Salmonellae are globally important Gram-negative bacterial pathogens that infect a range of hosts and cause several diseases, including gastroenteritis and typhoid fever. Orally ingested bacteria can survive in the inhospitable environment of the digestive tract and relocate to the intestine, where they invade the intestinal epithelia and either stimulate inflammation and fluid secretion (gastroenteritis) or cross the intestinal barrier and disseminate throughout the reticuloendothelial system (typhoid fever).
Salmonellae use two type III secretion systems (T3SSs) to deliver bacterial virulence proteins, called effectors, directly into host cells. The T3SS that is encoded on Salmonella pathogenicity island (SPI)-1 is responsible for delivering effectors across the plasma membrane and is involved in the invasion of epithelial cells and modulation of inflammation responses. The SPI2-encoded T3SS delivers effectors across the vacuolar membrane and contributes to the survival and replication of intracellular salmonellae. Recent findings suggest that the functions of these two T3SSs are not completely separate and might overlap.
The activities of several SPI1 T3SS effectors stimulate host actin-cytoskeletal rearrangements by either directly modulating actin dynamics or activating host GTPases, which results in membrane ruffling and bacterial uptake. The activation of host GTPases also triggers cell-signalling cascades, which promotes the production of host inflammatory responses.
After bacterial internalization, the host-cell actin cytoskeleton is returned to its normal shape and the inflammatory response is down-modulated. This reversal of actin rearrangement is modulated by SPI1 T3SS effectors, which manipulate the host-cell GTPases and signalling molecules that are involved in inflammation. Intracellular salmonellae resist killing by a range of host innate immune responses and reside in a specialized vacuole, called the Salmonella-containing vacuole (SCV). Sensing of antimicrobial peptides and the low pH of the SCV activates a large number of Salmonella genes that are involved in the remodelling of surface proteins and regulation of virulence genes
The intracellular environment induces expression of the SPI2 T3SS, which is responsible for specific intracellular phenotypes, such as the formation of Salmonella-induced filaments, maintenance of the SCV membrane, perinuclear localization of the SCV and manipulation of the microtubule and actin networks around the SCV.
Salmonellae are important causes of enteric diseases in all vertebrates. Characterization of the molecular mechanisms that underpin the interactions of salmonellae with their animal hosts has advanced greatly over the past decade, mainly through the study of Salmonella enterica serovar Typhimurium in tissue culture and animal models of infection. Knowledge of these bacterial processes and host responses has painted a dynamic and complex picture of the interaction between salmonellae and animal cells. This Review focuses on the molecular mechanisms of these host–pathogen interactions, in terms of their context, significance and future perspectives.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Genome-wide characterization of Salmonella Typhimurium genes required for the fitness under iron restriction
BMC Genomic Data Open Access 22 July 2022
Analytics and visualization tools to characterize single-cell stochasticity using bacterial single-cell movie cytometry data
BMC Bioinformatics Open Access 29 October 2021
Refrigeration of eggs influences the virulence of Salmonella Typhimurium
Scientific Reports Open Access 09 September 2021
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Pegues, D. A., Ohl, M. E. & Miller, S. I. in Principles and Practice of Infectious Diseases (eds Mandell, G. L., Bennet, J. E. & Dolin, R.) 2636–2654 (Churchill Livingstone, New York, 2005).
Garcia-del Portillo, F., Foster, J. W. & Finlay, B. B. Role of acid tolerance response genes in Salmonella typhimurium virulence. Infect. Immun. 61, 4489–4492 (1993).
Michetti, P., Mahan, M. J., Slauch, J. M., Mekalanos, J. J. & Neutra, M. R. Monoclonal secretory immunoglobulin A protects mice against oral challenge with the invasive pathogen Salmonella typhimurium. Infect. Immun. 60, 1786–1792 (1992).
Selsted, M. E., Miller, S. I., Henschen, A. H. & Ouellette, A. J. Enteric defensins: antibiotic peptide components of intestinal host defense. J. Cell Biol. 118, 929–936 (1992).
Prouty, A. M., Brodsky, I. E., Falkow, S. & Gunn, J. S. Bile-salt-mediated induction of antimicrobial and bile resistance in Salmonella typhimurium. Microbiology 150, 775–783 (2004).
Francis, C. L., Starnbach, M. N. & Falkow, S. Morphological and cytoskeletal changes in epithelial cells occur immediately upon interaction with Salmonella typhimurium grown under low-oxygen conditions. Mol. Microbiol. 6, 3077–3087 (1992).
Takeuchi, A. Electron microscope studies of experimental Salmonella infection. I. Penetration into the intestinal epithelium by Salmonella typhimurium. Am. J. Pathol. 50, 109–136 (1967). This reference showed membrane ruffling that is induced by Salmonella spp. in intestinal cells by microscopy for the first time.
Baumler, A. J., Tsolis, R. M. & Heffron, F. Contribution of fimbrial operons to attachment to and invasion of epithelial cell lines by Salmonella typhimurium. Infect. Immun. 64, 1862–1865 (1996).
Kohbata, S., Yokoyama, H. & Yabuuchi, E. Cytopathogenic effect of Salmonella typhi GIFU 10007 on M cells of murine ileal Peyer's patches in ligated ileal loops: an ultrastructural study. Microbiol. Immunol. 30, 1225–1237 (1986).
Jones, B. D., Ghori, N. & Falkow, S. Salmonella typhimurium initiates murine infection by penetrating and destroying the specialized epithelial M cells of the Peyer's patches. J. Exp. Med. 180, 15–23 (1994).
Vazquez-Torres, A. et al. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401, 804–808 (1999).
Jepson, M. A., Collares-Buzato, C. B., Clark, M. A., Hirst, B. H. & Simmons, N. L. Rapid disruption of epithelial barrier function by Salmonella typhimurium is associated with structural modification of intercellular junctions. Infect. Immun. 63, 356–359 (1995).
Zhang, S. et al. The Salmonella enterica serotype Typhimurium effector proteins SipA, SopA, SopB, SopD, and SopE2 act in concert to induce diarrhea in calves. Infect. Immun. 70, 3843–3855 (2002).
Raffatellu, M. et al. SipA, SopA, SopB, SopD, and SopE2 contribute to Salmonella enterica serotype Typhimurium invasion of epithelial cells. Infect. Immun. 73, 146–154 (2005).
Stecher, B. et al. Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin. Infect. Immun. 73, 3228–3241 (2005).
Hobbie, S., Chen, L. M., Davis, R. J. & Galan, J. E. Involvement of mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal epithelial cells. J. Immunol. 159, 5550–5559 (1997).
Galan, J. E. & Curtiss, R. 3rd Cloning and molecular characterization of genes whose products allow Salmonella typhimurium to penetrate tissue culture cells. Proc. Natl Acad. Sci. USA 86, 6383–6387 (1989).
Miller, S. I., Kukral, A. M. & Mekalanos, J. J. A two-component regulatory system (phoP phoQ) controls Salmonella typhimurium virulence. Proc. Natl Acad. Sci. USA 86, 5054–5058 (1989). This reference identified the PhoP/PhoQ two-component system as being important for the regulation of virulence.
Alpuche-Aranda, C. M., Swanson, J. A., Loomis, W. P. & Miller, S. I. Salmonella typhimurium activates virulence gene transcription within acidified macrophage phagosomes. Proc. Natl Acad. Sci. USA 89, 10079–10083 (1992).
Alpuche-Aranda, C. M., Racoosin, E. L., Swanson, J. A. & Miller, S. I. Salmonella stimulate macrophage macropinocytosis and persist within spacious phagosomes. J. Exp. Med. 179, 601–608 (1994).
Ochman, H., Soncini, F. C., Solomon, F. & Groisman, E. A. Identification of a pathogenicity island required for Salmonella survival in host cells. Proc. Natl Acad. Sci. USA 93, 7800–7804 (1996). References 21 and 22 were the first to show that the T3SS that is encoded on SPI2 is important for virulence.
Shea, J. E., Hensel, M., Gleeson, C. & Holden, D. W. Identification of a virulence locus encoding a second type III secretion system in Salmonella typhimurium. Proc. Natl Acad. Sci. USA 93, 2593–2597 (1996).
Vazquez-Torres, A. et al. Salmonella pathogenicity island 2-dependent evasion of the phagocyte NADPH oxidase. Science 287, 1655–1658 (2000).
Miao, E. A., Freeman, J. A. & Miller, S. I. Transcription of the SsrAB regulon is repressed by alkaline pH and is independent of PhoPQ and magnesium concentration. J. Bacteriol. 184, 1493–1497 (2002).
Bader, M. W. et al. Regulation of Salmonella typhimurium virulence gene expression by cationic antimicrobial peptides. Mol. Microbiol. 50, 219–230 (2003).
McCormick, B. A., Miller, S. I., Carnes, D. & Madara, J. L. Transepithelial signaling to neutrophils by salmonellae: a novel virulence mechanism for gastroenteritis. Infect. Immun. 63, 2302–2309 (1995).
McCormick, B. A. et al. Surface attachment of Salmonella typhimurium to intestinal epithelia imprints the subepithelial matrix with gradients chemotactic for neutrophils. J. Cell Biol. 131, 1599–1608 (1995).
Hansen-Wester, I. & Hensel, M. Salmonella pathogenicity islands encoding type III secretion systems. Microbes Infect. 3, 549–559 (2001).
Kubori, T. et al. Supramolecular structure of the Salmonella typhimurium type III protein secretion system. Science 280, 602–605 (1998). This study provided the first electron microscopy images of the T3SS needle complex.
Kimbrough, T. G. & Miller, S. I. Contribution of Salmonella typhimurium type III secretion components to needle complex formation. Proc. Natl Acad. Sci. USA 97, 11008–11013 (2000).
Kimbrough, T. G. & Miller, S. I. Assembly of the type III secretion needle complex of Salmonella typhimurium. Microbes Infect. 4, 75–82 (2002).
Miao, E. A. & Miller, S. I. A conserved amino acid sequence directing intracellular type III secretion by Salmonella typhimurium. Proc. Natl Acad. Sci. USA 97, 7539–7544 (2000).
Brumell, J. H. et al. SopD2 is a novel type III secreted effector of Salmonella typhimurium that targets late endocytic compartments upon delivery into host cells. Traffic 4, 36–48 (2003).
Lee, S. H. & Galan, J. E. Salmonella type III secretion-associated chaperones confer secretion-pathway specificity. Mol. Microbiol. 51, 483–495 (2004).
Karavolos, M. H. et al. Type III secretion of the Salmonella effector protein SopE is mediated via an N-terminal amino acid signal and not an mRNA sequence. J. Bacteriol. 187, 1559–1567 (2005).
Fu, Y. & Galan, J. E. Identification of a specific chaperone for SptP, a substrate of the centisome 63 type III secretion system of Salmonella typhimurium. J. Bacteriol. 180, 3393–3399 (1998).
Hong, K. H. & Miller, V. L. Identification of a novel Salmonella invasion locus homologous to Shigella ipgDE. J. Bacteriol. 180, 1793–1802 (1998).
Bronstein, P. A., Miao, E. A. & Miller, S. I. InvB is a type III secretion chaperone specific for SspA. J. Bacteriol. 182, 6638–6644 (2000).
Tucker, S. C. & Galan, J. E. Complex function for SicA, a Salmonella enterica serovar Typhimurium type III secretion-associated chaperone. J. Bacteriol. 182, 2262–2268 (2000).
Ehrbar, K., Friebel, A., Miller, S. I. & Hardt, W. D. Role of the Salmonella pathogenicity island 1 (SPI-1) protein InvB in type III secretion of SopE and SopE2, two Salmonella effector proteins encoded outside of SPI-1. J. Bacteriol. 185, 6950–6967 (2003).
Higashide, W. & Zhou, D. The first 45 amino acids of SopA are necessary for InvB binding and SPI-1 secretion. J. Bacteriol. 188, 2411–2420 (2006).
Akeda, Y. & Galan, J. E. Chaperone release and unfolding of substrates in type III secretion. Nature 437, 911–915 (2005).
Brown, N. F. et al. Salmonella pathogenicity island 2 is expressed prior to penetrating the intestine. PLoS Pathog. 1, e32 (2005).
Hensel, M. et al. Functional analysis of ssaJ and the ssaK/U operon, 13 genes encoding components of the type III secretion apparatus of Salmonella pathogenicity island 2. Mol. Microbiol. 24, 155–167 (1997).
Deiwick, J. et al. Mutations in Salmonella pathogenicity island 2 (SPI2) genes affecting transcription of SPI1 genes and resistance to antimicrobial agents. J. Bacteriol. 180, 4775–4780 (1998).
Steele-Mortimer, O. et al. The invasion-associated type III secretion system of Salmonella enterica serovar Typhimurium is necessary for intracellular proliferation and vacuole biogenesis in epithelial cells. Cell. Microbiol. 4, 43–54 (2002).
Hernandez, L. D., Hueffer, K., Wenk, M. R. & Galan, J. E. Salmonella modulates vesicular traffic by altering phosphoinositide metabolism. Science 304, 1805–1807 (2004).
Drecktrah, D., Knodler, L. A., Galbraith, K. & Steele-Mortimer, O. The Salmonella SPI1 effector SopB stimulates nitric oxide production long after invasion. Cell. Microbiol. 7, 105–113 (2005).
Lawley, T. D. et al. Genome-wide screen for Salmonella genes required for long-term systemic infection of the mouse. PLoS Pathog. 2, e11 (2006).
Brawn, L. C., Hayward, R. D. & Koronakis, V. Salmonella SPI1 effector SipA persists after entry and cooperates with a SPI2 effector to regulate phagosome maturation and intracellular replication. Cell Host Microbe 1, 63–75 (2007).
Giacomodonato, M. N. et al. SipA, SopA, SopB, SopD and SopE2 effector proteins of Salmonella enterica serovar Typhimurium are synthesized at late stages of infection in mice. Microbiology 153, 1221–1228 (2007).
Li, J. et al. Relationship between evolutionary rate and cellular location among the Inv/Spa invasion proteins of Salmonella enterica. Proc. Natl Acad. Sci. USA 92, 7252–7256 (1995).
Ochman, H. & Groisman, E. A. Distribution of pathogenicity islands in Salmonella spp. Infect. Immun. 64, 5410–5412 (1996).
Boyd, E. F., Li, J., Ochman, H. & Selander, R. K. Comparative genetics of the inv-spa invasion gene complex of Salmonella enterica. J. Bacteriol. 179, 1985–1991 (1997).
Hensel, M. et al. Analysis of the boundaries of Salmonella pathogenicity island 2 and the corresponding chromosomal region of Escherichia coli K-12. J. Bacteriol. 179, 1105–1111 (1997).
Hensel, M., Nikolaus, T. & Egelseer, C. Molecular and functional analysis indicates a mosaic structure of Salmonella pathogenicity island 2. Mol. Microbiol. 31, 489–498 (1999).
Porwollik, S., Wong, R. M. & McClelland, M. Evolutionary genomics of Salmonella: gene acquisitions revealed by microarray analysis. Proc. Natl Acad. Sci. USA 99, 8956–8961 (2002).
Hormaeche, C. E. Natural resistance to Salmonella typhimurium in different inbred mouse strains. Immunology 37, 311–318 (1979).
Vidal, S. M., Malo, D., Vogan, K., Skamene, E. & Gros, P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell 73, 469–485 (1993).
Hensel, M. et al. Genes encoding putative effector proteins of the type III secretion system of Salmonella pathogenicity island 2 are required for bacterial virulence and proliferation in macrophages. Mol. Microbiol. 30, 163–174 (1998).
Beuzon, C. R. & Holden, D. W. Use of mixed infections with Salmonella strains to study virulence genes and their interactions in vivo. Microbes Infect. 3, 1345–1352 (2001).
Monack, D. M., Bouley, D. M. & Falkow, S. Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFNgamma neutralization. J. Exp. Med. 199, 231–241 (2004).
Behlau, I. & Miller, S. I. A PhoP-repressed gene promotes Salmonella typhimurium invasion of epithelial cells. J. Bacteriol. 175, 4475–4484 (1993).
Barthel, M. et al. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71, 2839–2858 (2003).
Hardt, W. D., Chen, L. M., Schuebel, K. E., Bustelo, X. R. & Galan, J. E. S. typhimurium encodes an activator of Rho GTPases that induces membrane ruffling and nuclear responses in host cells. Cell 93, 815–826 (1998). This work elegantly demonstrated the ability of SopE to activate GTPases and subsequent actin rearrangements and transcriptional responses.
Bakshi, C. S. et al. Identification of SopE2, a Salmonella secreted protein which is highly homologous to SopE and involved in bacterial invasion of epithelial cells. J. Bacteriol. 182, 2341–2344 (2000).
Stender, S. et al. Identification of SopE2 from Salmonella typhimurium, a conserved guanine nucleotide exchange factor for Cdc42 of the host cell. Mol. Microbiol. 36, 1206–1221 (2000).
Friebel, A. et al. SopE and SopE2 from Salmonella typhimurium activate different sets of RhoGTPases of the host cell. J. Biol. Chem. 276, 34035–34040 (2001).
Zhou, D., Chen, L. M., Hernandez, L., Shears, S. B. & Galan, J. E. A Salmonella inositol polyphosphatase acts in conjunction with other bacterial effectors to promote host cell actin cytoskeleton rearrangements and bacterial internalization. Mol. Microbiol. 39, 248–259 (2001).
Patel, J. C. & Galan, J. E. Differential activation and function of Rho GTPases during Salmonella-host cell interactions. J. Cell Biol. 175, 453–463 (2006).
Ellerbroek, S. M. et al. SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis. Mol. Biol. Cell 15, 3309–3319 (2004).
Criss, A. K. & Casanova, J. E. Coordinate regulation of Salmonella enterica serovar Typhimurium invasion of epithelial cells by the Arp2/3 complex and Rho GTPases. Infect. Immun. 71, 2885–2891 (2003).
Unsworth, K. E., Way, M., McNiven, M., Machesky, L. & Holden, D. W. Analysis of the mechanisms of Salmonella-induced actin assembly during invasion of host cells and intracellular replication. Cell. Microbiol. 6, 1041–1055 (2004).
Shi, J., Scita, G. & Casanova, J. E. WAVE2 signaling mediates invasion of polarized epithelial cells by Salmonella typhimurium. J. Biol. Chem. 280, 29849–29855 (2005).
Hayward, R. D. & Koronakis, V. Direct nucleation and bundling of actin by the SipC protein of invasive Salmonella. EMBO J. 18, 4926–4934 (1999). References 75 and 76 detected direct manipulation of actin by the SPI1 T3SS effectors SipA and SipC.
Zhou, D., Mooseker, M. S. & Galan, J. E. Role of the S. typhimurium actin-binding protein SipA in bacterial internalization. Science 283, 2092–2095 (1999).
Scherer, C. A., Cooper, E. & Miller, S. I. The Salmonella type III secretion translocon protein SspC is inserted into the epithelial cell plasma membrane upon infection. Mol. Microbiol. 37, 1133–1145 (2000).
McGhie, E. J., Hayward, R. D. & Koronakis, V. Cooperation between actin-binding proteins of invasive Salmonella: SipA potentiates SipC nucleation and bundling of actin. EMBO J. 20, 2131–2139 (2001).
Higashide, W., Dai, S., Hombs, V. P. & Zhou, D. Involvement of SipA in modulating actin dynamics during Salmonella invasion into cultured epithelial cells. Cell. Microbiol. 4, 357–365 (2002).
Chen, L. M., Hobbie, S. & Galan, J. E. Requirement of CDC42 for Salmonella-induced cytoskeletal and nuclear responses. Science 274, 2115–2118 (1996).
Boyle, E. C., Brown, N. F. & Finlay, B. B. Salmonella enterica serovar Typhimurium effectors SopB, SopE, SopE2 and SipA disrupt tight junction structure and function. Cell. Microbiol. 8, 1946–1957 (2006).
Norris, F. A., Wilson, M. P., Wallis, T. S., Galyov, E. E. & Majerus, P. W. SopB, a protein required for virulence of Salmonella dublin, is an inositol phosphate phosphatase. Proc. Natl Acad. Sci. USA 95, 14057–14059 (1998).
Hersh, D. et al. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc. Natl. Acad. Sci. USA 96, 2396–2401 (1999).
Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in Salmonella-infected macrophages. Nature Immunol. 7, 576–582 (2006).
Miao, E. A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nature Immunol. 7, 569–575 (2006).
Lara-Tejero, M. et al. Role of the caspase-1 inflammasome in Salmonella typhimurium pathogenesis. J. Exp. Med. 203, 1407–1412 (2006).
Raupach, B., Peuschel, S. K., Monack, D. M. & Zychlinsky, A. Caspase-1-mediated activation of interleukin-1β (IL-1β) and IL-18 contributes to innate immune defenses against Salmonella enterica serovar Typhimurium infection. Infect. Immun. 74, 4922–4926 (2006).
Jones, M. A. et al. Secreted effector proteins of Salmonella dublin act in concert to induce enteritis. Infect. Immun. 66, 5799–5804 (1998).
Wood, M. W. et al. The secreted effector protein of Salmonella dublin, SopA, is translocated into eukaryotic cells and influences the induction of enteritis. Cell Microbiol. 2, 293–303 (2000).
Zhang, Y., Higashide, W. M., McCormick, B. A., Chen, J. & Zhou, D. The inflammation-associated Salmonella SopA is a HECT-like E3 ubiquitin ligase. Mol. Microbiol. 62, 786–793 (2006).
Jiang, X. et al. The related effector proteins SopD and SopD2 from Salmonella enterica serovar Typhimurium contribute to virulence during systemic infection of mice. Mol. Microbiol. 54, 1186–1198 (2004).
Fu, Y. & Galan, J. E. A Salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion. Nature 401, 293–297 (1999). References 92 and 93 identified the GTPase-antagonizing activity of SptP and showed how the activities of SopE and SptP are temporally regulated by proteasome-dependent degradation.
Kubori, T. & Galan, J. E. Temporal regulation of Salmonella virulence effector function by proteasome-dependent protein degradation. Cell 115, 333–342 (2003).
Murli, S., Watson, R. O. & Galan, J. E. Role of tyrosine kinases and the tyrosine phosphatase SptP in the interaction of Salmonella with host cells. Cell. Microbiol. 3, 795–810 (2001).
Haraga, A. & Miller, S. I. A Salmonella enterica serovar Typhimurium translocated leucine-rich repeat effector protein inhibits NF-kappa B-dependent gene expression. Infect. Immun. 71, 4052–4058 (2003).
Miao, E. A. et al. Salmonella typhimurium leucine-rich repeat proteins are targeted to the SPI1 and SPI2 type III secretion systems. Mol. Microbiol. 34, 850–864 (1999).
Rohde, J. R., Breitkreutz, A., Chenal, A., Sansonetti, P. J. & Parsot, C. Type III secretion effectors of the IpaH family are E3 ubiquitin ligases. Cell Host Microbe 1, 77–83 (2007).
Haraga, A. & Miller, S. I. A Salmonella type III secretion effector interacts with the mammalian serine/threonine protein kinase PKN1. Cell. Microbiol. 8, 837–846 (2006).
Collier-Hyams, L. S. et al. Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-kappaB pathway. J. Immunol. 169, 2846–2850 (2002).
Mittal, R., Peak-Chew, S. Y. & McMahon, H. T. Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling. Proc. Natl Acad. Sci. USA 103, 18574–18579 (2006).
Mukherjee, S. et al. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science 312, 1211–1214 (2006).
Buchwald, D. S. & Blaser, M. J. A review of human salmonellosis: II. Duration of excretion following infection with nontyphi Salmonella. Rev. Infect. Dis. 6, 345–356 (1984).
Richter-Dahlfors, A., Buchan, A. M. & Finlay, B. B. Murine salmonellosis studied by confocal microscopy: Salmonella typhimurium resides intracellularly inside macrophages and exerts a cytotoxic effect on phagocytes in vivo. J. Exp. Med. 186, 569–580 (1997).
Fields, P. I., Swanson, R. V., Haidaris, C. G. & Heffron, F. Mutants of Salmonella typhimurium that cannot survive within the macrophage are avirulent. Proc. Natl Acad. Sci. USA 83, 5189–5193 (1986). This important study demonstrated that survival within macrophages is important for S. typhimurium virulence.
O'Callaghan, D., Maskell, D., Liew, F. Y., Easmon, C. S. & Dougan, G. Characterization of aromatic- and purine-dependent Salmonella typhimurium: attention, persistence, and ability to induce protective immunity in BALB/c mice. Infect. Immun. 56, 419–423 (1988).
Dukes, J. D. et al. The secreted Salmonella dublin phosphoinositide phosphatase, SopB, localizes to PtdIns(3)P-containing endosomes and perturbs normal endosome to lysosome trafficking. Biochem. J. 395, 239–247 (2006).
Carrol, M. E., Jackett, P. S., Aber, V. R. & Lowrie, D. B. Phagolysosome formation, cyclic adenosine 3′:5′-monophosphate and the fate of Salmonella typhimurium within mouse peritoneal macrophages. J. Gen. Microbiol. 110, 421–429 (1979).
Buchmeier, N. A. & Heffron, F. Inhibition of macrophage phagosome–lysosome fusion by Salmonella typhimurium. Infect. Immun. 59, 2232–2238 (1991).
Oh, Y. K. et al. Rapid and complete fusion of macrophage lysosomes with phagosomes containing Salmonella typhimurium. Infect. Immun. 64, 3877–3883 (1996).
Drecktrah, D., Knodler, L. A., Howe, D. & Steele-Mortimer, O. Salmonella trafficking is defined by continuous dynamic interactions with the endolysosomal system. Traffic 8, 212–225 (2007).
Rathman, M., Sjaastad, M. D. & Falkow, S. Acidification of phagosomes containing Salmonella typhimurium in murine macrophages. Infect. Immun. 64, 2765–2773 (1996).
Martin-Orozco, N. et al. Visualization of vacuolar acidification-induced transcription of genes of pathogens inside macrophages. Mol. Biol. Cell 17, 498–510 (2006).
Steele-Mortimer, O., Meresse, S., Gorvel, J. P., Toh, B. H. & Finlay, B. B. Biogenesis of Salmonella typhimurium-containing vacuoles in epithelial cells involves interactions with the early endocytic pathway. Cell. Microbiol. 1, 33–49 (1999).
Smith, A. C., Cirulis, J. T., Casanova, J. E., Scidmore, M. A. & Brumell, J. H. Interaction of the Salmonella-containing vacuole with the endocytic recycling system. J. Biol. Chem. 280, 24634–24641 (2005).
Garcia-del Portillo, F. & Finlay, B. B. Targeting of Salmonella typhimurium to vesicles containing lysosomal membrane glycoproteins bypasses compartments with mannose 6-phosphate receptors. J. Cell Biol. 129, 81–97 (1995).
Meresse, S., Steele-Mortimer, O., Finlay, B. B. & Gorvel, J. P. The rab7 GTPase controls the maturation of Salmonella typhimurium-containing vacuoles in HeLa cells. EMBO J. 18, 4394–4403 (1999).
Hashim, S., Mukherjee, K., Raje, M., Basu, S. K. & Mukhopadhyay, A. Live Salmonella modulate expression of Rab proteins to persist in a specialized compartment and escape transport to lysosomes. J. Biol. Chem. 275, 16281–16288 (2000).
Brumell, J. H., Tang, P., Mills, S. D. & Finlay, B. B. Characterization of Salmonella-induced filaments (Sifs) reveals a delayed interaction between Salmonella-containing vacuoles and late endocytic compartments. Traffic 2, 643–653 (2001).
Garvis, S. G., Beuzon, C. R. & Holden, D. W. A role for the PhoP/Q regulon in inhibition of fusion between lysosomes and Salmonella-containing vacuoles in macrophages. Cell. Microbiol. 3, 731–744 (2001).
Cuellar-Mata, P. et al. Nramp1 modifies the fusion of Salmonella typhimurium-containing vacuoles with cellular endomembranes in macrophages. J. Biol. Chem. 277, 2258–2265 (2002).
Catron, D. M. et al. The Salmonella-containing vacuole is a major site of intracellular cholesterol accumulation and recruits the GPI-anchored protein CD55. Cell. Microbiol. 4, 315–328 (2002).
Fields, P. I., Groisman, E. A. & Heffron, F. A Salmonella locus that controls resistance to microbicidal proteins from phagocytic cells. Science 243, 1059–1062 (1989).
Miller, S. I. & Mekalanos, J. J. Constitutive expression of the PhoP regulon attenuates Salmonella virulence and survival within macrophages. J. Bacteriol. 172, 2485–2490 (1990).
Nickerson, C. A. & Curtiss, R. Role of sigma factor RpoS in initial stages of Salmonella typhimurium infection. Infect. Immun. 65, 1814–1823 (1997).
Bearson, B. L., Wilson, L. & Foster, J. W. A low pH-inducible, PhoPQ-dependent acid tolerance response protects Salmonella typhimurium against inorganic acid stress. J. Bacteriol. 180, 2409–2417 (1998).
Shiloh, M. U. et al. Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible nitric oxide synthase. Immunity 10, 29–38 (1999).
Gunn, J. S., Ryan, S. S., Van Velkinburgh, J. C., Ernst, R. K. & Miller, S. I. Genetic and functional analysis of a PmrA–PmrB-regulated locus necessary for lipopolysaccharide modification, antimicrobial peptide resistance, and oral virulence of Salmonella enterica serovar Typhimurium. Infect. Immun. 68, 6139–6146 (2000).
Vazquez-Torres, A., Jones-Carson, J., Mastroeni, P., Ischiropoulos, H. & Fang, F. C. Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro. J. Exp. Med. 192, 227–236 (2000).
Hisert, K. B. et al. A glutamate-alanine-leucine (EAL) domain protein of Salmonella controls bacterial survival in mice, antioxidant defence and killing of macrophages: role of cyclic diGMP. Mol. Microbiol. 56, 1234–1245 (2005).
Humphreys, S., Stevenson, A., Bacon, A., Weinhardt, A. B. & Roberts, M. The alternative sigma factor, sigmaE, is critically important for the virulence of Salmonella typhimurium. Infect. Immun. 67, 1560–1568 (1999).
Rosenberger, C. M., Gallo, R. L. & Finlay, B. B. Interplay between antibacterial effectors: a macrophage antimicrobial peptide impairs intracellular Salmonella replication. Proc. Natl Acad. Sci. USA 101, 2422–2427 (2004).
Curtiss, R. & Kelly, S. M. Salmonella typhimurium deletion mutants lacking adenylate cyclase and cyclic AMP receptor protein are avirulent and immunogenic. Infect. Immun. 55, 3035–3043 (1987).
Fang, F. C. et al. The alternative sigma factor katF (rpoS) regulates Salmonella virulence. Proc. Natl Acad. Sci. USA 89, 11978–11982 (1992).
Lee, A. K., Detweiler, C. S. & Falkow, S. OmpR regulates the two-component system SsrA-SsrB in Salmonella pathogenicity island 2. J. Bacteriol. 182, 771–781 (2000).
Testerman, T. L. et al. The alternative sigma factor σE controls antioxidant defences required for Salmonella virulence and stationary-phase survival. Mol. Microbiol. 43, 771–782 (2002).
Prost, L. R. et al. Activation of the bacterial sensor kinase PhoQ by acidic pH. Mol. Cell 26, 165–174 (2007). References 136 and 138 show that PhoQ directly senses antimicrobial peptides and low pH.
Heithoff, D. M. et al. Coordinate intracellular expression of Salmonella genes induced during infection. J. Bacteriol. 181, 799–807 (1999).
Bader, M. W. et al. Recognition of antimicrobial peptides by a bacterial sensor kinase. Cell 122, 461–472 (2005).
Cho, U. S. et al. Metal bridges between the PhoQ sensor domain and the membrane regulate transmembrane signaling. J. Mol. Biol. 356, 1193–1206 (2006).
Gibbons, H. S., Kalb, S. R., Cotter, R. J. & Raetz, C. R. Role of Mg2+ and pH in the modification of Salmonella lipid A after endocytosis by macrophage tumour cells. Mol. Microbiol. 55, 425–440 (2005).
Ernst, R. K., Guina, T. & Miller, S. I. Salmonella typhimurium outer membrane remodeling: role in resistance to host innate immunity. Microbes Infect. 3, 1327–1334 (2001).
Guo, L. et al. Regulation of lipid A modifications by Salmonella typhimurium virulence genes phoP-phoQ. Science 276, 250–253 (1997). This study demonstrates that PhoP/PhoQ regulates the remodelling of the LPS structure in a way that makes it less immunostimulatory by TLR4 signalling.
Gunn, J. S. et al. PmrA-PmrB-regulated genes necessary for 4-aminoarabinose lipid A modification and polymyxin resistance. Mol. Microbiol. 27, 1171–1182 (1998).
Guo, L. et al. Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 95, 189–198 (1998).
Hilbert, F., Garcia-del Portillo, F. & Groisman, E. A. A periplasmic D-alanyl-D-alanine dipeptidase in the Gram-negative bacterium Salmonella enterica. J. Bacteriol. 181, 2158–2165 (1999).
Fang, F. C. et al. Virulent Salmonella typhimurium has two periplasmic Cu, Zn-superoxide dismutases. Proc. Natl Acad. Sci. USA 96, 7502–7507 (1999).
Eriksson, S., Lucchini, S., Thompson, A., Rhen, M. & Hinton, J. C. Unravelling the biology of macrophage infection by gene expression profiling of intracellular Salmonella enterica. Mol. Microbiol. 47, 103–118 (2003).
Cirillo, D. M., Valdivia, R. H., Monack, D. M. & Falkow, S. Macrophage-dependent induction of the Salmonella pathogenicity island 2 type III secretion system and its role in intracellular survival. Mol. Microbiol. 30, 175–188 (1998).
Hensel, M. et al. Simultaneous identification of bacterial virulence genes by negative selection. Science 269, 400–403 (1995).
Uchiya, K. et al. A Salmonella virulence protein that inhibits cellular trafficking. EMBO J. 18, 3924–3933 (1999).
Shotland, Y., Kramer, H. & Groisman, E. A. The Salmonella SpiC protein targets the mammalian Hook3 protein function to alter cellular trafficking. Mol. Microbiol. 49, 1565–1576 (2003).
Freeman, J. A., Rappl, C., Kuhle, V., Hensel, M. & Miller, S. I. SpiC is required for translocation of Salmonella pathogenicity island 2 effectors and secretion of translocon proteins SseB and SseC. J. Bacteriol. 184, 4971–4980 (2002).
Yu, X. J. et al. SpiC is required for secretion of Salmonella pathogenicity island 2 type III secretion system proteins. Cell. Microbiol. 4, 531–540 (2002).
Beuzon, C. R. et al. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. EMBO J. 19, 3235–3249 (2000).
Ruiz-Albert, J. et al. Complementary activities of SseJ and SifA regulate dynamics of the Salmonella typhimurium vacuolar membrane. Mol. Microbiol. 44, 645–661 (2002).
Freeman, J. A., Ohl, M. E. & Miller, S. I. The Salmonella enterica serovar Typhimurium translocated effectors SseJ and SifsB are targeted to the Salmonella-containing vacuole. Infect. Immun. 71, 418–427 (2003).
Knodler, L. A. et al. Salmonella type III effectors PipB and PipB2 are targeted to detergent-resistant microdomains on internal host cell membranes. Mol. Microbiol. 49, 685–704 (2003).
Deiwick, J. et al. The translocated Salmonella effector proteins SseF and SseG interact and are required to establish an intracellular replication niche. Infect. Immun. 74, 6965–6972 (2006).
Brumell, J. H., Goosney, D. L. & Finlay, B. B. SifA, a type III secreted effector of Salmonella typhimurium, directs Salmonella-induced filament (Sif) formation along microtubules. Traffic 3, 407–415 (2002).
Miao, E. A. et al. Salmonella effectors translocated across the vacuolar membrane interact with the actin cytoskeleton. Mol. Microbiol. 48, 401–415 (2003).
Salcedo, S. P. & Holden, D. W. SseG, a virulence protein that targets Salmonella to the Golgi network. EMBO J. 22, 5003–5014 (2003).
Kuhle, V., Jackel, D. & Hensel, M. Effector proteins encoded by Salmonella pathogenicity island 2 interfere with the microtubule cytoskeleton after translocation into host cells. Traffic 5, 356–370 (2004).
Garcia-del Portillo, F., Zwick, M. B., Leung, K. Y. & Finlay, B. B. Salmonella induces the formation of filamentous structures containing lysosomal membrane glycoproteins in epithelial cells. Proc. Natl Acad. Sci. USA 90, 10544–10548 (1993). References 163 and 164 were the first to show that S. typhimurium produces Sifs in infected cultured cells and that the effector that is responsible for this activity is SifA.
Stein, M. A., Leung, K. Y., Zwick, M., Garcia-del Portillo, F. & Finlay, B. B. Identification of a Salmonella virulence gene required for formation of filamentous structures containing lysosomal membrane glycoproteins within epithelial cells. Mol. Microbiol. 20, 151–164 (1996).
Knodler, L. A. & Steele-Mortimer, O. The Salmonella effector PipB2 affects late endosome/lysosome distribution to mediate Sif extension. Mol. Biol. Cell. 16, 4108–4123 (2005).
Boucrot, E., Henry, T., Borg, J. P., Gorvel, J. P. & Meresse, S. The intracellular fate of Salmonella depends on the recruitment of kinesin. Science 308, 1174–1178 (2005).
Alto, N. M. et al. Identification of a bacterial type III effector family with G protein mimicry functions. Cell 124, 133–145 (2006).
Reinicke, A. T. et al. A Salmonella typhimurium effector protein SifA is modified by host cell prenylation and S-acylation machinery. J. Biol. Chem. 280, 14620–14627 (2005).
Guy, R. L., Gonias, L. A. & Stein, M. A. Aggregation of host endosomes by Salmonella requires SPI2 translocation of SseFG and involves SpvR and the fms-aroE intragenic region. Mol. Microbiol. 37, 1417–1435 (2000).
Henry, T. et al. The Salmonella effector protein PipB2 is a linker for kinesin-1. Proc. Natl Acad. Sci. USA 103, 13497–13502 (2006).
Hansen-Wester, I., Stecher, B. & Hensel, M. Type III secretion of Salmonella enterica serovar Typhimurium translocated effectors and SseFG. Infect. Immun. 70, 1403–1409 (2002).
Kuhle, V. & Hensel, M. SseF and SseG are translocated effectors of the type III secretion system of Salmonella pathogenicity island 2 that modulate aggregation of endosomal compartments. Cell. Microbiol. 4, 813–824 (2002).
Abrahams, G. L., Muller, P. & Hensel, M. Functional dissection of SseF, a type III effector protein involved in positioning the Salmonella-containing vacuole. Traffic 7, 950–965 (2006).
Kuhle, V., Abrahams, G. L. & Hensel, M. Intracellular Salmonella enterica redirect exocytic transport processes in a Salmonella pathogenicity island 2-dependent manner. Traffic 7, 716–730 (2006).
Birmingham, C. L., Jiang, X., Ohlson, M. B., Miller, S. I. & Brumell, J. H. Salmonella-induced filament formation is a dynamic phenotype induced by rapidly replicating Salmonella enterica serovar Typhimurium in epithelial cells. Infect. Immun. 73, 1204–1208 (2005).
Lesnick, M. L., Reiner, N. E., Fierer, J. & Guiney, D. G. The Salmonella spvB virulence gene encodes an enzyme that ADP-ribosylates actin and destabilizes the cytoskeleton of eukaryotic cells. Mol. Microbiol. 39, 1464–1470 (2001).
Browne, S. H., Lesnick, M. L. & Guiney, D. G. Genetic requirements for Salmonella-induced cytopathology in human monocyte-derived macrophages. Infect. Immun. 70, 7126–7135 (2002).
Gotoh, H. et al. Extracellular secretion of the virulence plasmid-encoded ADP-ribosyltransferase SpvB in Salmonella. Microb. Pathog. 34, 227–238 (2003).
Brumlik, M. J. & Buckley, J. T. Identification of the catalytic triad of the lipase/acyltransferase from Aeromonas hydrophila. J. Bacteriol. 178, 2060–2064 (1996).
Ohlson, M. B., Fluhr, K., Birmingham, C. L., Brumell, J. H. & Miller, S. I. SseJ deacylase activity by Salmonella enterica serovar Typhimurium promotes virulence in mice. Infect. Immun. 73, 6249–6259 (2005).
Harrison, R. E. et al. Salmonella impairs RILP recruitment to Rab7 during maturation of invasion vacuoles. Mol. Biol. Cell 15, 3146–3154 (2004).
Marsman, M., Jordens, I., Kuijl, C., Janssen, L. & Neefjes, J. Dynein-mediated vesicle transport controls intracellular Salmonella replication. Mol. Biol. Cell 15, 2954–2964 (2004).
Meresse, S. et al. Remodelling of the actin cytoskeleton is essential for replication of intravacuolar Salmonella. Cell. Microbiol. 3, 567–577 (2001).
Viboud, G. I. & Bliska, J. B. A bacterial type III secretion system inhibits actin polymerization to prevent pore formation in host cell membranes. EMBO J. 20, 5373–5382 (2001).
Marlovits, T. C. et al. Structural insights into the assembly of the type III secretion needle complex. Science 306, 1040–1042 (2004).
Sun, J., Hobert, M. E., Rao, A. S., Neish, A. S. & Madara, J. L. Bacterial activation of β-catenin signaling in human epithelia. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G220–227 (2004).
Zhou, D., Mooseker, M. S. & Galan, J. E. An invasion-associated Salmonella protein modulates the actin-bundling activity of plastin. Proc. Natl Acad. Sci. USA 96, 10176–10181 (1999).
Lee, C. A. et al. A secreted Salmonella protein induces a proinflammatory response in epithelial cells, which promotes neutrophil migration. Proc. Natl Acad. Sci. USA 97, 12283–12288 (2000).
Hernandez, L. D., Pypaert, M., Flavell, R. A. & Galan, J. E. A Salmonella protein causes macrophage cell death by inducing autophagy. J. Cell Biol. 163, 1123–1131 (2003).
Hayward, R. D. et al. Cholesterol binding by the bacterial type III translocon is essential for virulence effector delivery into mammalian cells. Mol. Microbiol. 56, 590–603 (2005).
Carlson, S. A., Omary, M. B. & Jones, B. D. Identification of cytokeratins as accessory mediators of Salmonella entry into eukaryotic cells. Life Sci. 70, 1415–1426 (2002).
Knodler, L. A., Finlay, B. B. & Steele-Mortimer, O. The Salmonella effector protein SopB protects epithelial cells from apoptosis by sustained activation of Akt. J. Biol. Chem. 280, 9058–9064 (2005).
Mukherjee, K., Parashuraman, S., Raje, M. & Mukhopadhyay, A. SopE acts as an Rab5-specific nucleotide exchange factor and recruits non-prenylated Rab5 on Salmonella-containing phagosomes to promote fusion with early endosomes. J. Biol. Chem. 276, 23607–23615 (2001).
Coombes, B. K. et al. Genetic and molecular analysis of GogB, a phage-encoded type III-secreted substrate in Salmonella enterica serovar Typhimurium with autonomous expression from its associated phage. J. Mol. Biol. 348, 817–830 (2005).
Brumell, J. H., Rosenberger, C. M., Gotto, G. T., Marcus, S. L. & Finlay, B. B. SifA permits survival and replication of Salmonella typhimurium in murine macrophages. Cell. Microbiol. 3, 75–84 (2001).
Tezcan-Merdol, D. et al. Actin is ADP-ribosylated by the Salmonella enterica virulence-associated protein SpvB. Mol. Microbiol. 39, 606–619 (2001).
Worley, M. J., Nieman, G. S., Geddes, K. & Heffron, F. Salmonella typhimurium disseminates within its host by manipulating the motility of infected cells. Proc. Natl Acad. Sci. USA 103, 17915–17920 (2006).
Kujat Choy, S. L. et al. SseK1 and SseK2 are novel translocated proteins of Salmonella enterica serovar Typhimurium. Infect. Immun. 72, 5115–5125 (2004).
Rytkonen, A. et al. SseL, a Salmonella deubiquitinase required for macrophage killing and virulence. Proc. Natl Acad. Sci. USA 104, 3502–3507 (2007).
Geddes, K., Worley, M., Niemann, G. & Heffron, F. Identification of new secreted effectors in Salmonella enterica serovar Typhimurium. Infect. Immun. 73, 6260–6271 (2005).
Tsolis, R. M., Adams, L. G., Ficht, T. A. & Baumler, A. J. Contribution of Salmonella typhimurium virulence factors to diarrheal disease in calves. Infect. Immun. 67, 4879–4885 (1999).
We would like to thank the entire Salmonella pathogenesis community for its work that made this Review possible. In particular, we are grateful to members of the Miller laboratory, past and present, for their contributions to the ideas that are presented here. We would also like to apologize to those authors whose work was not cited owing to space limitations. A.H. is supported by a Career Development Award from the Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (National Institute of Allergy and Infectious Diseases (NIAID) grant U54 AI057141). M.B.O. is supported by the Comprehensive Training in Inter-Disciplinary Oral Health Research T32 grant DE07132. S.I.M. is supported by the National Institutes of Health, NIAID grants R01 AI30479, R01 AI048683 and U54 AI057141 for the Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research.
Entrez Genome Project
A nonspecific process by which small volumes of extracellular fluid are taken up by certain eukaryotic cells owing to the engulfment of fluid in small membrane vesicles.
- Tight junction
The connection between two adjacent cells in a monolayer that is formed by extracellular-matrix and protein complexes; impermeable to water and other molecules.
Used to refer to the endocytosis of large volumes of extracellular fluid and particles by membrane ruffles.
- Reticuloendothelial system
(RES). The meshwork of connective tissue that contains immune cells, such as macrophages, and surrounds tissues that are associated with the immune system, such as the spleen and lymph nodes. Immune cells in the RES provide surveillance of antigens that the body encounters and can be quickly recruited to sites of infection.
- Pathogenicity island
A large region of genomic DNA that encodes genes that are associated with virulence. A pathogenicity island is typically transferred horizontally between bacterial strains and is often inserted into tRNA genes within the genome.
- Transepithelial migration
The movement of cells, such as neutrophils and invading bacteria, from the basolateral (bottom) to the apical (top) surface, or the reverse, of an epithelial cell layer. Migration can also occur between two adjacent cells through tight junctions.
An organism that cannot synthesize certain organic compounds, such as amino acids, that are necessary for its metabolism. For growth, auxotrophic organisms must be able to take up the lacking compound from the surrounding environment.
The post-translational addition of lipid chains, such as farnesyl or geranylgeranyl, to cysteine residues in proteins that contain a prenylation motif called a CaaX box. This process facilitates membrane localization and/or protein–protein interactions.
Rights and permissions
About this article
Cite this article
Haraga, A., Ohlson, M. & Miller, S. Salmonellae interplay with host cells. Nat Rev Microbiol 6, 53–66 (2008). https://doi.org/10.1038/nrmicro1788
This article is cited by
Genome-wide characterization of Salmonella Typhimurium genes required for the fitness under iron restriction
BMC Genomic Data (2022)
Oral GSH Exerts a Therapeutic Effect on Experimental Salmonella Meningitis by Protecting BBB Integrity and Inhibiting Salmonella-induced Apoptosis
Journal of Neuroimmune Pharmacology (2022)
The crosstalk between bacteria and host autophagy: host defense or bacteria offense
Journal of Microbiology (2022)
Analytics and visualization tools to characterize single-cell stochasticity using bacterial single-cell movie cytometry data
BMC Bioinformatics (2021)
Refrigeration of eggs influences the virulence of Salmonella Typhimurium
Scientific Reports (2021)