Salmonella enterica is a genus of bacteria responsible for a wide spectrum of diseases in humans and animals, ranging from localized foodborne illness to life-threatening systemic infections. The outcome of a Salmonella infection is heavily determined by the array of toxins the bacterium produces and how it delivers them to host cells. Non-typhoidal Salmonella serovars typically cause self-limiting gastroenteritis, characterized by severe diarrhea and inflammation. Conversely, typhoidal serovars, such as Salmonella Typhi, cause a systemic disease known as typhoid fever, where the bacteria spread throughout the body. The difference in disease presentation is rooted in the specific toxins each serovar utilizes and the mechanisms they employ to exert their influence on host biology.
Specialized Mechanisms for Toxin Delivery
The primary method Salmonella uses to inject its protein toxins directly into a host cell is through the Type III Secretion System (T3SS). This complex molecular machine is often compared to a nanoscale syringe or an injectisome, capable of spanning the bacterial envelope and the host cell membrane. The T3SS is built from a conserved set of bacterial proteins that assemble into a base structure embedded in the bacterial membranes, an external needle-like filament, and a translocon tip that inserts into the host cell membrane. This apparatus allows the bacteria to bypass the need for traditional secretion pathways, delivering the toxic cargo directly into the host cell cytoplasm upon contact.
Salmonella possesses two functionally distinct T3SSs, each encoded on separate regions of the bacterial genome called Salmonella Pathogenicity Islands (SPIs). The SPI-1 T3SS (T3SS-1) is primarily expressed when the bacterium is in the intestinal lumen and is associated with the initial stages of infection. Its function is to facilitate the bacterial invasion of non-phagocytic cells, like the epithelial cells lining the intestine.
Once inside the host cell, the bacterium switches its machinery to utilize the SPI-2 T3SS (T3SS-2). This second system is not involved in the initial invasion process but is crucial for the bacterium’s survival and replication within the intracellular environment. T3SS-2 injects a different set of effector proteins that manipulate the host cell’s internal trafficking pathways and allow the bacteria to evade destruction by immune cells like macrophages.
Key Toxins and Effector Molecules
The protein toxins injected by the T3SSs are highly specialized molecules that manipulate specific host cell processes. One set of effectors, including SopE and SipA, targets the host cell’s cytoskeleton to facilitate immediate entry. SopE functions as a guanine nucleotide exchange factor (GEF) that activates host Rho GTPases, such as Rac-1 and Cdc42. This activation triggers the reorganization of the host cell’s internal scaffolding, leading to the physical engulfment of the bacterium. SipA also contributes to this process by binding directly to actin filaments, promoting their polymerization and bundling, which stabilizes the invading structure.
SopB is an enzyme known as a phosphatidylinositol phosphatase. This molecule removes phosphate groups from signaling lipids within the host cell membrane, particularly phosphatidylinositol 3,4,5-trisphosphate. By altering the concentration of these lipids, SopB disrupts normal cellular signaling and is a major driver of the profound fluid loss seen in gastroenteritis. Other effectors like SspH1 and SspH2 are E3 ubiquitin ligases that chemically tag host proteins with ubiquitin, thereby altering their function or marking them for degradation. These molecules are deployed later in infection to modulate the host immune response and promote intracellular survival.
A distinct virulence factor, Cytolethal Distending Toxin (CDT), is produced by typhoidal and some non-typhoidal Salmonella serovars and is not delivered by the T3SS. Salmonella CDT (S-CDT) is an unusual toxin composed of multiple subunits, including the active CdtB component and the PltA and PltB subunits for delivery. CdtB possesses a DNAase-like activity that is delivered to the host cell nucleus where it causes double-strand breaks in the host cell’s DNA. This genotoxic damage halts the host cell’s proliferation by causing it to arrest permanently in the G2/M phase of the cell cycle.
Cellular Consequences of Toxin Activity
The immediate and most visible consequence of T3SS-1 toxin activity is the dramatic structural change it induces in the host cell membrane, known as membrane ruffling. The combined action of SopE and SipA effectors causes the host cell’s surface to erupt in large, wave-like protrusions that quickly surround and internalize the bacterium. This process, called bacterial-mediated endocytosis, allows the bacterium to force its way into non-immune cells that would not normally engulf foreign material. The rapid and localized rearrangement of the host cell’s membrane reservoirs is a highly energy-intensive process that quickly seals the bacterium within a membrane-bound compartment.
Once inside, the toxins shift their focus to establishing an environment for survival and causing symptoms. The phosphatase activity of SopB leads to a massive disruption of ion balance across the intestinal epithelial layer. By hydrolyzing specific phosphoinositides, SopB removes an inhibitory signal that normally regulates chloride ion channels. The resulting uncontrolled secretion of chloride ions into the intestinal lumen draws water out of the body by osmosis, causing the severe secretory diarrhea characteristic of acute salmonellosis. This process is amplified by the inflammatory response triggered by other T3SS-1 effectors, which cause the epithelial cells to release signaling molecules that recruit massive numbers of immune cells.
Toxins injected by the T3SS-2 system are responsible for the pathogen’s ability to evade destruction and cause systemic disease. These effectors, such as SseF, SseG, and SifA, manipulate the Salmonella-containing vacuole (SCV), the specialized compartment where the bacteria reside within immune cells. The SCV is actively prevented from fusing with the host cell’s degradative lysosomes, which would otherwise eliminate the pathogen. T3SS-2 effectors also position the SCV near the host cell’s Golgi apparatus and nucleus, creating a stable, nutrient-rich niche that allows Salmonella to replicate and spread throughout the body, particularly within macrophages.
Endotoxin: The Systemic Driver of Illness
In contrast to the injected protein toxins, which act inside the host cell, Salmonella also produces a structural molecule known as endotoxin. This molecule is Lipopolysaccharide (LPS), a large component that forms the outer leaflet of the outer membrane in all Gram-negative bacteria. LPS is composed of three distinct parts: the Lipid A anchor, a core oligosaccharide, and the O-antigen polysaccharide chain. Lipid A is the portion of the molecule responsible for the molecule’s toxicity.
LPS is continuously shed during bacterial growth and division, and massive amounts are released when bacteria are killed by the immune system or antibiotics. Once released into the bloodstream, the Lipid A moiety is recognized by the host’s innate immune system through a receptor complex that includes Toll-like Receptor 4 (TLR4). This recognition system is remarkably sensitive and triggers an immediate, powerful inflammatory cascade.
The resulting systemic inflammation involves the massive production of inflammatory signaling proteins like Tumor Necrosis Factor-alpha (TNF-\(\alpha\)). This excessive immune response is the primary cause of fever and the severe, life-threatening symptoms associated with systemic Salmonella infections, culminating in septic shock.