In silico-defined therapy cures chronic Staphylococcus aureus infection in vivo

Papaxenopoulou, Lito

doi:10.24355/dbbs.084-202305221327-0

Published

In silico-defined therapy cures chronic Staphylococcus aureus infection in vivo

English
German

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, a mathematical model of chronic S. aureus infection was developed that incorporates the T-cell suppression by MDSCs and suggests therapeutic strategies to eradicate S. aureus. A therapeutic protocol with heat-killed S. aureus (HKSA) was quantified in silico and tested in vivo. Contrary to conventional administration of heat-killed bacteria as vaccination prior to infection, here, HKSA was administered as treatment, when the hosts were already chronically infected. The treatment cured all chronically S. aureus-infected mice, reduced MDSCs, and reversed T-cell dysfunction by inducing acute inflammation during on- going, chronic infection without any use of standard treatments that involve antibiotics, MDSC-targeting drugs (chemotherapy), or invasive 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. The mathematical model further explains why previous treatment with inactivated S. aureus administered to long-term infected human patients has not led to cure. Overall, the results presented in this thesis can have direct relevance to the design of human therapeutics against chronic S. aureus infections and associated renal abscesses.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, a mathematical model of chronic S. aureus infection was developed that incorporates the T-cell suppression by MDSCs and suggests therapeutic strategies to eradicate S. aureus. A therapeutic protocol with heat-killed S. aureus (HKSA) was quantified in silico and tested in vivo. Contrary to conventional administration of heat-killed bacteria as vaccination prior to infection, here, HKSA was administered as treatment, when the hosts were already chronically infected. The treatment cured all chronically S. aureus-infected mice, reduced MDSCs, and reversed T-cell dysfunction by inducing acute inflammation during on- going, chronic infection without any use of standard treatments that involve antibiotics, MDSC-targeting drugs (chemotherapy), or invasive 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. The mathematical model further explains why previous treatment with inactivated S. aureus administered to long-term infected human patients has not led to cure. Overall, the results presented in this thesis can have direct relevance to the design of human therapeutics against chronic S. aureus infections and associated renal abscesses.

Staphylococcus aureus gilt aufgrund seiner Fähigkeit, dem Immunsystem auszuweichen und mehreren Antibiotika zu widerstehen, als gefährlicher Erreger. Diese Ausweichstrategien führen zu schwer-zu-behandeln chronischen Infektionen und Abszessen in inneren Organen einschließlich der Nieren, die mit der Expansion von myeloid- derived suppressor cells (MDSCs) und ihrer unterdrückenden Wirkung auf T-Zellen verbunden sind. Hier wurde ein mathematisches Modell der chronischen S. aureus Infektion entwickelt, das die T-Zell-Suppression durch MDSCs beinhaltet und therapeutische Strategien vorschlägt, um S. aureus abzutöten. Ein therapeutisches Protokoll mit hitzegetötetem S. aureus (HKSA) wurde in silico quantifiziert und in vivo getestet. Im Gegensatz zur herkömmlichen Verabreichung von hitzegetötenden Bakterien als Impfung vor einer Infektion wurde hier HKSA als Behandlung verabreicht, wenn die Wirte schon chronisch infiziert waren. Die Behandlung heilte alle chronisch S. aureus-infizierten Mäusen, reduzierte die MDSCs und kehrte die T-Zell-Dysfunktion um, indem sie während einer anhaltenden, chronischen Infektion eine akute Entzündung induziert hat, ohne den Einsatz von Standardbehandlungen, wie Antibiotika, MDSC-zielende Medikamente (Chemotherapie) oder invasive Techniken wie Abszess-drainage. Diese Studie bietet Evidenz für ein Behandlungsprotokoll gegen chronische S. aureus Infektion und Nierenabszessen durch Umnutzung hitzegetöteter Behandlungen, die durch mathematische Modellierung geleitet und quantifiziert ist. Das mathematische Modell erklärt weiter, warum frühere Behandlungen mit inaktiviertem S. aureus an Patienten, die langzeit infiziert mit S. aureus waren, nicht zur Heilung geführt haben. Insgesamt können die in dieser Dissertation präsentierten Ergebnisse direkte Relevanz für das Design von Humantherapeutika gegen chronische S. aureus Infektionen und Nierenabszesse haben.