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• Type Three Secretion System (TTSS)

  A remarkable virulence mechanism employed by Salmonella enterica to evade host defenses and facilitate infection
• TTSS


  • Acts as a molecular syringe, allowing Salmonella to directly inject effector proteins into host cells and manipulate cellular processes to its advantage
  • Plays a pivotal role in Salmonella's ability to invade, survive, and disseminate within the host
• Induction and Assembly of TTSS

  1. Upon contact with host epithelial cells, Salmonella senses environmental cues, such as changes in pH, osmolarity, and nutrient availability, which trigger the expression and assembly of the TTSS apparatus

  2. This complex machinery spans the bacterial inner and outer membranes and is composed of more than 20 structural proteins
• Effector Protein Translocation


  1. The TTSS apparatus acts as a conduit for the translocation of effector proteins directly into the host cell cytoplasm

  2. These effector proteins are encoded by Salmonella pathogenicity islands (SPIs) and play crucial roles in subverting host cellular processes
• Cytoskeletal Rearrangement


  1. Salmonella injects effector proteins, such as SopE, SopE2, and SipA, into host cells, leading to the activation of Rho GTPases and the subsequent rearrangement of the host cell actin cytoskeleton

  2. This results in the formation of membrane ruffles and macropinocytic protrusions, facilitating the engulfment and internalization of Salmonella by the host cell
• Modulation of Vacuolar Trafficking

  1. Once internalized, Salmonella resides within a specialized compartment known as the Salmonella-containing vacuole (SCV)

  2. TTSS effectors, such as SifA and PipB2, manipulate host vesicular trafficking pathways to prevent the fusion of the SCV with lysosomes, thereby protecting Salmonella from degradation
• SCV Remodeling


  1. TTSS effectors, including SseF and SseG, induce the formation of Salmonella-induced filaments (Sifs) from the SCV membrane

  2. These tubular membrane extensions provide a source of nutrients and membrane components, enabling Salmonella to replicate within the SCV and potentially spread to neighboring cells
• Salmonella enterica serovar Typhi (S. Typhi)

  A bacterium that employs various toxins to facilitate its pathogenesis and host specificity
• Nutrient Acquisition


  1. Salmonella utilizes TTSS effectors to acquire essential nutrients from the host cell

  2. For example, the effector SseJ degrades host deubiquitinating enzymes, leading to the accumulation of ubiquitinated proteins that can serve as a source of amino acids for the bacteria
• Toxins of S. Typhi

  • Interact with host cells and manipulate cellular processes
  • Contribute to bacterial invasion, immune evasion, and systemic dissemination
• Suppression of Inflammatory Responses

  1. TTSS effectors play a crucial role in modulating host immune signaling pathways to evade immune detection and clearance

  2. Effectors such as AvrA, SspH1, and SseL interfere with the NF-κB and MAPK signaling pathways, leading to the suppression of pro-inflammatory cytokine production and the inhibition of antimicrobial responses
• Typhoid Toxin (Vi Antigen)

  A surface-associated polysaccharide composed of N-acetylated oligosaccharide units with α(1→4) linkages
• Typhoid Toxin


  • Acts as an anti-phagocytic capsule, shielding S. Typhi from recognition and phagocytosis by host immune cells
  • Can modulate host immune responses by interfering with complement activation and inhibiting the deposition of complement components on the bacterial surface
  • May contribute to the survival of S. Typhi within host cells by mediating the inhibition of phagosome-lysosome fusion
• Interference with Antigen Presentation

  1. Salmonella employs TTSS effectors to disrupt antigen presentation pathways, thereby evading recognition and elimination by the adaptive immune system

  2. For example, the effector GogB targets the host Golgi complex, interfering with the loading of peptides onto MHC class I molecules and impairing the presentation of Salmonella antigens to cytotoxic T cells
• Salmonella Pathogenicity Island (SPI) Effectors

  Effector proteins that facilitate the invasion of non-phagocytic cells and the intracellular survival and replication within host phagocytic cells
• Type III Secretion Systems (TTSS)

  1. SPI-1 TTSS: Facilitates the invasion of non-phagocytic cells

  2. SPI-2 TTSS: Necessary for intracellular survival and replication within host phagocytic cells
• Modulation of Apoptosis


  1. TTSS effectors can modulate host cell apoptosis pathways to promote Salmonella survival and dissemination

  2. Effectors like SseL and SopB can either inhibit or induce apoptosis in host cells, depending on the stage of infection, allowing Salmonella to evade immune defenses and spread to other tissues
• TTSS


  • Acts as a molecular syringe, allowing S. Typhi to inject effector proteins directly into the cytoplasm of host cells
  • SPI-1 effectors induce cytoskeletal rearrangements and membrane ruffling in host epithelial cells, facilitating bacterial invasion and uptake
  • SPI-2 effectors modulate host vesicular trafficking pathways, inhibit phagosome-lysosome fusion, and promote the formation of Salmonella-containing vacuoles (SCVs), creating a replicative niche for S. Typhi within host cells
• Invasion of Intestinal Epithelium


  1. In the case of systemic infections, such as typhoid fever caused by Salmonella enterica serovar Typhi, the TTSS plays a crucial role in facilitating the invasion of the intestinal epithelium

  2. Effectors like SipA, SipC, and SopB disrupt tight junctions and induce cytoskeletal rearrangements, allowing Salmonella to translocate across the epithelial barrier and access underlying tissues
• Cytotoxic Effectors


  • Hemolysins and cytolysins that disrupt host cell membranes, leading to cell lysis and the release of pro-inflammatory cytokines and chemokines
  • Pore-forming toxins that disrupt membrane integrity and potentially induce apoptosis or necrosis
• Cytotoxic Effectors

  • Cause tissue damage and promote local inflammation, facilitating bacterial dissemination and systemic infection
• Survival in Phagocytic Cells

  1. TTSS effectors also enable Salmonella to survive and replicate within phagocytic cells, such as macrophages and dendritic cells

  2. Effectors like SseF and SseG modulate vacuolar trafficking and prevent phagolysosome fusion, creating a replicative niche for the bacteria within these immune cells
• Enterotoxins


  Heat-labile toxin (LT) and heat-stable toxin (ST) that disrupt epithelial barrier function and cause gastrointestinal symptoms
• Enterotoxins


  • LT binds to host cell receptors and enters the cell via endocytosis
  • ST binds to and activates guanylate cyclase C (GC-C) on intestinal epithelial cells, leading to the dysregulation of ion transport and fluid secretion, resulting in diarrhea
• Dissemination to Systemic Sites

  By evading immune defenses and exploiting phagocytic cells as vehicles for dissemination, Salmonella can spread from the intestine to systemic sites, such as the liver, spleen, and bone marrow, where it can establish chronic infections and cause severe complications like typhoid fever
• Human Host Specificity of S. Typhi

  • Toxins may interact with human-specific receptors or target human-specific cellular pathways, facilitating bacterial colonization and pathogenesis
  • Toxins can modulate the human immune response by interfering with human-specific immune cell functions, cytokine signaling pathways, or complement activation, promoting immune evasion and bacterial survival
  • The ability of toxins to disrupt specific human cell types or tissues may contribute to the colonization of specific host niches, facilitating S. Typhi's adaptation to the human host environment
  • S. Typhi has likely evolved to produce toxins tailored to the human host through genetic modifications, gene acquisitions, or regulatory mechanisms
• The Type Three Secretion System is a remarkable example of Salmonella's evolved virulence strategies, enabling the bacterium to manipulate host cellular processes, evade immune responses, and establish successful infections
• Targeting this crucial virulence mechanism holds great promise for developing effective therapies and vaccines against Salmonella-related diseases, including typhoid fever