Fc-engineered antibodies promote neutrophil-dependent control of Mycobacterium tuberculosis.

Autor: Irvine EB; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Nikolov A; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Khan MZ; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Peters JM; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Lu R; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Sixsmith J; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Wallace A; MassBiologics of the University of Massachusetts Chan Medical School, Boston, MA, USA., van Woudenbergh E; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Shin S; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Karpinski W; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA., Hsiao JC; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Casadevall A; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA., Bryson BD; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Cavacini L; MassBiologics of the University of Massachusetts Chan Medical School, Boston, MA, USA., Grace PS; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Alter G; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. galit.alter@modernatx.com.; Division of Infectious Disease, Massachusetts General Hospital, Boston, MA, USA. galit.alter@modernatx.com., Fortune SM; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. sfortune@hsph.harvard.edu.; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. sfortune@hsph.harvard.edu.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2024 Sep; Vol. 9 (9), pp. 2369-2382. Date of Electronic Publication: 2024 Aug 22.
DOI: 10.1038/s41564-024-01777-9
Abstrakt: Mounting evidence indicates that antibodies can contribute towards control of tuberculosis (TB). However, the underlying mechanisms of humoral immune protection and whether antibodies can be exploited in therapeutic strategies to combat TB are relatively understudied. Here we engineered the receptor-binding Fc (fragment crystallizable) region of an antibody recognizing the Mycobacterium tuberculosis (Mtb) capsule, to define antibody Fc-mediated mechanism(s) of Mtb restriction. We generated 52 Fc variants that either promote or inhibit specific antibody effector functions, rationally building antibodies with enhanced capacity to promote Mtb restriction in a human whole-blood model of infection. While there is likely no singular Fc profile that universally drives control of Mtb, here we found that several Fc-engineered antibodies drove Mtb restriction in a neutrophil-dependent manner. Single-cell RNA sequencing analysis showed that a restrictive Fc-engineered antibody promoted neutrophil survival and expression of cell-intrinsic antimicrobial programs. These data show the potential of Fc-engineered antibodies as therapeutics able to harness the protective functions of neutrophils to promote control of TB.
(© 2024. The Author(s).)
Databáze: MEDLINE
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