|
|
 |
 |
Introduction to Salmonella |
|
Salmonella enterica serovar Typhimurium (S. typhimurium) causes enteric disease in humans.
It is a food- and water-borne pathogen that can be easily disseminated in a population: for instance
outbreaks of salmonellosis can occur by contamination of salad. Although salmonellosis can be
controlled by antibiotics, drug resistant and hypervirulent strains are difficult to combat. At
the time of writing, strains simultaneously resistant to seven antibiotics exist. Thus,
understanding the basis of virulence determinants and their response to drugs is an important
feature of controlling infection. Moreover S. typhimurium causes a systemic, typhoid-like
disease in mice. S. typhi, which is responsible for human typhoid fever, has restricted host
specificity. It cannot be studied in mice. S. typhimurium is widely studied because of the
ease of genetic manipulation and a robust murine infection model.
The mammalian intestinal tract is lined by columnar epithelial cells that are covered by glycocalyx
and thick mucus. While the primary functions of intestinal epithelia are adsorptive, they must also
provide a barrier for infections and provide local immunity against pathogens, even while they
tolerate commensal organisms. S. typhimurium breaches the intestinal barrier by infecting
M cells, which are present in the follicle associated epithelium (FAE) containing thinner glycocalyx
and mucous and lymphoid cells at their base. Aggregates of lymphoid follicles are called Peyer's
patches (Peyer 1677) which serve as the inductor arm of the immune system termed gut associated
lymphopid tissue (GALT). Thus, entry into epithelial (M) cells and the induction of the immune
response is a critical step in onset of S. typhimurium infection (see Figure 1 below). Subsequent
systemic dissemination of the organism to the liver and spleen (two major organs of bacterial
proliferation) requires infection of macrophages.
|
|
|
Several genetic loci are involved in the virulence of S. typhimurium. Two discrete Type II
secretion systems, regulated by distinct pathogenicity islands SPI-1 and SPI-2, secrete effectors
that modulate vacuolar trafficking functions in host cells. SPI-1 appears to be important to the
establishment of infection while SPI-2 is linked to subsequent proliferation in the vacuole (see
Figure 2 right). Mutants in both SPI-1 and SPI-2 show severe attenuation of disease proliferation
in mice. Although mechanisms by which S. typhimurium effectors interact with host cells are starting
to be elucidated, little is known about the molecular processes that regulate disease. |
 |
|
We have recently shown that cholesterol from the host cell is recruited to the Salmonella-containing
vacuole (SCV) in both macrophages and epithelial cells in a SPI-2-dependent manner. Host proteins
such as GPI-anchored proteins that associate with cholesterol are also recruited, showing that the
SCV perturbs endosomal trafficking. In addition, S. typhimurium perturbs mammalian sterol
metabolism and sterol precursors in host cells.
|
|
