Infectious Diseases Translational Research Program
Our research focus
KLA is the single most important cause of monomicrobial liver abscess and its subsequent complications in many parts of Asia, including Singapore. We examine bacterial factors and the ensuing host immune responses in the encounter between hypervirulent and its mammalian host. It is believed that many infections initiate from bacteria colonized in the intestines as they translocate across the intestinal barrier and travel via the hepatic portal vein to the liver. We are interested in examining both bacterial and host factors at play at each stage of the infection, including during the colonization stage. We routinely use a hypervirulent strain isolated from a liver abscess patient designated as a reference strain, SGH10, for our investigations. Using murine colonization and infection models, as well as primary human intestinal organoids, we hope to understand when and how the bacteria transition from a gut colonizer to a potentially deadly pathogen.
Klebsiella induced liver abscess (KLA)
Scanning Electron Microscope (SEM) images of SGH10 WT strain at 40,000X magnification (left) and SGH10 ΔwcaJ capsule mutant strain at 60,000X magnification (right). 🌐
Transcriptional phenotypic switch between T3F and capsule hypermucoviscosity in response to changing iron levels. (A) Low iron condition results in hypermucoid capsule production and repressed T3F, leading to low biofilm formation and cell adhesion. (B) Iron-rich condition results in expression of T3F and downregulation of capule mucoviscosity, leading to high biofilm formation and cell adhesion. 🌐
Genomic Islands GIE492 and ICEKp10 enable hypervirulent K. pneumoniae to kill several commensal bacterial taxa during interspecies interactions in the gut. Thus, acquisition of GIE492 and ICEKp10 could enable better carriage in host populations and explain the dominance of the CG23-I HvKp lineage. 🌐
Klebsiella pneumoniae gut colonization and evolutionary fates are distinct under different types of gut dysbiosis
We found that transient exposure to ampicillin results in restructuring of microbiota to favour oxygen-tolerant bacteria whereas osmotic laxative perturbation preserves Bacteriodota. Ampicillin- but not laxative-exposed environment favours establishment of rmpA phase variants that lost hypermucoviscosity but short-chain fatty acids present in the laxative-exposed gut constrains the establishment of these phase variants. Thus antibiotic exposure could shape the persistence of K. pneumoniae in the gut. There seems to be a trade-off between persistence versus virulence.
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Multidrug resistance plasmid transmission in Klebsiella pneumoniae
We are interested in understanding the factors driving the transmission of carbapenem-resistance and multi-drug resistance plasmids in hospitals. We track plasmid and resistance genes dominance over time in a multi-centre collaboration, then apply molecular genetics to determine plasmid and bacterial host factors favouring spread and stability of carriage. In particular, we focus on the emergence of hypervirulent and carbapenem-resistant K. pneumoniae strains and aim to define factors and conditions leading to this convergence.
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Conjugation frequency of pKPC2 and pNDM1 among various Enterobacterales donor-recipient pairs. (A) Conjugation frequency of pKPC2 and pNDM1 from K. pneumoniae SGH10 plasmid donor strain to a panel of Enterobacterales recipient strains; and B) from the panel of Enterobacterales as plasmid donor strains to K. pneumoniae SGH10 recipient strain. Each symbol represents 1 experimental replicate with a total of 12 replicates. Data points that are not seen on the graphs indicate no detectable transconjugant. 🌐
We discovered that pKPC2, together with other IncP clade II plasmids have the ability to transmit well in the anaerobic environment in the gut. This is in contrast to IncP clade I plasmids. Incidentally, clade II plasmids are predominantly present in clinical Enterobacteriaceae whereas clade I plasmids are associated with the environment.
