Clinical Staphylococcus aureus inhibits human T-cell activity through interaction with the PD-1 receptor
Maiken Mellergaard,
Sarah Line Skovbakke,
Stine Dam Jepsen,
Nafsika Panagiotopoulou,
Amalie Bøge Rud Hansen,
Weihua Tian,
Astrid Lund,
Rikke Illum Høgh,
Sofie Hedlund Møller,
Romain Guérillot,
Ashleigh S. Hayes,
Lise Tornvig Erikstrup,
Lars Andresen,
Anton Y. Peleg,
Anders Rhod Larsen,
Timothy P. Stinear,
Aase Handberg,
Christian Erikstrup,
Benjamin P. Howden,
Steffen Goletz,
Dorte Frees,
Søren Skov
Affiliations
Maiken Mellergaard
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Sarah Line Skovbakke
Biotherapeutic Glycoengineering and Immunology, DTU Bioengineering, Department of Biotechnology and Biomedicine, Technical University of Denmark , Lyngby, Denmark
Stine Dam Jepsen
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Nafsika Panagiotopoulou
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Amalie Bøge Rud Hansen
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Weihua Tian
Biotherapeutic Glycoengineering and Immunology, DTU Bioengineering, Department of Biotechnology and Biomedicine, Technical University of Denmark , Lyngby, Denmark
Astrid Lund
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Rikke Illum Høgh
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Sofie Hedlund Møller
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Romain Guérillot
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity , Melbourne, Victoria, Australia
Ashleigh S. Hayes
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity , Melbourne, Victoria, Australia
Lise Tornvig Erikstrup
Department of Clinical Microbiology, Aarhus University Hospital , Aarhus, Denmark
Lars Andresen
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Anton Y. Peleg
Department of Microbiology, Monash University , Melbourne, Victoria, Australia
Anders Rhod Larsen
Statens Serum Institute, Microbiology and Infection Control , Copenhagen, Denmark
Timothy P. Stinear
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity , Melbourne, Victoria, Australia
Aase Handberg
Department of Clinical Biochemistry, Aalborg University Hospital, North Denmark Region , Aalborg, Denmark
Christian Erikstrup
Department of Clinical Immunology, Aarhus University Hospital , Aarhus, Denmark
Benjamin P. Howden
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity , Melbourne, Victoria, Australia
Steffen Goletz
Biotherapeutic Glycoengineering and Immunology, DTU Bioengineering, Department of Biotechnology and Biomedicine, Technical University of Denmark , Lyngby, Denmark
Dorte Frees
Food Safety and Zoonosis, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
Søren Skov
Department of Veterinary and Animal Sciences, Laboratory of immunology, Section for Preclinical Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark
ABSTRACT Staphylococcus aureus (S. aureus) represents a major clinical challenge due to its explicit capacity to select mutations that increase antibiotic resistance and immune evasion. However, the molecular mechanisms are poorly defined, especially for adaptive immunity. Cancer immunotherapy targeting programmed cell death protein 1 (PD-1) enhances T-cell activity and is emerging for the treatment of certain viral infections, while its potential against bacterial infections remains elusive. We show that an S. aureus clpP mutant, selected during clinical antibiotic therapy, inhibits T-cell activity by directly interacting with PD-1 on human T cells. Specificity of the interaction was confirmed using recombinant PD-1, as well as PD-1 overexpressing and knock out cells. Moreover, the PD-1-binding S. aureus inhibited intracellular calcium mobilization, T-cell proliferation, CD25 expression, and IL-2 secretion, while the key effects were alleviated by antibody-mediated PD-1 blockade using an engineered IgG1-based anti-PD-1 antibody. Our results suggest that clpP mutant S. aureus directly targets PD-1 to evade immune activation and that therapeutic targeting of PD-1 may be used against certain staphylococcal infections. IMPORTANCE Therapies that target and aid the host immune defense to repel cancer cells or invading pathogens are rapidly emerging. Antibiotic resistance is among the largest threats to human health globally. Staphylococcus aureus (S. aureus) is the most common bacterial infection, and it poses a challenge to the healthcare system due to its significant ability to develop resistance toward current available therapies. In long-term infections, S. aureus further adapt to avoid clearance by the host immune defense. In this study, we discover a new interaction that allows S. aureus to avoid elimination by the immune system, which likely supports its persistence in the host. Moreover, we find that blocking the specific receptor (PD-1) using antibodies significantly relieves the S. aureus-imposed inhibition. Our findings suggest that therapeutically targeting PD-1 is a possible future strategy for treating certain antibiotic-resistant staphylococcal infections.
