Shigella

Etiology

Four species of Shigella are responsible for shigellosis: Shigella dysenteriae (group A), Shigella flexneri (group B), Shigella boydii (group C), and Shigella sonnei (group D). Serotypes are used to distinguish members of each group: 15, 19, 19, and 1 in groups A-D, respectively. Species/group distributions vary geographically and have important therapeutic implications because of variations in species antimicrobial susceptibility.

Epidemiology

The World Health Organization (WHO) estimates 80-165 million cases of shigellosis each year worldwide and 600,000 deaths annually. Shigella spp. are endemic to temperate and tropical climates. Most of these cases and deaths occur in developing countries where public health sanitation and hygiene are inadequate. In the U.S. Foodborne Disease Active Surveillance Network ( FoodNet ), Shigella remains the 3rd most important pathogen. In 2016 the top 3 pathogens, Salmonella , Campylobacter , and Shigella, had laboratory-confirmed incidence rates (cases per 100,000 population) of 15.74, 12.82, and 5.39, respectively. Although infection can occur at any age, children <10 yr old have the highest incidence rates, with males having an approximately 1.3-fold higher incidence than females. Approximately 70% of all episodes and 60% of all Shigella -related deaths involve children <5 yr old. Infection in the 1st 6 mo of life is rare for reasons that are not clear. Breast milk from women living in endemic areas contains antibodies to both virulence plasmid-coded antigens and lipopolysaccharides, and breastfeeding might partially explain the age-related incidence.

Asymptomatic infection of children and adults occurs frequently in endemic areas. In cases of Shigella dysentery, up to 75% of family member contacts may have asymptomatic infection. Infection with Shigella occurs most often during the warm months in temperate climates and during the rainy season in tropical climates. In industrialized societies, up to 50% of locally diagnosed cases are associated with international travel; the highest-risk travel designation is Africa, followed by Central America, South America, and parts of Asia. In recent years in the United States, travel to Haiti, the Dominican Republic, and India, in particular, have been associated with antibiotic-resistant (fluoroquinolone) S. sonnei infections. Additional risk factors include men who have sex with men (MSM), including recent U.S. outbreaks of azithromycin-resistant S. sonnei infections among affected individuals in the Midwest.

In developed countries, S. sonnei is the most common cause and S. flexneri is the 2nd most common cause of bacillary dysentery; in preindustrial societies, S. flexneri is most common, and S. sonnei 2nd in frequency. S. boydii is found primarily in India. S. dysenteriae serotype 1 tends to occur in massive epidemics, but is also endemic in Asia and Africa, where it is associated with high mortality rates (5–15%). The epidemiologic transition has favored the emergence of S. sonnei as the dominant serogroup in some countries, although the reason for this epidemiologic shift is not clear.

Contaminated food (often a salad or other item requiring extensive handling of the ingredients) and water are important vectors. Exposure to both contaminated fresh water and contaminated salt water is a risk factor for infection. Rapid spread within families, custodial institutions, and childcare centers demonstrates the ability of Shigella to be transmitted from one individual to the next and the requirement for ingestion of very few organisms to cause illness. Human challenge studies have demonstrated the high infectivity and low infectious dose for Shigella spp. Ten bacteria of the species S. sonnei and S. dysenteriae can cause dysentery. In contrast, ingestion of 10 ⁸ -10 ¹⁰ Vibrio cholerae is necessary to cause cholera.

Pathogenesis

Shigella has specialized mechanisms to survive the low gastric pH. Shigella survives the acid environment in the stomach and moves through the gut to the colon, its target organ. The basic virulence trait shared by all shigellae is the ability to invade colonic epithelial cells by turning on a series of temperature-regulated and host-dependent proteins. This invasion mechanism is encoded on a large (220 kb) plasmid that at body temperature results in synthesis of a group of polypeptides involved in cell invasion and killing. Shigellae that lose the virulence plasmid are no longer pathogenic. Enteroinvasive Escherichia coli (EIEC) that harbor a closely related plasmid containing these invasion genes behave clinically similar to shigellae (see Chapter 227 ). The virulence plasmid encodes a type III secretion system 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 through a needle-like appendage. The type III secretion system is composed of approximately 50 proteins, including the Mxi and Spa proteins involved in assembly and regulation of the type III secretion system, chaperones (IpgA, IpgC, IpgE, and Spa15), transcription activators (VirF, VirB, and MxiE), translocators (IpaB, IpaC, and IpaD), and approximately 30 effector proteins. In addition to the major plasmid-encoded virulence traits, chromosomally encoded factors are also required for full virulence.

The pathologic changes of shigellosis take place primarily in the colon. 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.

After Shigella transcytosis through M cells, it encounters resident macrophages and subverts macrophage killing by activating the inflammasome and inducing pyroptosis, apoptosis, and 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 natural killer 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. It is produced in significant amounts by S. dysenteriae serotype 1, by a subset of E. coli , which are known as enterohemorrhagic E. coli (EHEC), or Shiga toxin–producing E. coli , and occasionally by other Shigella spp. Shiga toxin inhibits protein synthesis to injure vascular endothelial cells and trigger the severe complication of hemolytic-uremic syndrome (see Chapter 227 ). Targeted deletion of the genes for other enterotoxins (ShET1 and ShET2) decreases the incidence of fever and dysentery in human challenge studies. Lipopolysaccharides are virulence factors for all shigellae; other traits are important for only a few serotypes (e.g., Shiga toxin synthesis by S. dysenteriae serotype 1 and ShET1 by S. flexneri 2a).