My primary research goal is to elevate our ability to study infectious diseases caused by bacteria. I believe we should be constantly advancing (in terms of both rapidity and accuracy) in our ability to take any infectious disease, define its root causes, and devise strategies for prevention and treatment.
The overall strategy is to use a tractable model system of disease as a testing grounds for novel approaches. My lab uses a mouse model of urinary tract infection (UTI), which is caused by uropathogenic Escherichia coli (UPEC). This is an outstanding system for its correspondence with human disease and for the combination of mice (the best studied and most easily manipulated experimental animal) and E. coli (the most well studied organism of all). However, many other infectious diseases lack animal models and many bacteria are not tractable in the lab; thus, the only viable general approach to improving our study of infectious disease is genomics. My lab therefore has focused on applying new genomics tools to the study of UTI and infectious diseases in general.
From my initial work in the UTI system, my lab has now grown to encompass three themes of work, all of which share the common goal of developing new tools to elevate our study of UTI in the further service of studying other infectious diseases. These themes are functional genomics, genetics and synthetic biology, and computational sequence analysis.
In functional genomics, we are building on single cell genomics expertise in GIS to perform niche-specific, single cell, simultaneous host and pathogen expression profiling to understand intracellular stages of urinary tract infections. These are important because they may explain recurrent urinary tract infections, which can sometimes plague patients for many years or decades. We have also used novel sequencing-based approaches (with PacBio and Illumina sequencing) to derive a global understanding of the regulation of Type 1 pili, the most important virulence factor for E. coli to cause urinary tract infection.
For genetics and synthetic biology, my lab has spent 7 years developing techniques specifically for wild type, clinical isolates of E. coli. Decades of research have provided numerous genetic tools usable in lab-adapted, cloning strains of E. coli; we have essentially arbitrary control over making any change to the genome of this bacterium. However, lab-adapted strains do not typically cause infections; understanding disease-causing clinical isolates has been much more difficult, as much of the wealth of E. coli genetics techniques are less efficient or unusable in wild type E. coli isolates. We developed a stringent negative selection system usable in nearly all isolates of E. coli and other Enteric bacteria, which enables us to perform "perfect" genetics and achieve arbitrary control over the genomes of disease-causing E. coli isolates, just as we can with cloning strains.
For sequence analysis, I work with the GIS GERMS platform to collaborate with the local clinical community to understand the genomics of local Singaporean bacterial isolates. Microbiology is local; Singapore and Asia have different strains and sometimes different infections than elsewhere in the world. We use whole genome sequencing to do outbreak analysis, which helps to trace the extent and source of an infection. We also are exploring computational methods to use local genome sequences to understand the overall evolution of bacteria in Singapore and Asia. Two two highlights from this theme are the 2015 Streptococcus agalactiae (Group B Streptococcus, GBS) outbreak in Singapore and an analysis of Campylobacter-mediated abortion in livestock in the United States. The genomics work on GBS helped prove that GBS could indeed be transmitted by eating contaminated food, a new paradigm for GBS disease. The Campylobacter project, done in collaboration with Qijing Zhang at Iowa State University, found a single gene responsible for enabling one clone of C. jejuni to cause abortion in livestock. This was found using a new experimental technique we call sexual genetics (akin to using F1 hybrids in mice to map a phenotype). We also found a population genetics analysis could identify the same gene just from computational analysis of Campylobacter genome sequences.
These three themes are distinct yet related, all coming back to improving our ability to study infectious disease. As an example of the interplay between the three themes, the Campylobacter work (Theme 3) has launched new projects to develop sexual genetics techniques for E. coli (Theme 2) as well as using population genetics to understand the evolution of virulence in GBS and E. coli (Themes 1 and 3).
- Kalimuddin S, Chen SL, Lim CTK, Koh TH, Tan TY, Kam M, Wong CW, Mehershahi KS, Chau ML, Ng LC, Tang WY, Badaruddin H, Teo J, Apisarnthanarak A, Suwantarat N, Ip M, Holden MTG, Hsu LY, Barkham T "2015 Epidemic of Severe Streptococcus agalactiae Sequence Type 283 Infections in Singapore Associated With the Consumption of Raw Freshwater Fish: A Detailed Analysis of Clinical, Epidemiological, and Bacterial Sequencing Data." Clin Infect Dis 2017 May 15 ; 64(suppl_2) : S145-S152 Abstract
- Chen S, Larsson M, Robinson RC, Chen SL "Direct and convenient measurement of plasmid stability in lab and clinical isolates of E. coli." Sci Rep 2017 Jul 06 ; 7(1) : 4788 Abstract
- Zhang H, Susanto TT, Wan Y, Chen SL "Comprehensive mutagenesis of the fimS promoter regulatory switch reveals novel regulation of type 1 pili in uropathogenic Escherichia coli." Proc Natl Acad Sci U S A 2016 Apr 12 ; 113(15) : 4182-7 Abstract
- Wu Z, Periaswamy B, Sahin O, Yaeger M, Plummer P, Zhai W, Shen Z, Dai L, Chen SL, Zhang Q "Point mutations in the major outer membrane protein drive hypervirulence of a rapidly expanding clone of Campylobacter jejuni." Proc Natl Acad Sci U S A 2016 09 20 ; 113(38) : 10690-5 Abstract
- Khetrapal V, Mehershahi K, Rafee S, Chen S, Lim CL, Chen SL "A set of powerful negative selection systems for unmodified Enterobacteriaceae." Nucleic Acids Res 2015 Mar 23 Abstract
- Eshaghi M, Sun G, Grüter A, Lim CL, Chee YC, Jung G, Jauch R, Wohland T, Chen SL "Rational Structure-Based Design of Bright GFP-Based Complexes with Tunable Dimerization." Angew Chem Int Ed Engl 2015 Nov 16 ; 54(47) : 13952-6 Abstract
- Chen SL, Wu M, Henderson JP, Hooton TM, Hibbing ME, Hultgren SJ, Gordon JI "Genomic diversity and fitness of E. coli strains recovered from the intestinal and urinary tracts of women with recurrent urinary tract infection." Sci Transl Med 2013 May 8 ; 5(184) : 184ra60 Abstract