Chronic Staphylococcus aureus infection is cured by theory-driven therapy

Abstract

Staphylococcus aureus is considered a dangerous pathogen due to its ability to evade the immune system and resist multiple antibiotics. These evasive strategies lead to difficult-to-treat chronic infections and abscesses in internal organs including kidneys, which are associated with the expansion of myeloid-derived suppressor cells (MDSCs) and their suppressive effect on T cells. Here, we developed a mathematical model of chronic S. aureus infection that incorporates the T-cell suppression by MDSCs and suggests therapeutic strategies to eradicate S. aureus. We quantified in silico a therapeutic protocol with heat-killed S. aureus (HKSA), which we tested in vivo. Contrary to conventional administration of heat-killed bacteria as vaccination prior to infection, we administered HKSA as treatment, when the hosts were already chronically infected. Our treatment cured all chronically S. aureus-infected mice, reduced MDSCs, and reversed T-cell dysfunction by inducing acute inflammation during ongoing, chronic infection without any use of standard treatments that involve antibiotics, MDSC-targeting drugs (chemotherapy), or procedures such as abscess drainage. This study is a proof-of-principle for a treatment protocol against chronic S. aureus infection and renal abscesses by repurposing heat-killed treatments, guided and quantified by mathematical modelling. Our mathematical model further explains why previous treatment with inactivated S. aureus administered to long-term infected human patients has not led to cure. Overall, our results can have direct relevance to the design of human therapeutics against chronic S. aureus infections. In briefA theory-driven treatment protocol with heat-killed S. aureus eradicates S. aureus, reduces MDSCs, and reverses T-cell dysfunction in vivo. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=157 HEIGHT=200 SRC="FIGDIR/small/910786v3_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@1e2d0c9org.highwire.dtl.DTLVardef@1f97374org.highwire.dtl.DTLVardef@b0235org.highwire.dtl.DTLVardef@bdf2ee_HPS_FORMAT_FIGEXP M_FIG C_FIG