Research Article: Staphylococcus aureus infection dynamics

Date Published: June 14, 2018

Publisher: Public Library of Science

Author(s): Eric J. G. Pollitt, Piotr T. Szkuta, Nicola Burns, Simon J. Foster, Alice Prince.


Staphylococcus aureus is a human commensal that can also cause systemic infections. This transition requires evasion of the immune response and the ability to exploit different niches within the host. However, the disease mechanisms and the dominant immune mediators against infection are poorly understood. Previously it has been shown that the infecting S. aureus population goes through a population bottleneck, from which very few bacteria escape to establish the abscesses that are characteristic of many infections. Here we examine the host factors underlying the population bottleneck and subsequent clonal expansion in S. aureus infection models, to identify underpinning principles of infection. The bottleneck is a common feature between models and is independent of S. aureus strain. Interestingly, the high doses of S. aureus required for the widely used “survival” model results in a reduced population bottleneck, suggesting that host defences have been simply overloaded. This brings into question the applicability of the survival model. Depletion of immune mediators revealed key breakpoints and the dynamics of systemic infection. Loss of macrophages, including the liver Kupffer cells, led to increased sensitivity to infection as expected but also loss of the population bottleneck and the spread to other organs still occurred. Conversely, neutrophil depletion led to greater susceptibility to disease but with a concomitant maintenance of the bottleneck and lack of systemic spread. We also used a novel microscopy approach to examine abscess architecture and distribution within organs. From these observations we developed a conceptual model for S. aureus disease from initial infection to mature abscess. This work highlights the need to understand the complexities of the infectious process to be able to assign functions for host and bacterial components, and why S. aureus disease requires a seemingly high infectious dose and how interventions such as a vaccine may be more rationally developed.

Partial Text

Staphylococcus aureus is a leading opportunistic human pathogen renowned for its ability to evade the immune system and cause a variety of different infections [1]. S. aureus infections can vary from superficial skin lesions, through deep seated abscesses to life threatening sepsis [1]. The diversity of disease modalities has made an understanding of the underlying principles of infection challenging. S. aureus primarily occurs as a human commensal, mostly in the nares from whence it is able to seed infection. Many S. aureus infections are iatrogenic, and these are commonly associated with the colonisation of indwelling medical devices [2]. Typically during an infection, after invasion, an immune reaction is initiated by macrophages and these release cytokines to summon neutrophils [3]. Fibrosis also occurs, as well as the death of many of the invading immune cells leading to the pus filled abscesses associated with S. aureus infections. S. aureus can also regularly escape local infection sites and disseminate further. If it enters the bloodstream this can lead to sepsis as well as invasion of other organs whereby further local infections can occur. Thus S. aureus infection is a highly dynamic process with broad dissemination and repeated metastases.

As an opportunistic pathogen, S. aureus is able to cause a wide range of human diseases from the superficial to potentially life threatening. There are multiple animal models of S. aureus infection that all aim to recapitulate those events that shape the interaction between the pathogen and the human host. However, increasingly there is evidence that many of the virulence determinants are human specific and thus are not relevant to the widely used animal models. Also the route and mode of human infection is difficult to replicate in models. Murine models of S. aureus infection are commonplace and have been one of the main tools in developing our understanding of the disease processes. Models of sepsis (bacteraemia) are well-established and are characterised by kidney abscesses as a primary outcome [21,23,24]. Establishment of sepsis requires a high inoculum as is apparent in other murine models. This has been suggested to be due to a bolus of bacteria being required to initiate disease [13,15]. Recently we have shown that, in fact, there is a population bottleneck whereby likely single bacteria found kidney abscesses [13,18]. This therefore requires an explanation as to what the series of events that precedes abscess formation are, and the mechanism(s) involved. The individual bacteria that found lesions occur randomly from the population in that they do not have a genetic advantage [13,18]. Thus the initiation of abscesses is a stochastic event that is enhanced by a large inoculum. Here we aimed to investigate within-host population dynamics and determine the cellular basis of bottlenecks in S. aureus infection models.