TY - JOUR
T1 - In silico predicted therapy against chronic Staphylococcus aureus infection leads to bacterial clearance in vivo
AU - Papaxenopoulou, Lito A.
AU - Zhao, Gang
AU - Khailaie, Sahamoddin
AU - Katsoulis-Dimitriou, Konstantinos
AU - Schmitz, Ingo
AU - Medina, Eva
AU - Hatzikirou, Haralampos
AU - Meyer-Hermann, Michael
N1 - Funding Information:
LP was supported by the German Federal Ministry of Education and Research within the initiative e:Med-network of systems-medicine, project MultiCellML (FKZ: 01ZX01707C ). SK was supported by the German Federal Ministry of Education and Research within the Measures for the Establishment of Systems Medicine, project SYSIMIT (BMBF eMed project SYSIMIT, FKZ: 01ZX1308B and by the Helmholtz Association, Zukunftsthema “Immunology and Inflammation” (ZT-0027). GZ was supported by the Helmholtz Association within the initiative Immunology and Inflammation, project “Aging and Metabolic Programming” (AMPro). HH was supported by the Helmholtz Initiative on Personalized Medicine - iMed . H. H. has received funding from the Bundesministerium für Bildung, und Forschung (BMBF) under grant agreement No. 031L0237C (MiEDGE project/ERACOSYSMED). Moreover, H.H. would like to acknowledge the support of the Volkswagenstiftung for “Life?” initiative (96732). H.H. acknowledges the support of the FSU grant 2021-2023 grant from Khalifa University. The authors thank Sabine Lehne and Lothar Gröbe for excellent technical assistance, and Drs. Anna Dalli, Heiko Enderling, Andreas Papaxenopoulos, Yasmina Marin-Felix, Andreas I. Andreou, and Kamila Tomoko Yuyama for useful comments on a draft of this article.
Publisher Copyright:
© 2022 The Authors
PY - 2022/12/22
Y1 - 2022/12/22
N2 - 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.
AB - 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.
KW - Immunity
UR - https://www.scopus.com/pages/publications/85142483926
U2 - 10.1016/j.isci.2022.105522
DO - 10.1016/j.isci.2022.105522
M3 - Article
AN - SCOPUS:85142483926
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 12
M1 - 105522
ER -