Coordinate Regulation of Salmonella Pathogenicity Islands 1 (SPI1) and 4 (SPI4) in Salmonella enterica sv. Typhimurium

Departments of Microbiology, Laboratory Medicine, and Medicine, University of Washington School of Medicine, Seattle, WA 98195; Mount Holyoke College, South Hadley, MA 01075; North Carolina State University, Raleigh, NC 27606

^* To whom correspondence should be addressed. Email: slibby{at}u.washington.edu.

	Abstract

Salmonella enterica serovar Typhimurium harbors five pathogenicity islands (SPI) required for infection in vertebrate hosts. Although the role of SPI1 in promoting epithelial invasion and proinflammatory cell death has been amply documented, SPI4 has only more recently been implicated in Salmonella virulence. SPI4 is a 24kb pathogenicity island containing six ORFs, siiA-siiF. Secretion of the 595kD SiiE protein requires a type 1 secretory system encoded by siiC, siiD and siiF. An operon polarity suppressor (ops) sequence within the 5' untranslated region upstream of siiA is required for optimal SPI4 expression and predicted to bind the antiterminator RfaH. SiiE concentrations are decreased in a SPI1-mutant strain, suggesting that SPI1 and SPI4 may have common regulatory inputs. SPI1 gene expression is positively regulated by the transcriptional activators HilA, HilC and HilD, encoded within SPI1, and negatively regulated by the regulators HilE and PhoP. Here we show that mutations in hilA, hilC, or hilD similarly reduce expression of siiE, and mutations in hilE or phoP enhance siiE expression. Individual overexpression of HilA, HilC, or HilD in the absence of SPI1 cannot activate siiE expression, suggesting that these transcriptional regulators act in concert or in combination with additional SPI1-encoded regulatory loci to activate SPI4. HilA is no longer required for siiE expression in an hns mutant strain, suggesting that HilA promotes SPI4 expression by antagonizing the global transcriptional silencer H-NS. Coordinate regulation suggests that SPI1 and SPI4 play complementary roles in the interaction of S. Typhimurium with the host intestinal mucosa.