Pa Tho Physiology

PATHOPHYSIOLOGY
After ingestion by the host, Salmonella typhi invades through the gut and multiplies
within the mononuclear phagocytic cells in the liver, spleen, lymph nodes, and Peyer
patches of the ileum.
After successfully passing through the stomach, any Salmonella subspecies may be
phagocytized by the gut's intraluminal dendritic cells, causing inflammation that leads to
diarrhea. Its specialized fimbriae adhere to the epithelium that overlies Peyer patches.
Peyer patches are grossly visible aggregates of 5-100 lymphoid follicles in the small
bowel submucosa; these patches are larger and more numerous distally. They are the
primary mechanism for sampling antigens in the gut and initiating response. S enterica
enters them via 1 of 3 pathways.
Intraluminal dendritic cells may infiltrate through the gut epithelium while carrying the
bacterium. M cells may transport it as well. Immobile and interspersed among regular
enterocytes in Peyer patches, M cells are epithelial cells that mature into professional
phagocytes. They phagocytize bacteria such as S enterica and present them to
macrophages and T cells in the lamina propria. Most interestingly, S enterica may convert
normally nonphagocytic epithelial cells into bacterially-mediated endocytosis (BME).
In BME, Salmonella uses a type III secretion system—macromolecular channels those

gram-negative bacteria such as Salmonella insert into eukaryotic cells and intracellular
membranes to inject virulence proteins—to inject proteins SipA and SipC into the
epithelial cell. These disrupt the normal brush border and force the cell to form
membrane ruffles. The ruffles engulf the bacilli and create vesicles that carry them across
the epithelial cell cytoplasm and the basolateral membrane. Salmonella pathogenicity
island 1 (SPI-1) in the genome encodes the elements of BME.
In the submucosa, Salmonella enters macrophages via bacteria-triggered pinocytosis or

via macrophage receptor–mediated phagocytosis. The intravacuolar environment
activates the PhoP/PhoQ regulon, leading to modification of protein and
lipopolysaccharide elements of the bacterial inner and outer membranes. Thus,
Salmonella resists lysis and decreases host pro-inflammatory signaling. The bacterium
also produces homocysteine to inactivate nitric oxide and enzymes against other
microbicides. Finally, with the VI antigen, a polysaccharide capsule, S typhi and S
paratyphi further protect themselves from lysis within the macrophage and from
neutrophils and complement without. The infected macrophage provides Salmonella a
vehicle safe from other elements of the immune system and in which it can multiply and
travel. It passes through the mesenteric lymph nodes into the thoracic duct and the
lymphatics beyond to seed the reticuloendothelial tissues—liver, spleen, bone marrow,
and lymph nodes. In these havens, it multiplies until some critical density is reached. It
causes the apoptosis in the macrophages and enters the bloodstream to attack the rest of
the body. At this stage, the VI antigen comes into play. It forms a capsule to protect the
bacterium from complement and from phagocytic immune cells.
From blood or from the liver via bile ducts, it infects the gallbladder and reenters the
gastrointestinal tract in the bile, spreading to other hosts via stool. In addition, it
occasionally invades the urinary tract and spreads via urine.
After primary intestinal infection, further seeding of the Peyer patches occurs through
infected bile. They may become hyperplastic and necrotic with infiltration of
mononuclear cells and neutrophils, forming ulcers that may hemorrhage through eroded
blood vessels or perforate the bowel wall, causing peritonitis.
The host recognizes the invader with toll-like receptors 2, 4, and 5. These induce
cytokines such as interferon alpha, interleukin (IL)–12, and tumor necrosis factor-alpha,
which recruit macrophages and cause the high fevers of the disease. Macrophages and
neutrophils suppress the active infection. Later, humoral and CD4 T-cell–mediated
immunity clears it.

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PATHOPHYSIOLOGY

In BME, Salmonella uses a type III secretion system—macromolecular channels those

In the submucosa, Salmonella enters macrophages via bacteria-triggered pinocytosis or

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