Abstract
Staphylococcus aureus is a major cause of bovine mastitis, commonly leading to long-lasting, persistent and recurrent infections. Thereby, S. aureus constantly refines and permanently adapts to the bovine udder environment. In this work, we followed S. aureus within-host adaptation over the course of three months in a naturally infected dairy cattle with chronic, subclinical mastitis. Whole genome sequence analysis revealed a complete replacement of the initial predominant variant by another isogenic variant. We report for the first time within-host evolution towards a sigma factor SigB-deficient pathotype in S. aureus bovine mastitis, associated with a single nucleotide polymorphism in rsbU (G368A → G122D), a contributor to SigB-functionality. The emerged SigB-deficient pathotype exhibits a substantial shift to new phenotypic traits comprising strong proteolytic activity and poly-N-acetylglucosamine (PNAG)-based biofilm production. This possibly unlocks new nutritional resources and promotes immune evasion, presumably facilitating extracellular persistence within the host. Moreover, we observed an adaptation towards attenuated virulence using a mouse infection model. This study extends the role of sigma factor SigB in S. aureus pathogenesis, so far described to be required for intracellular persistence during chronic infections. Our findings suggest that S. aureus SigB-deficiency is an alternative mechanism for persistence and underpin the clinical relevance of staphylococcal SigB-deficient variants which are consistently isolated during human chronic infections.
Highlights
In cattle, two clonal complexes (CC97, CC151) have been described as the most successful lineages which carry distinct molecular genetic features, optimized to induce and maintain infections within the udder www.nature.com/scientificreports/
We recently demonstrated that capsule loss, as well as the capacity to invade endothelial cells and to form biofilms are properties linked to long-term persistence in the mammary gland[8]
Recent studies focused on the comparison of genetic and phenotypic traits based on mastitis reference strains, or clinical mastitis isolates of different clonal origin or of different within-herd prevalence[8,14,15]
Summary
Two clonal complexes (CC97, CC151) have been described as the most successful lineages which carry distinct molecular genetic features, optimized to induce and maintain infections within the udder www.nature.com/scientificreports/. Several studies reported a recurrent recovery of isolates belonging to the same clone, indicating that S. aureus host adaptation to the bovine mammary gland results in single or a few persisting subtypes in a herd[7,8]. Several studies showed a high prevalence of non-encapsulated S. aureus strains in bovine, chronic mastitis (up to 86%)[11,12]. As the prevalence of non-encapsulated strains is higher in chronic than in acute infections in humans[13], diminished CP expression might be a key S. aureus phenotypic feature associated with chronicity. Recent studies focused on the comparison of genetic and phenotypic traits based on mastitis reference strains, or clinical mastitis isolates of different clonal origin or of different within-herd prevalence[8,14,15]. No study followed S. aureus within-host adaptation during the progression in chronic, bovine mastitis. To obtain a comprehensive picture of within-host adaptation, we carried out an in– depth investigation of the evolution of this pathogen within the bovine host
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