Abstract
ABSTRACTMethicillin-resistant Staphylococcus aureus (MRSA) is the common name for a heterogeneous group of highly drug-resistant staphylococci. Two major MRSA classes are distinguished based on epidemiology, namely community-associated (CA) and hospital-associated (HA) MRSA. Notably, the distinction of CA- and HA-MRSA based on molecular traits remains difficult due to the high genomic plasticity of S. aureus. Here we sought to pinpoint global distinguishing features of CA- and HA-MRSA through a comparative genome and proteome analysis of the notorious MRSA lineage USA300. We show for the first time that CA- and HA-MRSA isolates can be distinguished by 2 distinct extracellular protein abundance clusters that are predictive not only for epidemiologic behavior, but also for their growth and survival within epithelial cells. This ‘exoproteome profiling’ also groups more distantly related HA-MRSA isolates into the HA exoproteome cluster. Comparative genome analysis suggests that these distinctive features of CA- and HA-MRSA isolates relate predominantly to the accessory genome. Intriguingly, the identified exoproteome clusters differ in the relative abundance of typical cytoplasmic proteins, suggesting that signatures of cytoplasmic proteins in the exoproteome represent a new distinguishing feature of CA- and HA-MRSA. Our comparative genome and proteome analysis focuses attention on potentially distinctive roles of ‘liberated’ cytoplasmic proteins in the epidemiology and intracellular survival of CA- and HA-MRSA isolates. Such extracellular cytoplasmic proteins were recently invoked in staphylococcal virulence, but their implication in the epidemiology of MRSA is unprecedented.
Highlights
Staphylococcus aureus is a wide-spread commensal bacterium, and a notoriously drug-resistant pathogen that causes a wide range of diseases, varying from mild skin infections to life-threatening invasive diseases.[1]
Spa typing has insufficient discriminatory power to distinguish closely related CA and HA isolates as it assigns CAUSA300 isolates with the multi-locus sequence type ST8 and more distantly related HA isolates with the sequence type ST8 to the same spa type t008.18 we have previously shown that a multiple-locus variable number tandem repeat fingerprinting (MLVF) approach may distinguish these highly related S. aureus isolates.[19]
The CADK group had the sequence type ST8, the spa type t008 and was PVL-positive, whereas the HADK group was characterized by the sequence type ST8 and the spa type t024.18,21 As a control group, we investigated the exoproteomes of 3 HA-methicillin-resistant S. aureus (MRSA) isolates from the Dutch (NL) - German (DE) border region, here referred to as HANL-DE, which have the sequence type ST8, and spa type t008 or t024.19 The genomes of all 15 isolates were sequenced, and their extracellular proteins were analyzed by liquid chromatography and mass spectrometry (LCMS)
Summary
Staphylococcus aureus is a wide-spread commensal bacterium, and a notoriously drug-resistant pathogen that causes a wide range of diseases, varying from mild skin infections to life-threatening invasive diseases.[1]. Since the clinical implementation of antibiotics, S. aureus has acquired a range of resistance traits through mutations and horizontal gene transfer. This has culminated in the emergence of methicillin-resistant S. aureus (MRSA), a major healthcare problem worldwide.[3,4] The emergence of MRSA is a worrisome development since it is associated with increased morbidity and mortality, especially if very young, immune-compromised or elderly individuals are infected.[5,6] no effective vaccine against MRSA is currently available.[7,8,9]
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