Synergistic effect of mutations in invA and lpfC on the ability of Salmonella typhimurium to cause murine typhoid

Abstract

Penetration of the intestinal mucosa at areas of Peyer's patches is an important first step for Salmonella typhimurium to produce lethal systemic disease in mice. However, mutations in genes that are important for intestinal invasion result in only moderately decreased virulence of S. typhimurium for mice. Here we report that combining mutations in invA and lpfC, two genes necessary for entry into Peyer's patches, results in a much stronger attenuation of S. typhimurium than inactivation of either of these genes alone. An S. typhimurium invA lpfC mutant was 150-fold attenuated by the oral route of infection but was fully virulent when the intestine was bypassed by intraperitoneal challenge of mice. During mixed-infection experiments, the S. typhimurium invA lpfC mutant showed a strong defect in colonizing Peyer's patches and mesenteric lymph nodes. These data suggest that mutations in invA and lpfC deactivate distinct pathways for intestinal penetration and colonization of Peyer's patches. While the inv-mediated pathway is widely distributed, the lpf operon is absent from many phylogenetic groups within the genus Salmonella. To investigate how acquisition of the lpf-mediated pathway for mucosal penetration contributed to evolution of virulence, we studied the relationship between the presence of the lpf operon and the pathogenicity for mice of 18 isolates representing 14 Salmonella serotypes. Only strains possessing the lpf operon were able to cause lethal infection in mice. These data show that both the invA-and lpfC-mediated pathways of intestinal perforation are conserved in mouse virulent Salmonella serotypes.

The Rcs phosphorelay system is specific to enteric pathogens/commensals and activates ydeI, a gene important for persistent Salmonella infection of mice

“…For instance, mutants lacking a functional Salmonella pathogenicity island-1 (SPI1) type three secretion system (T3SS) are out-competed by wild type 10-fold in the MLN and spleen only after oral inoculation (Galan and Curtiss, 1989;Jones and Falkow, 1994;Baumler et al, 1997). SPI1 mediates epithelial cell invasion, suggesting that invasion of intestinal epithelial cells is important for bacterial access to deep tissues (Baumler et al, 1997). These experiments were performed in a mouse model of acute infection (BALB/c, Nramp1 -/mice).…”

Functions and effectors of the Salmonella pathogenicity island 2 type III secretion system

“…The SPI-1 translocon protein SipB binds to and activates caspase-1, leading to the induction of apoptosis in macrophages (Hersh et al ., 1999). Mutations which prevent secretion through the SPI-1 TTSS lead to a 10 to 100-fold increase in attenuation in the mouse model of systemic infection, when the bacterial inoculum is administered orally (Galan and Curtiss, 1989;Jones et al ., 1994;Baumler et al ., 1997). This lack of complete attenuation of SPI-1 null mutants reflects the ability of Salmonella to disseminate to the liver and spleen from the intestinal tract via an alternative route: carriage within transmigrating, CD-18 expressing phagocytic cells (Vazquez-Torres et al ., 1999).…”

Salmonella‐induced SipB‐independent cell death requires Toll‐like receptor‐4 signalling via the adapter proteins Tram and Trif

“…5,6 SPI-1 mutants of S. typhimurium are attenuated in oral infection of mice, but not in systemic mouse typhoid infection. 7 Caspase-1 is a serine protease that cleaves pro-interleukin (IL)-1b into active IL-1b. Although activation of caspase-1 is required for early macrophage cell death the underlying mechanisms are unclear.…”