Determinants of immune responses predictive of protection against shigellosis in an endemic zone: a systems analysis of antibody profiles and function.

Autor:	Bernshtein B; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA. Electronic address: bbernshtein@mgh.harvard.edu., Kelly M; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA., Cizmeci D; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA., Zhiteneva JA; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA., Macvicar R; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA., Kamruzzaman M; International Centre for Diarrheal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh; Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Tangail, Bangladesh., Bhuiyan TR; International Centre for Diarrheal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh., Chowdhury F; International Centre for Diarrheal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh., Khan AI; International Centre for Diarrheal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh., Qadri F; International Centre for Diarrheal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh., Charles RC; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA., Xu P; National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, MD, USA., Kováč P; National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, MD, USA., Clarkson KA; Department of Diarrheal Disease Research, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA., Kaminski RW; Department of Diarrheal Disease Research, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Latham BioPharm Group, Cambridge, MA, USA., Alter G; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA., Ryan ET; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T H Chan School of Public Health, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Microbe [Lancet Microbe] 2024 Oct; Vol. 5 (10), pp. 100889. Date of Electronic Publication: 2024 Aug 05.
DOI:	10.1016/S2666-5247(24)00112-5
Abstrakt:	Background: Shigella is the third leading global cause of moderate or severe diarrhoea among children younger than 5 years globally, and is the leading cause in children aged 24-59 months. The mechanism of protection against Shigella infection and disease in endemic areas is uncertain. We aimed to compare the Shigella-specific antibody responses in individuals living in Shigella-endemic and non-endemic areas, and to identify correlates of protection in a Shigella-endemic location. Methods: We applied a systems approach to retrospectively analyse serological responses to Shigella across endemic and non-endemic populations. We profiled serum samples collected from 44 individuals from the USA without previous exposure to Shigella and who were experimentally challenged with Shigella sonnei (non-endemic setting), and serum samples collected from 55 Peruvian army recruits (endemic setting). In the endemic setting, a subset of 37 samples collected from individuals infected with culture-confirmed Shigella flexneri 2a were divided into two groups: susceptible, which included individuals infected within 90 days of entering the camp (n=29); or resistant, which included individuals infected later than 90 days after entering the camp (n=8). We analysed Shigella-specific antibody isotype, subclass, and Fc receptor binding profiles across IpaB, IpaC, IpaD, and lipopolysaccharide from S flexneri 2a, 3a, and 6, and S sonnei, and O-specific polysaccharide (OSP) from S flexneri 2a and 3a and S sonnei. We also evaluated antibody-mediated complement deposition and innate immune cell activation. The main outcome of interest was the detection of antibody markers and functionality associated with protection against shigellosis in a high-burden endemic setting. Findings: Adults with endemic exposure to Shigella possessed broad and functional antibody responses across polysaccharide, glycolipid, and protein antigens compared with individuals from non-endemic regions. In a setting with high Shigella burden, elevated levels of OSP-specific Fcα receptor (FcαR) binding antibodies were associated with resistance to shigellosis, whereas total OSP-specific IgA was not, suggesting a potentially unique functionality. OSP-specific FcαR binding IgA found in resistant individuals activated bactericidal neutrophil functions including phagocytosis, degranulation, and production of reactive oxygen species. Moreover, IgA depletion from resistant serum significantly reduced binding of OSP-specific antibodies to FcαR and antibody-mediated activation of neutrophils and monocytes. Interpretation: Our findings suggest that OSP-specific functional IgA responses contribute to protective immunity against Shigella infection in a high-burden setting. These findings will assist in the development and evaluation of Shigella vaccines. Funding: US National Institutes of Health. Competing Interests: Declaration of interests GA is an employee of Moderna Therapeutics and holds equity in Leyden Labs and Systems Seromyx. All other authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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