Increased susceptibility to Mycobacterium avium complex infection in miniature Schnauzer dogs caused by a codon deletion in CARD9

Keijiro Mizukami, Angella Dorsey-Oresto, Karthik Raj, Anna Eringis, Eva Furrow, Errolyn Martin, Daisuke Yamanaka, Alexandra Kehl, Ana Kolicheski, Vidhya Jagannathan, Tosso Leeb, Michail S. Lionakis, Urs Giger

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Mammals are generally resistant to Mycobacterium avium complex (MAC) infections. We report here on a primary immunodeficiency disorder causing increased susceptibility to MAC infections in a canine breed. Adult Miniature Schnauzers developing progressive systemic MAC infections were related to a common founder, and pedigree analysis was consistent with an autosomal recessive trait. A genome-wide association study and homozygosity mapping using 8 infected, 9 non-infected relatives, and 160 control Miniature Schnauzers detected an associated region on chromosome 9. Whole genome sequencing of 2 MAC-infected dogs identified a codon deletion in the CARD9 gene (c.493_495del; p.Lys165del). Genotyping of Miniature Schnauzers revealed the presence of this mutant CARD9 allele worldwide, and all tested MAC-infected dogs were homozygous mutants. Peripheral blood mononuclear cells from a dog homozygous for the CARD9 variant exhibited a dysfunctional CARD9 protein with impaired TNF-α production upon stimulation with the fungal polysaccharide β-glucan that activates the CARD9-coupled C-type lectin receptor, Dectin-1. While CARD9-deficient knockout mice are susceptible to experimental challenges by fungi and mycobacteria, Miniature Schnauzer dogs with systemic MAC susceptibility represent the first spontaneous animal model of CARD9 deficiency, which will help to further elucidate host defense mechanisms against mycobacteria and fungi and assess potential therapies for animals and humans.

Original languageEnglish (US)
Article number10346
JournalScientific reports
Volume14
Issue number1
DOIs
StatePublished - Dec 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Keywords

  • Animal model
  • Canine
  • Canis lupus familiaris
  • Dog
  • Fungal infection
  • Genetics
  • Hereditary defect
  • Primary immunodeficiency disorder
  • Tuberculosis
  • Zoonosis

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Increased susceptibility to Mycobacterium avium complex infection in miniature Schnauzer dogs caused by a codon deletion in CARD9'. Together they form a unique fingerprint.

Cite this