Antibody signatures against viruses and microbiome reflect past and chronic exposures and associate with aging and inflammation

Prior encounters with pathogens and other molecules can imprint long-lasting effects on our immune system, potentially influencing future physiological outcomes. However, given the wide range of pathogens and commensal microbes to which humans are exposed, their collective impact on the health and aging processes in the general population is still not fully understood. In this study, we aimed to explore relations between exposures, including to pathogens, microbiome and common allergens, and biological aging and inflammation. We capitalized on an extensive repository of the antibody-binding repertoire against 2,815 microbial, viral, and environmental peptides in a deeply-phenotyped population cohort of 1,443 participants. Utilizing antibody-binding as a proxy for past exposures, we investigated their impact on biological aging markers, immune cell composition and systemic inflammation. This identified that immune response against cytomegalovirus (CMV), rhinovirus and specific gut bacterial species influences the telomere length of different immune cell types. Using blood single-cell RNA-seq measurements, we identified a large effect of CMV infection on the transcriptional landscape of specific immune cells, in particular subpopulations of CD8 and CD4 T-cells. Our work provides a broad examination of the role of past and chronic exposures in biological aging and inflammation, highlighting a role for chronic infections (CMV and Epstein-Barr Virus) and common pathogens (rhinoviruses and adenovirus C). ### Competing Interest Statement Peter Lansdorp is a founding shareholder in Repeat Diagnostics, a CLIA certified company specializing in leukocyte telomere length measurements using Flow-FISH, where Geraldine Buchanan is also employed. The other authors declare no competing interests. ### Funding Statement A.Z.: Netherlands Heart Foundation (IN-CONTROL CVON 2018-27). EU Horizon Europe Program grant INITIALISE (101094099). NWO Gravitation project ExposomeNL (024.004.017) and NWO-VIDI (016.178.056). J.F.: Netherlands Heart Foundation (IN-CONTROL CVON 2012-03). NWO-VIDI (864.13.013). NWO-VICI (VI.C.202.022). ERC Consolidator Grant (grant agreement no. 101001678). T.V.: European Union - ERC STG, project number 101075733. M.M.: RYC- 2017-22249. PID2019-107937GA-I00. A.R.: FPI [grant no. PRE2019-090193]. M.W.: Dutch Research Council (NWO-VENI 192.029 and NWO-VIDI 223.041) A.R.B.: NWO Rubicon grant [grant no. 452022317]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at: https://ega-archive.org/datasets/EGAD00001010104 and https://ega-archive.org/studies/EGAS00001001704 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data presented were collected by the Lifelines cohort study. Lifelines is specifically organized to make assessment results available for (re)use by third parties. PhIP-Seq: Raw and processed, previously generated PhIP-Seq data are available in the European Genome-Phenome Archive (EGA) under the accession EGA: EGAS00001006999. Biological aging data, including sj-TRECs expression, methylation age predictions and TL measurements, in addition to cytokines and chemokine measurements, cell-type counts and predictions, can be requested through Lifelines. A research proposal must be submitted for evaluation by the Lifelines Research Office. Processed (de-anonymized) scRNA-seq data, including a text file that links each cell barcode to its respective individual, has been deposited at the EGA, which is hosted by the EBI and the CRG, under accession number EGAS00001005376 for Oelen2022 and EGAS00001002560 for Wijst2019. In addition to Lifelines data, we used data from the 1000IBD cohort study to train models for CMV prediction. PhIP-Seq data is available at EGA: EGAD00001004194. The 300BCG cohort was used for replication of several analyses. Telomere measurements for this cohort are available upon contact.