2. Academic Validation
  3. Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies

Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies

  • Cell. 2021 Feb 18;184(4):1017-1031.e14. doi: 10.1016/j.cell.2021.01.016.
Itai Doron 1,  Irina Leonardi 1,  Xin V Li 1,  William D Fiers 1,  Alexa Semon 1,  Meghan Bialt-DeCelie 1,  Mélanie Migaud 2,  Iris H Gao 3,  Woan-Yu Lin 3,  Takato Kusakabe 1,  Anne Puel 4,  Iliyan D Iliev 5
Affiliations

Affiliations

  • 1 Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA.
  • 2 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France.
  • 3 Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
  • 4 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065 USA; University of Paris, Imagine Institute, 75015 Paris, France.
  • 5 Gastroenterology and Hepatology Division, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA. Electronic address: iliev@med.cornell.edu.
PMID: 33548172 DOI: 10.1016/j.cell.2021.01.016
Abstract

Antibodies mediate natural and vaccine-induced immunity against viral and Bacterial pathogens, whereas fungi represent a widespread kingdom of pathogenic species for which neither vaccine nor neutralizing antibody therapies are clinically available. Here, using a multi-kingdom antibody profiling (multiKAP) approach, we explore the human antibody repertoires against gut commensal fungi (mycobiota). We identify species preferentially targeted by systemic Antibodies in humans, with Candida albicans being the major inducer of Antifungal immunoglobulin G (IgG). Fungal colonization of the gut induces germinal center (GC)-dependent B cell expansion in extraintestinal lymphoid tissues and generates systemic Antibodies that confer protection against disseminated C. albicans or C. auris Infection. Antifungal IgG production depends on the innate immunity regulator CARD9 and CARD9+CX3CR1+ macrophages. In individuals with invasive candidiasis, loss-of-function mutations in CARD9 are associated with impaired Antifungal IgG responses. These results reveal an important role of gut commensal fungi in shaping the human antibody repertoire through CARD9-dependent induction of host-protective Antifungal IgG.

Keywords

B cells; CARD9; CX3CR1 macrophages; Candida albicans; Candida auris; antifungal IgG antibodies; gut fungi; gut-disseminated fungal infections; invasive candidiasis; mycobiome.

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