocytosis, the bacterium lyses the phagocytic vacuole, releasing it into the host cell cytosol [57]. Short filaments of host cell actin then organize into a tight bundle that forms a tail several microns in length behind the bacterial body (picture 5) [42,58]. The bacterium uses this tail for movement through the cytosol and for passage into protrusions of the cell membrane (figure 1 and movie 1). The actin-based mechanisms usurped by Shigella are processes normally used by the eukaryotic cell for other purposes.
The Shigella surface protein IcsA (VirG) mediates the process of bacterial actin-based motility [42,58-61]. IcsA is unusual in that it is located on a single pole of the bacillus, the pole at which the actin tail forms [62]. IcsA binds the cellular protein neural Wiskott-Aldrich syndrome protein (N-WASP), after which N-WASP is activated at the bacterial surface by the cellular protein Toca-1 [42,63-65]. Active N-WASP in turn binds and activates the cellular complex known as Arp2/3. Arp2/3 induces both actin polymerization and cross-linking of actin filaments, thereby leading to tail formation (picture 5). As the bacterium moves forward, the tail itself remains stationary in the host cytoplasm, and disassembly of the tail occurs at its distal end [66].
Spread to adjacent cells — Shigella spreads into adjacent cells via bacterium-induced, membrane-bound protrusions from the surface of the host cell (figure 1) and (movie 2) [42]. Bacterium-containing protrusions are engulfed and taken up by adjacent cells, thereby transferring the bacterium into the adjacent cell. Thereafter, the bacterium lyses the membranes that surround it, freeing itself into the cytoplasm of the new cell.
This mechanism of cell-to-cell passage enables the bacteria to spread from host cell to host cell without being retained within a true macropinocytic vacuole or having contact with the contents of the intestinal lumen. By remaining within the cytoplasm, the microorganism evades the toxic consequences of phagolysosomal fusion as well as other elements of the host defense system.
Eukaryotic cells, both immune cells and nonimmune cells, are able to degrade abnormal cytosolic molecules and particles, including infecting bacteria, by a variety of processes. Shigella effector proteins that are secreted into the host cell cytoplasm via the type 3 secretion apparatus inhibit multiple cellular response pathways, thereby enhancing the ability of Shigella to survive within the cell [54].
Elaboration of toxins — Shigella strains elaborate three distinct enterotoxins: the virulence plasmid-encoded ShET2 (produced by all four species) [67], chromosomally-encoded ShET1 (produced by S. flexneri 2a) [68-70], and Shiga toxin (Stx) (produced by S. dysenteriae 1) [71]. S. sonnei and S. flexneri isolates that produce Stx have been identified, particularly in California and in individuals returning from Hispaniola, respectively [72,73]. These enterotoxins induce intestinal secretion of solutes and water. With the exception of Stx, the contribution of each of these toxins to the disease process is probably minor, since nontoxigenic strains cause significant disease.
Eight percent of children infected with S. dysenteriae 1 develop the hemolytic-uremic syndrome (HUS), which is mediated by Stx [74]. Stx is genetically and structurally similar to the Stx1 and Stx2 toxins produced by certain E. coli strains, such as enterohemorrhagic E. coli O157:H7, and the incidence of HUS among infected children is similar to for the two pathogens. Some S. flexneri and S. sonnei also produce Stx and thus have the potential to cause HUS, but no such cases have yet been reported. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Shiga toxin-induced TMA (ST-HUS)'.)
Immune response — The pocket formed within M cells and the underlying tissue is rich in macrophages, B and T lymphocytes, and dendritic cells [75]. When taken up by macrophages or epithelial cells, Shigella induce cell death by a variety of pathways with the release of proinflammatory cytokines [54].
Rectal biopsies from patients with acute Shigella diarrhea demonstrate intense acute inflammatory infiltrates with neutrophils and plasma cells in almost all samples [46]. The acute inflammatory response to Shigella invasion is clearly a major contributor to symptoms and the disease process.
Shigella modulates the innate immune response by secreting bacterial proteins capable of altering immune signaling pathways in host cells [54]. These effector proteins variably block recognition of intracellular bacteria by the innate immune system [76,77], caspase activation [78,79], block induction of NFkB signaling [80], alter signaling via the MAPK kinase pathway [80-83], and alter transcription of immunomodulatory proteins [84]. In addition, Shigella inhibits both T cell migration and the development of antigen-specific T cell responses [85,86].
Immunity following natural infection appears to occur, as evidenced by the observation that disease due to endemic Shigella species occurs primarily in children, whereas disease due to epidemic species occurs in all age groups [87]. Immune protection appears to be serotype-specific [87-91]. Serotype is determined by the O polysaccharide composition, and multiple serotypes have been described [92]. A significant component of naturally-acquired protection may be mediated by a specific response to the polysaccharide component of bacterial lipopolysaccharide. The significance of antibody responses to antigens other than lipopolysaccharide (eg, IpaBCD, IcsA, or ShETs) is not known.
No safe and effective Shigella vaccine is commercially available, although several are in advanced stages of human trials [93]. Because many that are promising appear to generate immunity only to the serotype contained in the vaccine, strategies include the combination of antigens specific to the most prevalent serotypes [93].
SUMMARY
●Bacterial dysentery due to Shigella species is a major cause of morbidity and mortality. In resource-limited settings, Shigella is the most common cause of dysentery and the second most common cause of diarrhea in young children. (See 'Epidemiology' above.)
●In resource-rich countries, most cases of Shigella are transmitted by fecal-oral spread from people with symptomatic infection. In resource-limited countries, both fecal-oral spread and contamination of common food and water supplies are important mechanisms of transmission. (See 'Epidemiology' above.)
●Shigella are nonmotile, facultatively anaerobic, gram-negative rods. There are four species of Shigella: Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei. In resource-limited countries, S. flexneri is the predominant species; S. sonnei is the second most prevalent. Most cases of shigellosis in the United States are caused by S. sonnei; S. flexneri is the next most frequent isolate. S. dysenteriae 1 (the Shiga bacillus) was the most common isolate both in Europe and the United States in the early 1900s but is now rare. In the United States, S. dysenteriae 1 infection is generally limited to imported cases from Mexico and Central America. (See 'Microbiology' above.)
●Shigella organisms can survive transit through the stomach since they are less susceptible to acid than many other bacteria. For this reason, the inoculum required for the development of clinical disease is quite low; as few as 10 to 100 organisms can cause disease. (See 'Introduction' above.)
●The pathogenesis of Shigella infection involves invasion of colonic mucosal cells and induction of an intense inflammatory response, leading to the death of epithelial and immune cells and the formation of colonic mucosal ulcerations and abscesses. Shigella-induced macropinocytosis occurs through extensive rearrangements of the host cell cytoskeleton that cause formation of large extensions of the host cell membrane, in which the bacteria become engulfed. Thereafter, the bacteria spreads from host cell to host cell without having contact with the contents of the intestinal lumen. (See 'Colonic entry' above and 'Macropinocytosis and cytoskeletal signaling' above and 'Spread to adjacent cells' above.)
●S. dysenteriae 1 can cause the hemolytic-uremic syndrome (HUS), mediated by Shiga toxin (Stx). Stx is genetically and structurally similar to the Stx1 and Stx2 toxins produced by certain Escherichia coli strains, such as enterohemorrhagic E. coli O157:H7. Some S. flexneri and S. sonnei also produce Stx and thus have the potential to cause HUS, but no such cases have yet been reported. (See 'Elaboration of toxins' above.)
●Immunity following natural infection appears to occur, as evidenced by the observation that disease due to endemic Shigella species occurs primarily in children, while disease due to epidemic species occurs in all age groups. (See 'Immune response' above.)
