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2018 ; 14
(6
): e1007112
Nephropedia Template TP
PLoS Pathog
2018[Jun]; 14
(6
): e1007112
PMID29902272
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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.
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