Phage display of environmental protein toxins and virulence factors reveals the prevalence, persistence, and genetics of antibody responses

Julia W Angkeow; Daniel R Monaco; Athena Chen; Thiagarajan Venkataraman; Sahana Jayaraman; Cristian Valencia; Brandon M Sie; Thomas Liechti; Payam N Farhadi; Gabriela Funez-dePagnier; Cheryl A Sherman-Baust; May Q Wong; Ingo Ruczinski; Patrizio Caturegli; Cynthia L Sears; Patricia J Simner; June L Round; Priya Duggal; Uri Laserson; Theodore S Steiner; Ranjan Sen; Thomas E Lloyd; Mario Roederer; Andrew L Mammen; Randy S Longman; Lisa G Rider; H Benjamin Larman

doi:10.1016/j.immuni.2022.05.002

Phage display of environmental protein toxins and virulence factors reveals the prevalence, persistence, and genetics of antibody responses

Immunity. 2022 Jun 14;55(6):1051-1066.e4. doi: 10.1016/j.immuni.2022.05.002. Epub 2022 May 31.

Authors

Julia W Angkeow¹, Daniel R Monaco¹, Athena Chen², Thiagarajan Venkataraman¹, Sahana Jayaraman¹, Cristian Valencia³, Brandon M Sie¹, Thomas Liechti⁴, Payam N Farhadi⁵, Gabriela Funez-dePagnier⁶, Cheryl A Sherman-Baust⁷, May Q Wong⁸, Ingo Ruczinski², Patrizio Caturegli⁹, Cynthia L Sears¹⁰, Patricia J Simner¹¹, June L Round¹², Priya Duggal³, Uri Laserson¹³, Theodore S Steiner⁸, Ranjan Sen⁷, Thomas E Lloyd¹⁴, Mario Roederer⁴, Andrew L Mammen¹⁵, Randy S Longman⁶, Lisa G Rider⁵, H Benjamin Larman¹⁶

Affiliations

¹ Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
³ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴ ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA.
⁵ Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, NIH, Bethesda, MD, USA.
⁶ Jill Roberts Institute for Research in IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁷ Laboratory of Molecular Biology and Immunology, NIH/National Institute on Aging, Baltimore, MD, USA.
⁸ BC Children's Hospital Research Institute, Vancouver, BC, Canada.
⁹ Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Departments of Medicine and Oncology, Johns Hopkins University School of Medicine, and Department of Molecular Microbiology & Immunology, Bloomberg School of Public Health, Baltimore, MD, USA.
¹¹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Neurology, Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁵ Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulations, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA.
¹⁶ Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: hlarman1@jhmi.edu.

Abstract

Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for detecting exposure and response to microbial protein products. We designed and constructed a library of 95,601 56-amino acid peptide tiles spanning 14,430 proteins with "toxin" or "virulence factor" keyword annotations. We used PhIP-Seq to profile the antibodies of ∼1,000 individuals against this "ToxScan" library. In addition to enumerating immunodominant antibody epitopes, we studied the age-dependent stability of the ToxScan profile and used a genome-wide association study to find that the MHC-II locus modulates bacterial epitope selection. We detected previously described anti-flagellin antibody responses in a Crohn's disease cohort and identified an association between anti-flagellin antibodies and juvenile dermatomyositis. PhIP-Seq with the ToxScan library is thus an effective tool for studying the environmental determinants of health and disease at cohort scale.

Keywords: Crohn's; ToxScan; antibody epitoe profiling; disease; humoral immunity; immunogenetics; juvenile dermatomyositis; microbiome.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Antibodies
Antibody Formation
Bacteriophages* / genetics
Genome-Wide Association Study
Humans
Immunodominant Epitopes
Peptide Library*
Prevalence
Virulence Factors / genetics

Substances

Antibodies
Immunodominant Epitopes
Peptide Library
Virulence Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding