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Differential contributions of CodY, SigB and the hibernation promoting factor HPF to interactions of Staphylococcus aureus USA300 with human lung epithelial cells explained by proteome analysis

ABSTRACT: The Gram-positive bacterium Staphylococcus aureus is a leading cause of severe pneumonia. Therefore, we recently investigated the fate of S. aureus upon internalization by human lung epithelial cells. This uncovered three major adaptive responses of the bacteria, involving the SigB and CodY regulons and an upregulation of the S. aureus hibernation-promoting factor (SaHPF). To explore the roles of CodY, SigB and SaHPF in the infection of human lung epithelial cells, we employed derivatives of the community-acquired MRSA strain USA300 with transposon mutations in the respective genes. Interestingly, the investigated codY mutant bacteria displayed a ‘small colony variant’-like phenotype that promotes their intracellular survival and localizes the bacteria to the host cell cytoplasm. Furthermore, our results show that CodY, SigB and saHPF contribute differentially to the different steps in the infectious process, including, host cell adhesion, invasion, intracellular survival and cytotoxicity. Notably, codY or sigB mutant bacteria experienced faster intracellular clearance compared to the parental strain, underscoring the importance of these regulators for intracellular persistence. Furthermore, we show an unprecedented role of SaHPF in human lung epithelial cell infection, including parallel effects of saHPF or SigB deficiency in adhesion and invasion. Altogether, our study focuses attention on the CodY-perceived metabolic state of the bacteria and the SigB-perceived stress in bacterial decision taking during infection. Conversely, our observations indicate important roles for the nutritional status and bacterial stress-inducing conditions in the host for the onset and subsequent course of invasive or chronic staphylococcal lung infection.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Larissa Busch

LAB HEAD: Uwe Völker

PROVIDER: PXD044962 | Pride | 2024-09-11

REPOSITORIES: Pride

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			Action	DRS
	20220912_HF_LB_Dijl_Sau_P_DcodY_exp_1.raw	Raw
	20220912_HF_LB_Dijl_Sau_P_DcodY_exp_2.raw	Raw
	20220912_HF_LB_Dijl_Sau_P_DcodY_exp_3.raw	Raw
	20220912_HF_LB_Dijl_Sau_P_DcodY_stat_1.raw	Raw
	20220912_HF_LB_Dijl_Sau_P_DcodY_stat_2.raw	Raw

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Project description:Livestock-associated (LA) methicillin-resistant Staphylococcus aureus (MRSA) and strains of sequence type 398 (ST398), which first became known for its widespread colonization of pigs but are now also rapidly emerging in the number of human colonization and infections. The ability of broad host adaption in combination with a consciously evolves by acquisition of virulence gene or mobile genetic elements (MGE) have been increasingly addressed ST398 lineage a serious threat to public health. The present study was aimed to track out how the diverse ST398 lineage, which colonized or infected in a broad range of reservoirs and various geographic regions, is actually reflected in the course of virulence evolution. We therefore profiled the extracellular proteome, representing the main reservoir of virulence factors, of 30 representative clinical isolates using label-free quantitative mass spectrometry. The results show that these isolates can be divided into five distinct clusters based on their exoproteome identities and abundance signatures. The majority of proteins identified were predicted as cytoplasmic proteins showing substantial heterogeneity among our 30 investigated isolates. Only 50% of isolates their exoproteome clustering of isolates can be correlated the clustering based on genome sequences suggested that the large-scale extend of genotype changes over time. To assess the virulence and cytotoxicity of the 30 investigated isolates, we employed infection models based on Galleria mellonella and HeLa cells. The results uncovered the grouping of clinical isolates based on their virulence or cytotoxicity have apparently distinctive exoproteome signatures and particular exoproteins could play decisive roles in pathogenicity of this specific S. aureus lineage. Altogether, the combination of exoproteome and virulence analysis contribute to the comprehensive insights for the impact of genome diversity on the global production of virulence factors of this zoonotic lineage, and more importantly, our outcomes as well as our approach provided an effective pipeline to define proteomic signatures of S. aureus virulence.

Dataset Information

Differential contributions of CodY, SigB and the hibernation promoting factor HPF to interactions of Staphylococcus aureus USA300 with human lung epithelial cells explained by proteome analysis

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