Browsing by Author "Liang, Haihua"

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    Modulation of MRSA virulence gene expression by the wall teichoic acid enzyme TarO
    (Springer Nature, 2023-03-22) Lu, Yunfu; Chen, Feifei; Zhao, Qingmin; Cao, Qiao; Chen, Rongrong; Pan, Huiwen; Wang, Yanhui; Huang, Haixin; Huang, Ruimin; Liu, Qian; Li, Min; Bae, Taeok; Liang, Haihua; Lan, Lefu; Microbiology and Immunology, School of Medicine
    Phenol-soluble modulins (PSMs) and Staphylococcal protein A (SpA) are key virulence determinants for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA), an important human pathogen that causes a wide range of diseases. Here, using chemical and genetic approaches, we show that inhibition of TarO, the first enzyme in the wall teichoic acid (WTA) biosynthetic pathway, decreases the expression of genes encoding PSMs and SpA in the prototypical CA-MRSA strain USA300 LAC. Mechanistically, these effects are linked to the activation of VraRS two-component system that directly represses the expression of accessory gene regulator (agr) locus and spa. The activation of VraRS was due in part to the loss of the functional integrity of penicillin-binding protein 2 (PBP2) in a PBP2a-dependent manner. TarO inhibition can also activate VraRS in a manner independent of PBP2a. We provide multiple lines of evidence that accumulation of lipid-linked peptidoglycan precursors is a trigger for the activation of VraRS. In sum, our results reveal that WTA biosynthesis plays an important role in the regulation of virulence gene expression in CA-MRSA, underlining TarO as an attractive target for anti-virulence therapy. Our data also suggest that acquisition of PBP2a-encoding mecA gene can impart an additional regulatory layer for the modulation of key signaling pathways in S. aureus.
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    Mutation-induced remodeling of the BfmRS two-component system in Pseudomonas aeruginosa clinical isolates
    (AAAS, 2020-11) Cao, Qiao; Yang, Nana; Wang, Yanhui; Xu, Chenchen; Zhang, Xue; Fan, Ke; Chen, Feifei; Liang, Haihua; Zhang, Yingchao; Deng, Xin; Feng, Youjun; Yang, Cai-Guang; Wu, Min; Bae, Taeok; Lan, Lefu; Microbiology and Immunology, School of Medicine
    Genetic mutations are a primary driving force behind the adaptive evolution of bacterial pathogens. Multiple clinical isolates of Pseudomonas aeruginosa, an important human pathogen, have naturally evolved one or more missense mutations in bfmS, which encodes the sensor histidine kinase of the BfmRS two-component system (TCS). A mutant BfmS protein containing both the L181P and E376Q substitutions increased the phosphorylation and thus the transcriptional regulatory activity of its cognate downstream response regulator, BfmR. This reduced acute virulence and enhanced biofilm formation, both of which are phenotypic changes associated with a chronic infection state. The increased phosphorylation of BfmR was due, at least in part, to the cross-phosphorylation of BfmR by GtrS, a noncognate sensor kinase. Other spontaneous missense mutations in bfmS, such as A42E/G347D, T242R, and R393H, also caused a similar remodeling of the BfmRS TCS in P. aeruginosa. This study highlights the plasticity of TCSs mediated by spontaneous mutations and suggests that mutation-induced activation of BfmRS may contribute to host adaptation by P. aeruginosa during chronic infections.