Salmonella is a genus of rod-shaped, Gram-negative bacteria responsible for a common group of foodborne illnesses known as salmonellosis. The infection is categorized into two forms based on the bacterial serotype and replication site. Non-typhoidal Salmonella (NTS) strains, such as S. Typhimurium, typically cause localized gastroenteritis, often called simple food poisoning. In contrast, typhoidal serotypes, like S. Typhi and S. Paratyphi, cause a much more severe, invasive disease known as enteric fever or typhoid fever. The specific locations where Salmonella grows are determined by the disease type, ranging from the superficial gut layers to deep internal organs.
Initial Entry and Gut Colonization
The journey of Salmonella begins when the bacteria are ingested, usually through contaminated food or water. The bacteria must survive the highly acidic stomach environment to reach the small intestine and colon, the primary infection sites. Once in the intestine, Salmonella actively seeks to breach the protective epithelial barrier.
The bacteria preferentially target specialized cells called M cells, which are located within the lining of the gut, directly overlying the Peyer’s patches. These patches are concentrations of lymphoid tissue designed to sample antigens from the intestinal lumen. Salmonella uses the Type III Secretion System 1 (T3SS-1) to inject effector proteins into the host cell. These proteins manipulate the host cell’s cytoskeleton, triggering membrane ruffling that pulls the bacteria inside the M cell.
For non-typhoidal strains, replication and inflammation are largely contained within this intestinal environment and the associated lymphoid tissue. This localized replication and the intense immune response in the gut-associated lymphoid tissue (GALT) lead to the characteristic inflammation and diarrhea seen in gastroenteritis.
Systemic Spread and Deep Organ Replication
Invasive typhoidal strains possess adaptations that allow them to escape the intestinal barrier and replicate systemically. After traversing the M cells and epithelium, the bacteria enter the lamina propria. Here, they are quickly encountered and engulfed by phagocytic immune cells, primarily macrophages and dendritic cells, which are designed to destroy pathogens.
Instead of being killed, typhoidal Salmonella strains survive and replicate within these immune cells. The immune cells then inadvertently transport the bacteria via the lymphatic system to the mesenteric lymph nodes and into the bloodstream. This systemic spread, known as bacteremia, is the hallmark of enteric fever.
The main hubs for bacterial replication during the systemic phase are organs rich in resident immune cells: the liver, the spleen, and the bone marrow. In the liver, the bacteria thrive inside resident macrophages known as Kupffer cells. Similarly, the spleen becomes heavily colonized as Salmonella multiplies within various subsets of splenic macrophages.
Massive bacterial growth in these deep organs causes the prolonged fever and systemic symptoms defining typhoid fever. The bacteria may also establish a persistent presence in the gallbladder, which serves as a reservoir for chronic carriage and continued shedding.
The Intracellular Niche: Survival in Host Cells
The ability of Salmonella to grow and replicate in deep organs depends entirely on its capacity to survive inside host immune cells, specifically macrophages and dendritic cells. Salmonella is considered a facultative intracellular pathogen, meaning it can live and multiply both outside and inside cells tasked with its destruction. Upon engulfment, the bacterium is encased within a membrane-bound compartment called the phagosome.
The bacterium actively prevents the phagosome from maturing into a hostile phagolysosome, which contains destructive enzymes and acids. Instead, Salmonella transforms the compartment into a protected growth environment known as the Salmonella-Containing Vacuole (SCV). This modification is controlled by the Type III Secretion System 2 (T3SS-2), which is induced once the bacteria are inside the host cell.
The T3SS-2 injects effector proteins across the SCV membrane into the host cell cytoplasm. These proteins interfere with trafficking pathways, preventing SCV fusion with lysosomes and directing nutrient-rich vesicles toward the SCV. By modifying the SCV and establishing a nutrient supply, the bacteria create an optimal niche for replication, often forming membrane tubules called Salmonella-induced filaments (Sifs).