Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes

Abstract

Specialized epithelia known as M cells overlying the lymphoid follicles of Peyer's patches are important in the mucosal immune system, but also provide a portal of entry for pathogens such as Salmonella typhimurium, Mycobacterium bovis, Shigella flexneri, Yersinia enterocolitica and reoviruses. Penetration of intestinal M cells and epithelial cells by Salmonella typhimurium requires the invasion genes of Salmonella Pathogenicity Island 1 (SPI1). SPI1-deficient S. typhimurium strains gain access to the spleen following oral administration and cause lethal infection in mice without invading M cells or localizing in Peyer's patches, which indicates that Salmonella uses an alternative strategy to disseminate from the gastrointestinal tract. Here we report that Salmonella is transported from the gastrointestinal tract to the bloodstream by CD18-expressing phagocytes, and that CD18-deficient mice are resistant to dissemination of Salmonella to the liver and spleen after oral administration. This CD18-dependent pathway of extraintestinal dissemination may be important for the development of systemic immunity to gastrointestinal pathogens, because oral challenge with SPI1-deficient S. typhimurium elicits a specific systemic IgG humoral immune response, despite an inability to stimulate production of specific mucosal IgA.

Intracellular replication ofSalmonella typhimuriumstrains in specific subsets of splenic macrophagesin vivo

“…typhimurium is located within splenic macrophages S. typhimurium has been found in CD18-positive phagocytes in the blood and liver (Richter-Dahlfors et al, 1997;Vazquez-Torres et al, 1999) and splenic CD11b-expressing cells (Matsui et al, 2000), which could include granulocytes, monocytes and NK cells, as well as subsets of B (e.g. CD5-positive) and T (mainly CD8-positive) lymphocytes.…”

“…In susceptible (Ity s ) host strains, less than 10 wild-type bacteria administered by the subcutaneous, intravenous or intraperitoneal route are sufficient to cause a fatal infection (Plant and Glynne, 1974;Shea et al, 1999). After oral inoculation, translocation of S. typhimurium across the gut epithelium into the bloodstream occurs by invasion of M cells in ileal Peyer's patches (Carter and Collins, 1974;Jones et al, 1994), and also via transmigrating CD18-expressing phagocytes (Vazquez-Torres et al, 1999). Regardless of the route of inoculation, a transient bacteraemia is followed over the course of several days by the accumulation of large numbers of bacteria within the spleen and liver, leading to a second, fatal bacteraemia (Carter and Collins, 1974;Shea et al, 1999).…”

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

“…In infections with intracellular parasites, including Salmonella serovars, the interplay between the activity of IFN-c and iron homeostasis within macrophages is a central battlefield deciding about the course of the disease [12,13]. S. typhimurium is a facultative intracellular microbe able to invade macrophages and to exploit these cells for multiplication and systemic spreading [14,15]. Within phagocytes, however, S. typhimurium has limited access to mammalian iron resources.…”

Salmonella pathogenicity island-2 and anticancer activity in mice

“…23 Further, these same mice were unable to accomplish systemic dissemination of salmonellae from the intestine, a phenomenon attributed to impaired phagocytic function. 28 Thus, the lack of tumor growth suppression by sseB À bacteria in CD18 À as well as CD18 + mice suggests that the impaired antitumor functions were not due to greater susceptibility of the SPI -2 mutants to immune attack; however. further studies are required in this area.…”

“…28 We reasoned that should the failure of SPI -2 mutations to suppress tumor growth in CD18 + mice be due to their increased susceptibility to macrophages and granulocytes, the antitumor functions might be restored in the CD18 -deficient mice. Therefore, the effects of SPI -2 + and SPI -2 À salmonellae on B16F10 melanoma tumor growth in C57B6 CD18 -deficient mice were investigated.…”