In silico predicted therapy against chronic Staphylococcus aureus infection leads to bacterial clearance in vivo

Lito A Papaxenopoulou; Gang Zhao; Sahamoddin Khailaie; Konstantinos Katsoulis-Dimitriou; Ingo Schmitz; Eva Medina; Haralampos Hatzikirou; Michael Meyer-Hermann

doi:10.1016/j.isci.2022.105522

In silico predicted therapy against chronic Staphylococcus aureus infection leads to bacterial clearance in vivo

iScience. 2022 Nov 8;25(12):105522. doi: 10.1016/j.isci.2022.105522. eCollection 2022 Dec 22.

Authors

Lito A Papaxenopoulou^{1

2}, Gang Zhao¹, Sahamoddin Khailaie¹, Konstantinos Katsoulis-Dimitriou³, Ingo Schmitz^{3

4

5}, Eva Medina⁶, Haralampos Hatzikirou^{1

7

8}, Michael Meyer-Hermann^{1

9}

Affiliations

¹ Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, 38106 Braunschweig, Germany.
² Faculty of Life Sciences, Technical University Braunschweig, 38106 Braunschweig, Germany.
³ Institute for Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
⁴ Systems-Oriented Immunology and Inflammation Research Group, Department of Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
⁵ Department of Molecular Immunology, ZKF2, Medical Faculty, Ruhr-University Bochum, 44780 Bochum, Germany.
⁶ Department of Infection Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
⁷ Technische Univesität Dresden, Center for Information Services and High Performance Computing, 01062 Dresden, Germany.
⁸ Mathematics Department, Khalifa University, 127788 Abu Dhabi, UAE.
⁹ Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, 38106 Braunschweig, Germany.

Abstract

Staphylococcus aureus can lead to 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 for S. aureus clearance. A therapeutic protocol with heat-killed S. aureus (HKSA) was quantified in silico and tested in vivo. Contrary to the conventional administration of heat-killed bacteria as vaccination prior to infection, we administered HKSA as treatment in chronically infected hosts. Our treatment eliminated S. aureus in kidneys of all chronically S. aureus-infected mice, reduced MDSCs, and reversed T-cell dysfunction by inducing acute inflammation during ongoing, chronic infection. This study is a guideline for a treatment protocol against chronic S. aureus infection and renal abscesses by repurposing heat-killed treatments, directed by mathematical modeling.

Keywords: Immunity.