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Child Health Research Center

Araceli Santiago, PhD

Araceli Santiago, PhD

Araceli Santiago, PhD, Research Associate Professor of Pediatrics

Diarrheal diseases account for 1 in 9 child deaths worldwide, making diarrhea the second leading cause of death among children under the age of 5. While there are many etiological agents responsible for diarrhea, pathogenic E. coli and Shigella are major contributors.

My research focuses on understanding the mechanism of regulation of AraC/XylS family members in pathogenic E. coli strains. AraC/Xyls is a large family of transcriptional regulators in Gram-negative bacteria controlling metabolic, cellular stress, and virulence. With the development of bioinformatics programs, new uncharacterized AraC/XylS members have been identified. Recently, nearly 2000 known and putative AraC/XylS members in 149 bacterial genomes have been identified.

Recently, we uncovered and characterized a new family of negative AraC/Xyls regulators (ANR) (AraC Negative Regulators) in Gram-negative bacteria. ANR family comprise at least 50 hypothetical proteins, present in 7 major species: Escherichia coli., Citrobacter spp., Haemophilus spp., Pasteurella spp., Mannheimia spp., Pantoea spp., and Aggregatibacter spp.

In pathogenic E. coli strains, ANR were subdivided into two main families (SFs), SF1 and SF2. SF1 comprised the ARN members found in enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), Shiga-toxin producing E. coli (STEC), enterotoxigenic E. coli (ETEC), extra-intestinal pathogenic E. coli (ExPEC), enteroinvasive E. coli (EIEC), while that SF2 family comprised homologs mainly found in enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC) and Shiga-toxin producing EAEC.

Members of the ANR family are small molecules (4.36-9.54 kDa). Alignment of ANR members revealed conserved alpha helical motifs with several highly conserved residues. Some of the ANR members characterized in our group include orf60 (termed Aar) in EAEC, orf02851 (termed Rnr) in Citrobacter rodentium, orf0450 and orf01070 (termed Cnr) in ETEC. Aar, Cnr and Rnr downregulate the expression of positive regulator partners AggR, CfaD/Rns and RegA, respectively, all members of the AraC/XylS family of regulators. Aar, in EAEC prototype strain 042 down regulates AggR and at least 44 genes identified as part of the AggR regulon, including AAF fimbria, dispersin and its secretion system aat, and type VI secretion.

My long-term goal is to identify the molecular regulatory mechanism of this new family of negative regulators and explore their potential in the treatment of diarrheal diseases. During last 4 years, I have been involved in the training of undergraduate students from SRIP Summer program at UVA.

Relevant Publications

  1. Morin N, Santiago AE, Ernst RK, Guillot SJ, Nataro JP. Characterization of the AggR regulon in enteroaggregative Escherichia coli. Infect Immun. 2013 Jan;81(1):122-32. PMCID: PMC3536136
  2. Santiago A, Ruiz-Perez F, Jo NY, Vijayakumar V, Gong MQ, Nataro JP. A large family of antivirulence regulators modulates the effects of transcriptional activators in Gram-negative pathogenic bacteria. PLOSPathogens. 2014 May; 10(5): e1004153. Doi:10.137/journal.ppat.1004153.
  3. Reed DS, Smith LP, Cole KS, Santiago EA, Mann BJ and Barry EM. “Live attenuated mutants of Francisella tularensis protect rabbits against aerosol challenge with a virulent type A strain”. Infect Immun. 2014 May;82(5):2098-105. doi: 10.1128/IAI.01498-14.
  4. Vijayakumar V, Santiago A, Smith R, Smith M, Robins-Browne RM, Nataro JP, Ruiz- Perez F. Role of class 1 serine protease autotransporter in the pathogenesis of Citrobacter rodentium colitis. Infection and immunity. 2014; 82(6):2626-36. PubMed PMID:24711562 PMCID:PMC4019172.
  5. Ayala-Lujan JL, Vijayakumar V, Gong M, Smith R, Santiago AE, Ruiz-Perez F. Broad spectrum activity of a lectin-like bacterial serine protease family on human leukocytes. PloS one. 2014; 9(9):e107920. PubMed PMID:25251283 PMCID:PMC4176022.
  6. Ochieng JB, Boisen N, Lindsay B, Santiago A, Ouma C, Ombok M, Fields B, Stine OC, Nataro JP. “Serratia marcescens is injurious to intestinal epithelial cells”. Gut Microbes. 2014;5(6):729-36. doi: 10.4161/19490976.2014.972223. PMID:25426769.
  7. Jonsson R, Struve C, Boisen N, Mateiu RV, Santiago AE, Jenssen H, Nataro JP and Krogfelt KA. “Novel Aggregative Adherence Fimbria Variant of Enteroaggregative Escherichia coli”. Infect. Immun. 2015; 83(4):1396-1405. doi: 10.1128/IAI.02820-14.
  8. Santiago AE, Mann BJ, Qin A, Cunningham AL, Cole LE, Grassel C, Vogel SN, Levine MM and Barry EM. “Characterization of Francisella tularensis Schu S4 defined mutants as live-attenuated vaccine candidates”. Pathog Dis. 2015 Aug;73(6). pii: ftv036. doi: 10.1093/femspd/ftv036.
  9. Santiago AE*, Yan MB, Tran M, Wright N, Luzader DH, Kendall MM, Ruiz-Perez F, Nataro JP. A large family of anti-activators accompanying XylS/AraC family regulatory proteins. Molecular microbiology. 2016;101(2):314-32. NIHMSID:NIHMS801645, PubMed PMID:27038276 PMCID:PMC4983702.
  10. Santiago AE*, Yan MB, Hazen TH, Sauder B, Meza-Segura M, Rasko DA, Kendall MM, Ruiz-Perez F, and Nataro JP. The AraC Negative Regulator family modulates the activity of histone-like proteins in pathogenic bacteria. PLOS Pathogens. 2017.
  11. Borgersen Q, Bolick DT, Kolling GL, Aijuka M, Ruiz-Perez F, Guerrant RL, Nataro JP and Santiago AE*. Abundant production of exopolysaccharide by EAEC strains enhances the formation of bacterial biofilms in contaminated sprouts. Gut Microbes. 2018;9(3):264-278.
  12. Aijuka M, Santiago AE, Giron JA, Nataro JP and Buys EM. Enteroaggregative Escherichia coli is the predominant diarrheagenic E. coli pathotype among irrigation water and food sources in South Africa. International journal of food microbiology. 2018; 278:44-51. PMID:29702315.
  13. Cunningham AL, Mann BJ, Qin A, Santiago AE, Grassel C, Lipsky M, Vogel SN, and Barry EM. Characterization of Schu S4 aro mutants as live attenuated tularemia vaccine candidates. Virulence, 2020; 11:1, 283-294, DOI: 10. 1080/21505594.2020.1746557.
  14. Laura Belmont-Monroy, Waleska Saitz-Rojas, Jorge Soria-Bustos, Abigail Mickey, Nicholas E Sherman, Benjamin C. Orsburn, Fernando Ruiz-Perez and Araceli E. Santiago*. “Characterization of a novel AraC/XylS-regulated family of N-acyltransferases in the pathogens of the Enterobacterales order”. PLoS Pathog. 2020;16(8):e1008776.
  15. Nadia Boisen, Mark T. Østerlund, Katrine G. Joensen, Araceli Santiago, Inacio Mandomando, Alejandro Cravioto, Marie A. Chattaway, Laura A. Gonyar, Søren Overballe-Petersen, O. Colin Stine, David A. Rasko, Flemming Scheutz, and James P. Nataro. 2020. “Redefining enteroaggregative Escherichia coli (EAEC): genomic characterization of epidemiological EAEC strains.” PLOS Negl Trop Dis. 2020 Sep 8;14(9):e0008613. Doi: 10.1371/journal.pntd.0008613. eCollection 2020 Sep.
  16. Brian Belyea, Araceli Santiago, Wilson Vasconez, Vidhya Nagalakshmi, Fang Xu, Theodore Mehalic, Maria Luisa Sequeira-Lopez and Ariel Gomez. “A primitive type of renin-expressing lymphocyte protects the organism against infections”. Sci Rep. 2021. Mar 31;11(1):7251. doi: 10.1038/s41598-021-86629-w. PubMed PMID: 33790364; PubMed Central PMCID: PMC8012387.
  17. Rodriguez-Valverde D, Giron JA, Hu Y, Nataro JP, Ruiz-Perez F and Santiago AE*. “Highly-conserved regulatory activity of the ANR family in the virulence of diarrheagenic bacteria through interaction with Master and Global regulators.” Sci Rep. 2023. April 13:7024. Doi:10.1038/s41598-023-33997-0
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