Discovery and engineering of the antibody response to a prominent skin commensal

Djenet Bousbaine; Katherine D Bauman; Y Erin Chen; Pranav V Lalgudi; Tam T D Nguyen; Joyce M Swenson; Victor K Yu; Eunice Tsang; Sean Conlan; David B Li; Amina Jbara; Aishan Zhao; Arash Naziripour; Alessandra Veinbachs; Yu E Lee; Jennie L Phung; Alex Dimas; Sunit Jain; Xiandong Meng; Thi Phuong Thao Pham; Martin I McLaughlin; Layla J Barkal; Inta Gribonika; Koen K A Van Rompay; Heidi H Kong; Julie A Segre; Yasmine Belkaid; Christopher O Barnes; Michael A Fischbach

doi:10.1038/s41586-024-08489-4

Discovery and engineering of the antibody response to a prominent skin commensal

Nature. 2024 Dec 11. doi: 10.1038/s41586-024-08489-4. Online ahead of print.

Authors

Djenet Bousbaine^{1

2}, Katherine D Bauman^{1

2}, Y Erin Chen^{1

2}, Pranav V Lalgudi^{2

3}, Tam T D Nguyen^{1

2}, Joyce M Swenson^{1

2}, Victor K Yu^{1

2}, Eunice Tsang^{1

2}, Sean Conlan⁴, David B Li^{1

2}, Amina Jbara^{1

2}, Aishan Zhao^{1

2}, Arash Naziripour^{1

2}, Alessandra Veinbachs^{1

2}, Yu E Lee⁵, Jennie L Phung⁵, Alex Dimas^{1

2}, Sunit Jain⁶, Xiandong Meng^{2

6}, Thi Phuong Thao Pham^{1

2}, Martin I McLaughlin^{1

2}, Layla J Barkal^{1

2

7}, Inta Gribonika^{8

9}, Koen K A Van Rompay^{10

11}, Heidi H Kong¹², Julie A Segre⁴, Yasmine Belkaid^{8

9}, Christopher O Barnes^{2

5

6}, Michael A Fischbach^{13

14

15}

Affiliations

¹ Department of Bioengineering, Stanford University, Stanford, CA, USA.
² ChEM-H Institute, Stanford University, Stanford, CA, USA.
³ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Biology, Stanford University, Stanford, CA, USA.
⁶ Chan Zuckerberg Biohub, Stanford, CA, USA.
⁷ Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹ NIAID Microbiome Program, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
¹⁰ California National Primate Research Center, University of California, Davis, CA, USA.
¹¹ Department of Pathology, Microbiology, and Immunology, University of California, Davis, CA, USA.
¹² Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
¹³ Department of Bioengineering, Stanford University, Stanford, CA, USA. [email protected].
¹⁴ ChEM-H Institute, Stanford University, Stanford, CA, USA. [email protected].
¹⁵ Chan Zuckerberg Biohub, Stanford, CA, USA. [email protected].

PMID: 39662508
DOI: 10.1038/s41586-024-08489-4

Abstract

The ubiquitous skin colonist Staphylococcus epidermidis elicits a CD8⁺ T cell response pre-emptively, in the absence of an infection¹. However, the scope and purpose of this anti-commensal immune program are not well defined, limiting our ability to harness it therapeutically. Here, we show that this colonist also induces a potent, durable, and specific antibody response that is conserved in humans and non-human primates. A series of S. epidermidis cell-wall mutants revealed that the cell surface protein Aap is a predominant target. By colonizing mice with a strain of S. epidermidis in which the parallel β-helix domain of Aap is replaced by tetanus toxin fragment C, we elicit a potent neutralizing antibody response that protects mice against a lethal challenge. A similar strain of S. epidermidis expressing an Aap-SpyCatcher chimera can be conjugated with recombinant immunogens; the resulting labeled commensal elicits high antibody titers under conditions of physiologic colonization, including a robust IgA response in the nasal and pulmonary mucosa. Thus, immunity to a common skin colonist involves a coordinated T and B cell response, the latter of which can be redirected against pathogens as a novel form of topical vaccination.