Comprehensive Study Notes on Shigella Infections and Pathogenesis and Characteristics of Shigella Infections

Overview of Shigella Infections

• Disease: Bacilliary Dysentry (also known as Shigellosie).

• Causative Agents:

  • Shigella dysenterice

  • Shigella Flexresi

  • Shigella sorrei

• Pathogen Type: An aerobic intracellular pathogen.

• Disease Characteristics:

  • Classified as an intestinal disease.

  • Occupies the GI tract.

  • Is actively invasive, similar to Ontmorilla, though activities occur at different times.

Transmission and Infectious Dose

• Transmission Pathways:

  • Person to person.

  • Unime to person.

  • Food.

  • Mainly from the fecal-oral route described by the 4Fs: fingers, feces, food, and flies.

• Infectious Dose: $10 - 200$ organisms.

Clinical Progression and Symptoms

• Incubation time: $1 - 3$ days.

• Duration: $4 - 7$ days.

• Standard Symptoms:

  • Painful bowel movements and cramps.

  • Nausea and vomiting.

  • Loss of appetite.

  • Diarrheal discharge, which is often bloody.

  • High fever.

• Symptoms in highly infected individuals: Kidney fever.

• Pediatric Complications: Seizures can occur in children under $2$ years of age, which can be fatal.

Epidemiology and Treatment

• Annual Global Burden: Approximately $160$ million cases every year.

• Mortality Rate: $600,000$ to $1$ million deaths annually.

• Demographic Impact: Deaths occur mostly among young kids in developing areas of the world.

• Current Treatment Challenges:

  • Resistance to many antibiotics has emerged, leading to a lack of effective treatments in many cases.

  • No vaccine is currently available.

Genomic and Structural Features

• Genomic Comparisons: Shigella has features common to Pathogenic E.coli (genomically very similar), Salmonella, and Listeria.

• Motility Features:

  • Shigella possesses no flagella.

  • The bacteria are non-mobile outside of cells (extracellular).

  • The bacteria are mobile inside cells.

• Molecular Mechanisms: Controls the host cell cytoskeleton, a trait shared with C.coli, Listeria, and Ontmorilla.

Invasion Mechanisms and Type 3 Secretion System (T3SS)

• Effector Injection: Uses a type 3 secretion system to inject effector PTs (proteins) into the host cell.

• Cellular Entry:

  • Causes active invasion.

  • Causes massive amounts of membrane ruffling to invade host cells.

  • Gains entry by controlling the actin dynamics of the cell.

• Gap Junction Manipulation:

  • During invasion, the bacteria use T3SS effectors to control gap junctions.

  • Specifically hijacks Connexin 26 gap junction hemichannels.

  • This hijacking causes the release of ATP from host cells into the surrounding media.

  • The release of ATP further increases bacterial invasion.

Intracellular Lifecycle and Motility

• Phases of Intracellular Colonization:

  • Enters the cells and is initially found in a vacuole.

  • Lyses the vacuole to enter the cytoplasm.

  • Replicates in the host cell cytoplasm.

• Actin Recruitment and Propelling:

  • Generates an effector called IcsA (comparable to ActA in Listeria).

  • IcsA is embedded in $1$ pole of the Shigella bacterium.

  • IcsA recruits actin filaments (F-actin and N-WASP/NCA-P) to propel the bacteria around the cell.

  • This is known as Shigella motility in infected cells; Shigella flexneri specifically uses IcsA for this purpose.

Shiga Toxin

• Origin: The Shiga toxin was initially described in Shigella, not E.coli.

• Functional Mechanism: The A subunit of the toxin can bind to host ribosomes, inhibiting PT synthesis.

• Pathological Effects:

  • Can generate diarrhea independently.

  • Causes watery diarrhea containing blood, mucus, and pus.

Study Models and Experimental Challenges

• Animal Models for Shigella:

  • Monkey: Expensive and ethically challenging, but gives a disease similar to humans.

  • Mice: Not susceptible to the infections; the reason for this is unknown.

  • Rabbit: Limited to the use of intestinal segments (loops) following bacterial injection.

  • Young Guinea Pigs ($250\,G$ or less): Develop shigellaris.

Cell-to-Cell Spreading and Junction Targeting

• Infection Strategy: Shigella targets the tricellular junctions of cells for efficient cell-to-cell spreading.

• Tricellular Junctions:

  • Unique types of tight junctions (TJ).

  • Use the PT "tricellulin" to fuse adjacent membranes.

  • Paired TJ strands, tricellulin, and occludin merge at these sites.

• Process of Cell-to-Cell Movement:

  • Shigella couples tricellulin identification with clathrin-mediated endocytosis to move between cells.

  • Step-by-step mechanism:

    1. Actin-based motility leads to protrusion formation.

    2. PI 3-kinase activation occurs.

    3. $PtdIns(3,4,5)P$ involvement.

    4. Clathrin-dependent endocytosis takes place.

    5. Vacuole lysis followed by resumed actin-based motility.