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Multipathogen Analysis of IgA and IgG Antigen Specificity for Selected Pathogens in Milk Produced by Women From Diverse Geographical Regions: The INSPIRE Study

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Michelle K. McGuire, Arlo Z. Randall, Antti E. Seppo, Kirsi M. Järvinen, Courtney L. Meehan, Debela Gindola, Janet E. Williams, Daniel W. Sellen, Elizabeth W. Kamau-Mbuthia, Egidioh W. Kamundia, Samwel Mbugua, Sophie E. Moore, Andrew M. Prentice, James A. Foster, Gloria E. Otoo, Juan M. Rodríguez, Rossina G. Pareja, Lars Bode, Mark A. McGuire, Joseph J. Campo

Original languageEnglish
Article number614372
JournalFrontiers in Immunology
Published11 Feb 2021

Bibliographical note

Funding Information: In addition to all of the women and infants who participated in this study, we would sincerely like to thank Linda Kvist (Lund University) and her team for overseeing milk and data collection for the Swedish cohort; Andrew Doel (MRC Unit, The Gambia) for field supervision and logistics planning, and Alansan Sey for questionnaire administration, and taking anthropometric measurements in The Gambia; Jane Odei (University of Ghana) for supervising field data collection in Ghana; Katherine Flores (Washington State University), Dubale Gebeyehu (Hawassa University), Haile Belachew (Hawassa University), and Birhanu Sintayehu for planning, logistics, recruiting, and data collection and administration and staff at Adare Hospital in Hawassa for assistance with logistics in Ethiopia; Catherine O. Sarange (Egerton University) for field supervision and logistics planning, and Milka W. Churuge and Minne M. Gachau for recruiting, questionnaire administration, and taking anthropometric measurements in Kenya; Gisella Barbagelatta (Instituto de Investigaci?n Nutricional) for field supervision and logistics planning, and Patricia Calderon (Instituto de Investigaci?n Nutricional) for recruiting, questionnaire administration, and taking anthropometric measurements, and Roxana Barrutia (Instituto de Investigaci?n Nutricional) for the management and shipping of samples in Peru; Lorena Ru?z (Complutense University of Madrid) for technical assistance and expertise, and M. ?ngeles Checa (Zaragoza, Spain), Katalina Legarra (Guernica, Spain), and Julia M?nguez (Huesca, Spain) for participation in the collection of samples in Spain; Kirsti Kaski and Maije Sj?strand (both Helsingborg Hospital) for participation in the collection of samples, questionnaire administration, and anthropometric measurements in Sweden; Renee Bridge and Kara Sunderland (both University of California, San Diego) and Kimberly Lackey and Janae Carrothers (University of Idaho and Washington State University) for logistics planning, recruiting, questionnaire administration, sample collection, and taking anthropometric measurements in Washington; Romana Hyde (University of Idaho) and Kimberly Lackey (University of Idaho) for technical assistance in preparing the samples for array analysis; and Glenn Miller (Washington State University) for his expertise and critical logistic help needed for shipping samples and supplies worldwide. From Antigen Discovery, Inc., we thank Andy Teng, Chris Hung, Jozelyn Pablo, Adam Shandling and Johnathon Truong for performing lab experiments; and Angela Yee and Xioawu Liang for leadership in initiation of the breast milk immunoprofiling platform. Funding Information: Sample collection was funded by the National Science Foundation (award #1344288). Sterile, single-use milk collection kits were kindly provided by Medela, Inc. (McHenry, IL). The Bill and Melinda Gates Foundation (OPP1174492) funded the immunospecificity work which makes up the majority of this report. Publisher Copyright: © Copyright © 2021 McGuire, Randall, Seppo, Järvinen, Meehan, Gindola, Williams, Sellen, Kamau-Mbuthia, Kamundia, Mbugua, Moore, Prentice, Foster, Otoo, Rodríguez, Pareja, Bode, McGuire and Campo. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Breastfeeding provides defense against infectious disease during early life. The mechanisms underlying this protection are complex but likely include the vast array of immune cells and components, such as immunoglobulins, in milk. Simply characterizing the concentrations of these bioactives, however, provides only limited information regarding their potential relationships with disease risk in the recipient infant. Rather, understanding pathogen and antigen specificity profiles of milk-borne immunoglobulins might lead to a more complete understanding of how maternal immunity impacts infant health and wellbeing. Milk produced by women living in 11 geographically dispersed populations was applied to a protein microarray containing antigens from 16 pathogens, including diarrheagenic E. coli, Shigella spp., Salmonella enterica serovar Typhi, Staphylococcus aureus, Streptococcus pneumoniae, Mycobacterium tuberculosis and other pathogens of global health concern, and specific IgA and IgG binding was measured. Our analysis identified novel disease-specific antigen responses and suggests that some IgA and IgG responses vary substantially within and among populations. Patterns of antibody reactivity analyzed by principal component analysis and differential reactivity analysis were associated with either lower-to-middle-income countries (LMICs) or high-income countries (HICs). Antibody levels were generally higher in LMICs than HICs, particularly for Shigella and diarrheagenic E. coli antigens, although sets of S. aureus, S. pneumoniae, and some M. tuberculosis antigens were more reactive in HICs. Differential responses were typically specific to canonical immunodominant antigens, but a set of nondifferential but highly reactive antibodies were specific to antigens possibly universally recognized by antibodies in human milk. This approach provides a promising means to understand how breastfeeding and human milk protect (or do not protect) infants from environmentally relevant pathogens. Furthermore, this approach might lead to interventions to boost population-specific immunity in at-risk breastfeeding mothers and their infants.

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