Shigella

Shigella is a genus of gram-negative, non-lactose-fermenting facultative intracellular bacilli. Infection spreads most commonly via person-to-person contact or through contaminated food and water. Humans are the only known reservoir. Because it is resistant to acid, Shigella spp. survive transit through the stomach; thus, only a small amount of inoculum is needed to cause disease. Shigellosis (Shigella dysentery) results in fever, abdominal pain, and bloody diarrhea, which are effects of the toxins and epithelial-cell invasion of the organism. In the majority of cases, symptoms resolve within a few days. However, complications of dehydration, hemolytic uremic syndrome, toxic megacolon, or reactive arthritis can arise. Treatment is primarily using fluid and electrolyte replacement and antibiotics.

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Classification

Gram-negative bacteria:
Most bacteria can be classified according to a lab procedure called Gram staining.
Bacteria with cell walls that have a thin layer of peptidoglycan do not retain the crystal violet stain utilized in Gram staining. These bacteria do, however, retain the safranin counterstain and thus appear as pinkish-red on the stain, making them gram negative. These bacteria can be further classified according to morphology (diplococci, curved rods, bacilli, and coccobacilli) and their ability to grow in the presence of oxygen (aerobic versus anaerobic). The bacteria can be more narrowly identified by growing them on specific media (triple sugar iron (TSI) agar) where their enzymes can be identified (urease, oxidase) and their ability to ferment lactose can be tested.
* Stains poorly on Gram stain
** Pleomorphic rod/coccobacillus
*** Require special transport media

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General Characteristics

Shigella spp.

  • General characteristics:
    • Structure: bacilli
    • Gram stain: gram negative
    • Facultative intracellular 
    • Motility: immotile, non-flagellated
    • Lactose fermentation: non-lactose fermenting
    • Oxidase negative
    • Acid stable
    • Culture:
      • No hydrogen sulfide (H₂S) production
      • On Hektoen enteric (HE) agar: green transparent colonies
  • Associated disease: shigellosis (dysentery or Shigella diarrhea)

Clinically relevant species

Serogroups defined by specific O antigens:

  • S. dysenteriae (serogroup A)
  • S. flexneri (serogroup B)
  • S. boydii (serogroup C)
  • S. sonnei (serogroup D)

Epidemiology

  • Shigellosis worldwide: 164,000 deaths annually
  • In low- to middle-income countries: 
    • Shigella: the most common etiology of dysentery in children
    • Most common: S. flexneri, followed by S. sonnei
    • S. dysenteriae: causes epidemic dysentery
    • Insufficient sewage disposal is one of the main culprits.
  • In the United States:
    • Incidence: 4.8 cases per 100,000 population
    • Children most affected
    • Most common: S. sonnei (> 75%), S. flexneri
    • Settings:
      • Institutions such as daycare centers
      • Untreated recreational water

Pathogenesis

Reservoir and transmission

  • Reservoir: human intestinal tract
  • Transmission:
    • Contaminated food or water, usually fecal-oral transmission
    • Person-to-person contact (e.g., lack of hand washing, sexual transmission in men who have sex with men)

Mnemonic

To help remember the modes of transmission of Shigella, remember the “4 Fs:

  • Fingers
  • Flies
  • Food
  • Feces

Virulence factors

  • Endotoxin: 
    • Toxic lipopolysaccharide
    • Causes bowel-wall irritation
  • Shiga toxin
    • Produced by S. dysenteriae type 1
    • Inhibits binding of aminoacyl-tRNA to the 60S ribosome, leading to cessation of protein synthesis 
    • Causes colonic mucosal damage, leading to sloughing and dysentery
    • Other changes (noted in hemolytic uremic syndrome (HUS)):
      • The toxin is translocated into circulation and induces endothelial damage, particularly in the glomeruli.
      • Damaged endothelium causes platelet aggregation. 
      • RBCs are lysed → schistocytes/schizocytes (fragmented RBCs)
  • Shigella enterotoxin 1 (ShET1; S. flexneri) and Shigella enterotoxin 2 (ShET2; 4 species) cause fluid secretion and subsequent watery diarrhea.
  • Type III secretion system:
    • Directly delivers virulence effectors to the host cell
    • Facilitates bacterial invasion of epithelial cells
  • Resistance to gastric acids:
    • Shigella can survive the acidic environment of the stomach during transit.
    • Thus, only a small inoculum is required to produce disease.

Disease process

  • Shigella:
    • Technically immobile
    • Invade host cells (ileum and colon) by induced phagocytosis
  • Invasion:
    • Entry via microfold (M) cells of the intestinal Peyer’s patches (transcytosis):
      • M cells engulf the pathogen from the lumen and then transport it to the sub-epithelium.
      • From the M cells, the pathogen is taken up by subepithelial macrophages (also by neutrophils, dendritic cells).
      • Macrophages undergo apoptosis, and the released pathogen invades intestinal epithelial cells. 
    • During apoptosis, released cytokines recruit polymorphonuclear leukocytes (PMNs):
      • PMNs destabilize the junctions between epithelial cells, allowing the pathogen to go across the disrupted junction.
      • PMN transmigration is another entryway for Shigella sp., leading to further invasion.
    • Uptake in epithelial cells:
      • Once in the epithelial cytosol, the pathogen hijacks the host cell actin nucleators.
      • Then, the host actin filaments (actin tail) are used to move within the cell (actin-based motility (ABM)).
    • Protrusion formation and resolution:
      • ABM propels the pathogen to the membrane and a protrusion is created in the membrane into the neighboring cell.
      • The protrusion elongates and resolves as a double-membrane vacuole. 
      • The pathogen lyses the vacuole, escapes, and infects the adjacent cell (cell-to-cell spread).
    • Invasion does not involve deep penetration; thus, no hematogenous spread
    • Effects: inflammatory response (colitis) → mucosal ulcerations, abscesses, bleeding, and formation of a “pseudomembrane” on the ulcerated area

Invasion and cell-to-cell spread by Shigella:

1. Pathogen invades and is engulfed by the M cell (transcytosis).
2. Pathogen reaches subepithelial macrophages and dendritic cells, then induces macrophage apoptosis. Shigella sp. is released along with interleukin-1 (IL-1) and other cytokines. The pathogen is then engulfed into the adjacent epithelial cell in a membrane-bound compartment (epithelial-cell entry).
3. Released interleukins also recruit polymorphonuclear leukocytes (PMNs), which destabilize the cellular junctions. This is another entryway for the pathogen (PMN transmigration).
4. Shigella sp. passes through the disrupted tight junctions and then the pathogen enters the epithelial cell. Once inside, the host cell actin nucleators are hijacked. Actin-based motility (ABM; actin tail) propels the pathogen to reach the plasma membrane, where the infected cell contacts another cell.
5. Multiplication and intercellular spread are facilitated by cellular protrusion (with Shigella) and elongation into the adjacent cell. The protrusion resolves as a double-membrane vacuole. The pathogen lyses the membrane, escapes, and enters the adjacent cell. The adjacent cell is infected and this process is repeated in other cells.
6. As each invaded epithelial cell dies, fluids are lost.

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Clinical Presentation

  • Shigellosis:
    • Incubation period: 1–4 days
    • Watery diarrhea initially, then dysentery (diarrhea with blood and mucus)
    • Accompanied by abdominal pain, tenesmus, and fever
    • In the majority of cases, resolution is noted within 5 days.
    • In high-risk populations (immunocompromised, elderly, and children < 5 years of age), fluid and electrolyte losses can lead to dehydration and possible death.
  • Other complications:
    • HUS:
      • Shigella is the 2nd most common cause of HUS.
      • Mediated by Shiga toxin
      • Usually occurs in children under 10 years of age
      • Typically associated with S. dysenteriae type 1
    • Toxic megacolon:
      • Inflammation involves the smooth muscular layer resulting in colonic paralysis and dilation.
      • Abdominal distention and tenderness
    • Other intestinal sequelae: bowel obstruction, perforation
    • Rectal prolapse:
      • Due to inflammation in the colon
      • Affects young children
    • Reactive arthritis:
      • Associated with S. flexneri
      • Joint pain 1–4 weeks after infection (oligoarthritis, enthesitis, dactylitis, inflammatory back pain)
      • Extraarticular findings: conjunctivitis, urethritis, oral ulcers
    • Neurological effects:
      • Generalized seizures: associated with fever and more common in children
      • Encephalopathy
    • Leukemoid reaction:
      • WBC count of > 50,000/mm³
      • Associated with increased mortality

Diagnosis and Management

Diagnosis

  • Gram stain and culture: fresh stool or rectal swab
    • Gram negative
    • Differential media: eosin methylene blue (EMB) or MacConkey’s agar, showing non-lactose-fermenting colonies
    • Selective media: HE agar (green transparent colonies) or xylose-lysine-deoxycholate agar
    • Triple sugar iron (TSI): alkaline slant, acid at the bottom, and no H₂S
  • Polymerase chain reaction (PCR): Shigella-specific deoxyribonucleic acid (DNA) in stool detected
  • Additional work-up especially in severe infections:
    • Complete blood count (anemia and thrombocytopenia in HUS)
    • Metabolic panel (renal failure and electrolyte abnormalities in dehydration or HUS)

Management

  • Management through oral hydration and electrolyte replacement
  • In high-risk populations (immunocompromised, malnourished, elderly, children): intravenous fluid replacement
  • Avoid anti-diarrheal medications (e.g., loperamide); may worsen infection
  • Antibiotics:
    • Shortens duration of infection
    • Prevents spread of infection
    • Options: ciprofloxacin, ceftriaxone, cefixime
    • For antibiotic-resistant infection: azithromycin
    • Trimethoprim-sulfamethoxazole (TMP-SMX) and ampicillin: 
      • Associated with high resistance in the United States
      • Given if culture shows sensitivity

Prevention

  • Fly control and proper sewage disposal
  • Sanitary measures (water, food, and milk) and proper hygiene
  • Isolation of infected patients
  • Detection of cases and carriers, especially food handlers and treatment of infected individuals

Comparison with Salmonella

Shigella and Salmonella invade the gastrointestinal tract, causing diarrhea.

Table: Shigella and Salmonella
ShigellaSalmonella
Gram stain/structureGram-negative bacilliGram-negative bacilli
Lactose fermentationNon-lactose-fermentingNon-lactose-fermenting
OxidaseNegativeNegative
H2S productionNoYes
MotilityNoYes (with flagella)
Virulence factorsEndotoxin, Shiga toxinEndotoxin, Vi capsular antigen
ReservoirHumansHumans (S. typhi), animals
Dose to produce diseaseSmall inoculum (acid stable)Large dose (inactivated by acids)
Infection spreadCell-to-cell (no hematogenous spread)Can spread hematogenously

Differential Diagnosis

  • Other infectious colitis: presents with acute-onset fever and diarrhea. Other causative enteric pathogens include Salmonella, Campylobacter, Escherichia coli (O157:H7), Yersinia, and Clostridioides difficile. These infections can be confirmed based on stool cultures and PCR. Course may be self-limiting or may require antibiotic treatment. 
  • Ulcerative colitis (UC): a type of inflammatory bowel disease (IBD) characterized by inflammation of the colon. Disease commonly involves the rectum and inflammation may extend continuously through the colon. Presentation includes bloody diarrhea, abdominal pain, and tenesmus. Diagnosis is established via endoscopy with biopsy. Findings include diffuse friability and erosions with bleeding. 
  • Crohn’s disease: a chronic, recurrent condition causing patchy transmural inflammation that can involve any part of the gastrointestinal tract. The terminal ileum and colon are usually affected. Disease typically presents with chronic intermittent diarrhea (bloody or non-bloody) and crampy abdominal pain. Extraintestinal manifestations may occur. Diagnosis is established based on endoscopy and biopsy.
  • Celiac disease: a disease associated with IgA anti-tissue transglutaminase antibodies. Symptoms include abdominal pain and diarrhea following gluten consumption. Diagnosis is confirmed based on intestinal biopsy demonstrating villous atrophy, crypt hyperplasia, and mucosal inflammation.

References

  1. Corry, J., Curtis, G., Baird, R. (2003) Progress in industrial microbiology. Elsevier Vol. 37 pp 481-483, https://www.sciencedirect.com/science/article/pii/S0079635203800565?via%3Dihub
  2. Goldberg, M., Calderwood, S., Edwards, M., Bloom, A. (2020) Shigella infection: Epidemiology, microbiology, and pathogenesis. UpToDate. Retrieved 3 Jan 2021 from https://www.uptodate.com/contents/shigella-infection-epidemiology-microbiology-and-pathogenesis
  3. Kroser, J., Singh, A. (2019) Shigellosis. Medscape. Retrieved 5 Jan 2020, from https://emedicine.medscape.com/article/182767-overview#a3
  4. Lucchini, S., Liu, H., Jin, Q., Hinton, J., Yu, J. (2005) Transcriptional adaptation of Shigella flexneri during infection of macrophages and epithelial cells: Insights into the strategies of a cytosolic bacterial pathogen. Infect Immun. 73(1): 88–102.
  5. Mattock, E., Blocker, J. (2017) How do the virulence factors of Shigella work together to cause disease? Front. Cell. Infect. Microbiol. 7:64. doi: 10.3389/fcimb.2017.00064
  6. Riedel S. et al. (Eds.). (2019). Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28e. McGraw-Hill. 
  7. Sansonetti P.J. et al. (Eds.). Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill.
  8. Weddle, E., Agaisse, H. (2018) Principles of intracellular bacterial pathogen spread from cell to cell. Retrieved 3 Jan 2021 from https://doi.org/10.1371/journal.ppat.1007380

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