Salmonella Infection
Explore and order pathway-specific siRNAs, real-time PCR assays, and expression vectors. View pathway information and literature references for your pathway.
  • Click on your proteins of interest in the pathway image or review below
  • Select your genes of interest and click "add selection"
  • When you have finished your gene selection, click "Find Products" to find assays, arrays, or create custom products
Download Image Terms of Use Download PPT
Pathway Navigator
Salmonella Infection
Phagocytic cells are a critical line of defense against infection. The ability of a pathogen to survive and even replicate within phagocytic cells is a potent method of evading the defense mechanisms of the host. A number of pathogens survive within macrophages after phagocytosis and this contributes to their virulence. Salmonella is one of these pathogens. Salmonella spp are Gram-negative bacteria capable of infecting a wide range of host species, including humans, domesticated and wild mammals, reptiles, birds and insects. They are the etiologic agents of a variety of diseases globally defined as salmonellosis. Salmonellosis is one of the most important human enteric diseases worldwide. Salmonella infections display a broad range of clinical manifestations that are dependent on both the host species and the serotype causing the infections. The genus Salmonella comprises two species: S. enterica, which is subdivided into over 2,000 serovars, and Salmonella bongori. Some serovars of S. enterica, such as S. typhi, cause systemic infections and typhoid fever, whereas others, such as S. typhimurium, cause gastroenteritis. Some serovars, such as S. typhi, are host specialists that infect only humans, whereas others such as S. typhimurium, are host generalists that occur in humans and many other mammalian species (Ref.1).

Salmonellae initiate infection by invading and multiplying within epithelial intestinal cells and Peyers patches. Salmonella bacteria adhere to specialized small intestinal epithelial cells called M cells via long polar fimbriae. Their strategy is to deliver virulence factors directly into the host cytosol, triggering host-cell signaling pathways that lead to localized membrane ruffling, macropinocytosis and bacterial uptake. Salmonella entry into nonphagocytic epithelial cells requires several chromosomal genes (inv/spa) clustered in a pathogenicity island termed SPI1 (Salmonella Pathogenicity Island-1). SPI1 encodes a TTSS (Type-III Secretion System) and several potential virulence factors secreted by this machinery. Composed of more than 20 proteins, these systems stand among the most complex protein secretion systems known. Such complexity is caused by their specialized function, which is not only to secrete proteins from the bacterial cytoplasm but also to deliver them to the inside of the eukaryotic host cell. Perhaps a more important factor contributing to their complexity is the temporal and spatial restrictions that govern their activity. The function of TTSS requires poorly characterized signals that cue the bacteria to secrete and deliver proteins at the appropriate time and in the appropriate environment. A number of components of the TTSS assemble into an organelle, appropriately termed the “needle complex,” that spans both the inner and outer membranes of the bacterial envelope. The architecture of the needle complex resembles that of the flagellar hook-basal body. It is composed of two pairs of inner and outer rings that presumably anchor the structure to the inner and outer membranes of the bacterial envelope. The rings are connected by a rod-like structure, which together form the base of the needle complex. The TTSS is activated upon host-cell contact and allows export of virulence determinants directly into the host cell, where they effect bacterial uptake (Ref.2).

Salmonella enters host cells by inducing host cell membrane ruffling. These membrane ruffles non-specifically wrap around the bacteria and pull them into the cell. The Salmonella end up in membrane-bound vesicles called SCV (Salmonella-Containing Vacuoles). SCV of epithelial cells and macrophages is a dynamic structure that undergoes a maturation process involving fusion with certain endosomal compartments, while avoiding fusion with others. Salmonella vacuole remodelling requires the concerted effort of several effector proteins of a second TTSS, encoded within SPI-2. Salmonella induce the formation of tubular membranous structures adjoining the SCV that are known as SIFs (Salmonella-Induced Filaments). SIF formation requires SIF-A, a bacterial effector protein translocated into host cells by the SPI-2 TTSS. SIF-A is actively involved in the recruitment of membrane to the SCV and that this acquisition is microtubule dependent. It is likely that Salmonella uses microtubules and their associated motor proteins to deliver membrane vesicles destined for fusion to the SCV, or to send out membranous SCV tentacles that fuse with vesicular compartments (Ref.3).

Salmonella is able to alter the cytoskeleton and membrane through the action of secreted bacterial Sip proteins (SipA, SipB and SipC), SopE, SopB, and SptP that are inserted into the cytosol of the infected cell. Salmonella directly activate Rho GTPases using secreted effectors and a TTSS encoded within the SPI1 locus. The SPI1-secreted effectors SopE and SopE2 act as GEFs (Guanine-nucleotide-Exchange Factors) for the small GTPases CDC42 (Cell Division Cycle-42) and Rac. Despite a lack of sequence and architectural similarity, SopE and eukaryotic GEFs induce virtually identical conformational changes in their target Rho proteins. Stimulation of these GTPases by Salmonella also leads to the activation of the downstream MAPKs (Mitogen-Activated Protein Kinases) like JNKs (Jun N-terminal Kinases) and p38. TTSS-dependent activation of the MAPK pathways leads to the stimulation of the transcription factors NF-KappaB (Nuclear Factor-KappaB) and Activating Protein-1 and to the production of proinflammatory cytokines. Additional SPI1-translocated effectors of Salmonella affect Actin dynamics during the invasion process. SipA binds to and stabilizes Actin, and SipC, which forms part of the TTSS delivery pore, nucleates and bundles Actin while anchored in the host cell membrane. One of the cellular targets of both CDC42 and Rac1 that affects Actin structure is the ARP2/3 (Actin Related Protein-2/3) complex. CDC42 and Rac1 activate WASP (Wiskott-Aldrich Syndrome Protein) and WAVE (WASP family Verprolin-homologous protein), which activate ARP2/3. The ARP2/3 protein complex has been implicated in the control of Actin polymerization in cells. The human complex consists of seven subunits, which include the Actin related proteins ARP2 and ARP3, and five others referred to as p41-Arc, p34-Arc, p21-Arc, p20-Arc, and p16-Arc. Activated ARP2/3 induces the formation of Actin Y branches, which in combination with changes in Actin caused by SipA and SipC help to form lamellipodia, and causes membrane ruffling, leading to entry of Salmonella into the affected cell (Ref.4).

Salmonella also alters the Actin cytoskeleton through manipulation of phosphoinositides. The plasma membrane is intimately associated with the Actin cytoskeleton, and this interaction depends on PtdIns (4,5)P2 (Phosphatidylinositol 4,5-Bisphosphate). SigD/SopB is a SPI1-translocated inositol phosphatase that induces the rapid disappearance of PtdIns(4,5)P2 from invaginating regions of the membrane during Salmonella invasion. This increases elasticity to facilitate the remodelling of the plasma membrane associated with Salmonella entry. PtdIns(4,5)P2 has also been implicated in vesicle fission during the creation of phagosomes and Clathrin-coated vesicles, and accordingly, SigD also is involved in sealing plasma membrane invaginations to form bonafide vacuoles. After invasion, an additional SPI1 effector, SptP, acts as a GAP (GTPase-Activating Protein) for CDC42 and Rac1, thereby inactivating these G-Proteins and returning cell morphology to a relatively normal state. SptP is a bifunctional protein, with its GAP domain at the amino terminus, and a protein tyrosine phosphatase domain at the carboxy terminus. A potential target for the tyrosine phosphatase activity of SptP is the intermediate filament protein Vimentin, which is recruited to the membrane ruffles stimulated by Salmonella. The Salmonella invasion-associated TTSS encodes at least three chaperone-like proteins: SicP, SicA, and SigD. SicP serves as chaperone for the effector protein SptP. Consistent with this role, SicP binds SptP, which in its absence completely is degraded within the bacterial cytoplasm. Thus, SicP seems to function as a partitioning factor for SptP, perhaps preventing it from interacting with an as-yet-unidentified protein. SicA, however, appears to play a more complex role. One of its functions is to prevent the association of SipB and SipC in the bacterial cytosol that would target these proteins for degradation. Absence of SicA results in the degradation of both SipB and SipC. Salmonella also induces a very rapid Caspase1-dependent death and is associated with small membrane ‘blisters’. death, 2 minutes. Macrophages killed by Salmonella spp. exhibited features of apoptosis such as condensation and fragmentation of chromatin, membrane blebbing, and the presence of cytoplasmic nucleosomes and apoptotic bodies. Salmonella infections are still a serious health problem worldwide. The recent emergence of multidrug-resistant Salmonella strains calls for a more rational approach to the treatment of the disease and increases the need for the rapid development of safer and more effective vaccines. A better understanding of the protective mechanisms of acquired immunity to Salmonella would undoubtedly be beneficial for improving vaccination strategies (Ref.5).