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TLR Signaling Is Required for Salmonella typhimurium Virulence
Nicholas Arpaia,1 Jernej Godec,1 Laura Lau,1 Kelsey E. Sivick,1 Laura M. McLaughlin,2 Marcus B. Jones,3 Tatiana Dracheva,3 Scott N. Peterson,3 Denise M. Monack,2 and Gregory M. Barton1,*
1Division of Immunology & Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3200, USA2Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA 3Pathogen Functional Genomics Resource Center, J. Craig Venter Institute, Rockville, MD 20850, USA *Correspondence: barton@berkeley.edu DOI 10.1016/j.cell.2011.01.031

SUMMARY

Toll-like receptors (TLRs) contribute to host resistance to microbial pathogens and can drive the evolution of virulencemechanisms. We have examined the relationship between host resistance and pathogen virulence using mice with a functional allele of the nramp-1 gene and lacking combinations of TLRs. Mice deficient in both TLR2 and TLR4 were highly susceptible to the intracellular bacterial pathogen Salmonella typhimurium, consistent with reduced innate immune function. However, mice lacking additional TLRs involved in S.typhimurium recognition were less susceptible to infection. In these TLR-deficient cells, bacteria failed to upregulate Salmonella pathogenicity island 2 (SPI-2) genes and did not form a replicative compartment. We demonstrate that TLR signaling enhances the rate of acidification of the Salmonella-containing phagosome, and inhibition of this acidification prevents SPI-2 induction. Our results indicatethat S. typhimurium requires cues from the innate immune system to regulate virulence genes necessary for intracellular survival, growth, and systemic infection.
INTRODUCTION During early stages of infection the innate immune system is essential for limiting microbial replication and spread before an adaptive response is mounted. Accordingly, pathogens have evolved virulence strategies toantagonize innate immune function (Hedrick, 2004; Rausher, 2001; Woolhouse et al., 2002). The interplay between host innate immune function and pathogen virulence mechanisms largely determines the outcome of most infections. Despite the logic of this conceptual framework, our understanding of the molecular interactions driving the emergence of virulence mechanisms remains relatively poor. Innate immunereceptors detect infection by recognizing conserved microbial features common to broad classes of

microbes (Janeway, 1989; Medzhitov, 2007). The Toll-like receptors (TLRs) target a range of microbial ligands, including lipopolysaccharide (TLR4), lipoproteins (TLR2), flagellin (TLR5), unmethylated CpG motifs in DNA (TLR9), doublestranded RNA (TLR3), and single-stranded RNA (TLR7 and TLR8) (Akiraet al., 2001; Kawai and Akira, 2005). Expression of TLRs on innate immune cells links microbial recognition to induction of antimicrobial mechanisms, such as production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and expression of antimicrobial peptides (AMPs). In addition, TLR activation can promote adaptive immunity through control of dendritic cell (DC) maturation(Iwasaki and Medzhitov, 2004). To study the evolution of pathogen virulence and its relationship to innate immunity, we have focused on TLR-mediated recognition of Salmonella enterica serovar typhimurium. S. typhimurium is a gram-negative bacterium that can survive and replicate within host macrophages (Coburn et al., 2007). Survival within macrophages requires a set of genes, many of which are encodedwithin Salmonella pathogenicity island 2 (SPI-2) (Galan, 2001; Shea et al., 1996; Waterman and Holden, 2003). SPI-2 encodes a type 3 secretion system (T3SS) that is expressed after the bacterium is phagocytosed (Cirillo et al., 1998; Pfeifer et al., 1999; Valdivia and Falkow, 1997). Translocation of SPI-2 effectors into the host cell transforms the phagosome into a compartment that supports...
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