Chapter 191 Shigella Theresa J. Ochoa, Thomas G. Cleary Shigella causes an acute invasive enteric infection clinically manifested by diarrhea that is often bloody. The term dysentery is used to describe the syndrome of bloody diarrhea with fever, abdominal cramps, rectal pain, and mucoid stools. Bacillary dysentery is a term often used to distinguish dysentery caused by Shigella from amoebic dysentery caused by Entamoeba histolytica. Etiology Four species of Shigella are responsible for bacillary dysentery: S. dysenteriae (serogroup A), S. flexneri (serogroup B), S. boydii (serogroup C), and S. sonnei (serogroup D). There are 13 serotypes in group A, six serotypes and 15 subserotypes in group B, 18 serotypes in group C, and one serotype in group D. Species classification has important therapeutic implications because the species differ in both geographic distribution and antimicrobial susceptibility. Epidemiology It is estimated that there are approximately 165 million cases of shigellosis each year, resulting in >1 million deaths; most of these cases and deaths occur in developing countries. In the USA, approximately 14,000 cases per year are documented. Although infection can occur at any age, it is most common in the 2nd and 3rd years of life. Approximately 70% of all episodes and 60% of all Shigella-related deaths involve children <5 years old. Infection in the first 6 mo of life is rare for reasons that are not clear. Breast milk contains antibodies to both virulence plasmid-coded antigens and lipopolysaccharides in endemic areas, and breast-feeding might partially explain the age-related incidence. Asymptomatic infection of children and adults occurs commonly in endemic areas. Infection with Shigella occurs most often during the warm months in temperate climates and during the rainy season in tropical climates. Both sexes are affected equally. In industrialized societies, S. sonnei is the most common cause of bacillary dysentery, with S. flexneri second in frequency; in preindustrial societies, S. flexneri is most common, with S. sonnei second in frequency. S. boydii is found primarily in India. S. dysenteriae serotype 1 tends to occur in massive epidemics, although it is also endemic in Asia and Africa, where it is associated with high mortality rates (5-15%). Contaminated food (often a salad or other item requiring extensive handling of the ingredients) and water are important vectors. Exposure to both fresh and saltwater is a risk factor for infection. Rapid spread within families, custodial institutions, and child-care centers demonstrates the ability of shigellae to be transmitted from one individual to the next and the requirement for ingestion of very few organisms to cause illness. As few as 10 S. dysenteriae serotype 1 organisms can cause dysentery. In contrast, ingestion of 108-1010 Vibrio cholerae is necessary to cause cholera. Pathogenesis The basic virulence trait shared by all shigellae is the ability to invade intestinal epithelial cells. This characteristic is encoded on a large (220 Kb) plasmid that is responsible for synthesis of a group of polypeptides involved in cell invasion and killing. Shigellae that lose the virulence plasmid are no longer pathogenic. Escherichia coli that harbor a closely related plasmid containing these invasion genes (enteroinvasive E. coli) behave clinically like shigellae. The virulence plasmid encodes a type III secretion system (TTSS) required to trigger entry into epithelial cells and apoptosis in macrophages. This secretion system translocates effector molecules from the bacterial cytoplasm to the membrane and cytoplasm of target host cells. The TTSS is composed of approximately 50 proteins, including Mxi and Spa proteins involved in assembly and regulation of the TTSS, chaperones (IpgA, IpgC, IpgE, and Spa15), transcription activators (VirF, VirB, and MxiE), translocators (IpaB, IpaC, and IpaD), and approximately 25 effector proteins. In addition to the major plasmid-encoded virulence traits, chromosomally encoded factors are also required for full virulence. Shigella passes the epithelial cell barrier by transcytosis through M cells and encounters resident macrophages. The bacteria evade degradation in macrophages by inducing apoptosis, which is accompanied by proinflammatory signaling. Free bacteria invade the epithelial cells from the basolateral side, move into the cytoplasm by actin polymerization, and spread to adjacent cells. Proinflammatory signaling by macrophages and epithelial cells further activates the innate immune response involving NK cells and attracts polymorphonuclear leukocytes (PMNs). The influx of PMNs disintegrates the epithelial cell lining, which initially exacerbates the infection and tissue destruction by facilitating the invasion of more bacteria. Ultimately, PMNs phagocytose and kill Shigella, thus contributing to the resolution of the infection. Some shigellae make toxins including Shiga toxin and enterotoxins. Shiga toxin is a potent exotoxin that inhibits protein synthesis and is produced in significant amounts by S. dysenteriae serotype 1, by a subset of E. coli, which are known as Shiga toxin–producing E. coli (STEC), and occasionally by other organisms. This toxin mediates the severe complication of hemolytic-uremic syndrome (HUS). It is unclear whether the watery diarrhea phase of shigellosis is caused by one of the other enterotoxins. Targeted deletion of the genes for enterotoxins (ShET1 and ShET2) decreased the incidence of fever and dysentery in volunteers during vaccine-development studies. Lipopolysaccharides are virulence factors for all shigellae; other traits are important for only a few serotypes (e.g., Shigatoxin synthesis by S. dysenteriae serotype 1 and ShET1 by S. flexneri 2a). The pathologic changes of shigellosis take place primarily in the colon, the target organ for Shigella. The changes are most intense in the distal colon, although pancolitis can occur. Shigellae cross the colonic epithelium through M cells in the follicle-associated epithelium overlying the Peyer patches. Grossly, localized or diffuse mucosal edema, ulcerations, friable mucosa, bleeding, and exudate may be seen. Microscopically, ulcerations, pseudomembranes, epithelial cell death, infiltration extending from the mucosa to the muscularis mucosae by PMNs and mononuclear cells, and submucosal edema occur. Immunity Innate immunity to Shigella infection is characterized by the induction of acute inflammation with massive recruitment of PMNs and subsequently massive tissue destruction. In humans, analysis of cytokine expression in rectal biopsies of infected patients at the acute phase of the disease has revealed upregulation of proinflammatory genes, such as those encoding interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and TNF-β, although antiinflammatory genes encoding IL-10 and TGF-β are also upregulated. Control of Shigella invasion in intestinal epithelial cells depends on interferon (IFN)-γ. Shigella-specific immunity elicited upon natural infection is characterized by the induction of a humoral response. Local secretory IgA and serum IgG are produced against LPS and some protein effectors (Ipas). Natural protective immunity arises only after several episodes of infection, is of short duration, and seems to be effective in limiting reinfection, particularly in young children. Clinical Manifestations and Complications Only gold members can continue reading. 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Chapter 191 Shigella Theresa J. Ochoa, Thomas G. Cleary Shigella causes an acute invasive enteric infection clinically manifested by diarrhea that is often bloody. The term dysentery is used to describe the syndrome of bloody diarrhea with fever, abdominal cramps, rectal pain, and mucoid stools. Bacillary dysentery is a term often used to distinguish dysentery caused by Shigella from amoebic dysentery caused by Entamoeba histolytica. Etiology Four species of Shigella are responsible for bacillary dysentery: S. dysenteriae (serogroup A), S. flexneri (serogroup B), S. boydii (serogroup C), and S. sonnei (serogroup D). There are 13 serotypes in group A, six serotypes and 15 subserotypes in group B, 18 serotypes in group C, and one serotype in group D. Species classification has important therapeutic implications because the species differ in both geographic distribution and antimicrobial susceptibility. Epidemiology It is estimated that there are approximately 165 million cases of shigellosis each year, resulting in >1 million deaths; most of these cases and deaths occur in developing countries. In the USA, approximately 14,000 cases per year are documented. Although infection can occur at any age, it is most common in the 2nd and 3rd years of life. Approximately 70% of all episodes and 60% of all Shigella-related deaths involve children <5 years old. Infection in the first 6 mo of life is rare for reasons that are not clear. Breast milk contains antibodies to both virulence plasmid-coded antigens and lipopolysaccharides in endemic areas, and breast-feeding might partially explain the age-related incidence. Asymptomatic infection of children and adults occurs commonly in endemic areas. Infection with Shigella occurs most often during the warm months in temperate climates and during the rainy season in tropical climates. Both sexes are affected equally. In industrialized societies, S. sonnei is the most common cause of bacillary dysentery, with S. flexneri second in frequency; in preindustrial societies, S. flexneri is most common, with S. sonnei second in frequency. S. boydii is found primarily in India. S. dysenteriae serotype 1 tends to occur in massive epidemics, although it is also endemic in Asia and Africa, where it is associated with high mortality rates (5-15%). Contaminated food (often a salad or other item requiring extensive handling of the ingredients) and water are important vectors. Exposure to both fresh and saltwater is a risk factor for infection. Rapid spread within families, custodial institutions, and child-care centers demonstrates the ability of shigellae to be transmitted from one individual to the next and the requirement for ingestion of very few organisms to cause illness. As few as 10 S. dysenteriae serotype 1 organisms can cause dysentery. In contrast, ingestion of 108-1010 Vibrio cholerae is necessary to cause cholera. Pathogenesis The basic virulence trait shared by all shigellae is the ability to invade intestinal epithelial cells. This characteristic is encoded on a large (220 Kb) plasmid that is responsible for synthesis of a group of polypeptides involved in cell invasion and killing. Shigellae that lose the virulence plasmid are no longer pathogenic. Escherichia coli that harbor a closely related plasmid containing these invasion genes (enteroinvasive E. coli) behave clinically like shigellae. The virulence plasmid encodes a type III secretion system (TTSS) required to trigger entry into epithelial cells and apoptosis in macrophages. This secretion system translocates effector molecules from the bacterial cytoplasm to the membrane and cytoplasm of target host cells. The TTSS is composed of approximately 50 proteins, including Mxi and Spa proteins involved in assembly and regulation of the TTSS, chaperones (IpgA, IpgC, IpgE, and Spa15), transcription activators (VirF, VirB, and MxiE), translocators (IpaB, IpaC, and IpaD), and approximately 25 effector proteins. In addition to the major plasmid-encoded virulence traits, chromosomally encoded factors are also required for full virulence. Shigella passes the epithelial cell barrier by transcytosis through M cells and encounters resident macrophages. The bacteria evade degradation in macrophages by inducing apoptosis, which is accompanied by proinflammatory signaling. Free bacteria invade the epithelial cells from the basolateral side, move into the cytoplasm by actin polymerization, and spread to adjacent cells. Proinflammatory signaling by macrophages and epithelial cells further activates the innate immune response involving NK cells and attracts polymorphonuclear leukocytes (PMNs). The influx of PMNs disintegrates the epithelial cell lining, which initially exacerbates the infection and tissue destruction by facilitating the invasion of more bacteria. Ultimately, PMNs phagocytose and kill Shigella, thus contributing to the resolution of the infection. Some shigellae make toxins including Shiga toxin and enterotoxins. Shiga toxin is a potent exotoxin that inhibits protein synthesis and is produced in significant amounts by S. dysenteriae serotype 1, by a subset of E. coli, which are known as Shiga toxin–producing E. coli (STEC), and occasionally by other organisms. This toxin mediates the severe complication of hemolytic-uremic syndrome (HUS). It is unclear whether the watery diarrhea phase of shigellosis is caused by one of the other enterotoxins. Targeted deletion of the genes for enterotoxins (ShET1 and ShET2) decreased the incidence of fever and dysentery in volunteers during vaccine-development studies. Lipopolysaccharides are virulence factors for all shigellae; other traits are important for only a few serotypes (e.g., Shigatoxin synthesis by S. dysenteriae serotype 1 and ShET1 by S. flexneri 2a). The pathologic changes of shigellosis take place primarily in the colon, the target organ for Shigella. The changes are most intense in the distal colon, although pancolitis can occur. Shigellae cross the colonic epithelium through M cells in the follicle-associated epithelium overlying the Peyer patches. Grossly, localized or diffuse mucosal edema, ulcerations, friable mucosa, bleeding, and exudate may be seen. Microscopically, ulcerations, pseudomembranes, epithelial cell death, infiltration extending from the mucosa to the muscularis mucosae by PMNs and mononuclear cells, and submucosal edema occur. Immunity Innate immunity to Shigella infection is characterized by the induction of acute inflammation with massive recruitment of PMNs and subsequently massive tissue destruction. In humans, analysis of cytokine expression in rectal biopsies of infected patients at the acute phase of the disease has revealed upregulation of proinflammatory genes, such as those encoding interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, and TNF-β, although antiinflammatory genes encoding IL-10 and TGF-β are also upregulated. Control of Shigella invasion in intestinal epithelial cells depends on interferon (IFN)-γ. Shigella-specific immunity elicited upon natural infection is characterized by the induction of a humoral response. Local secretory IgA and serum IgG are produced against LPS and some protein effectors (Ipas). Natural protective immunity arises only after several episodes of infection, is of short duration, and seems to be effective in limiting reinfection, particularly in young children. Clinical Manifestations and Complications Only gold members can continue reading. Log In or Register to continue Share this: Share on X (Opens in new window) X Share on Facebook (Opens in new window) Facebook Related Related posts: Rumination, Pica, and Elimination (Enuresis, Encopresis) Disorders Adolescent Pregnancy Yersinia Fever without a Focus Stay updated, free articles. Join our Telegram channel Join Tags: Nelson Textbook of Pediatrics Expert Consult Jun 18, 2016 | Posted by admin in PEDIATRICS | Comments Off on Shigella Full access? Get Clinical Tree
