Genetic dissection of inborn errors of immunity in Colombian patients with severe infectious diseases: lessons from patients with single to multiples infections

ABSTRACT: INTRODUCTION: Human genetics of infectious diseases propose that monogenic inborn errors of immunity (IEI) underlying resistance or susceptibility to specific infections. Life-threatening infectious diseases in otherwise healthy children, adolescents, and even young adults have been attributed to single-gene IEI. We aim to characterize a cohort of 53 Colombian patients with severe fungal, mycobacterial, virus and bacterial infections with the hypothesis that those patients potentially carriers an IEI underlying their clinical phenotypes. METHODS: Written informed consent was obtained from the patients and their relatives included in this study. Medical, immunological, and microbiological data of the patients were examined. We established pedigrees using patients and family information. Samples (from blood, skin, saliva) were obtained to perform whole-exome sequencing (WES) and Sanger sequencing to detect mutations in previously known or unknown IEI-causing genes or mechanism. Analysis of mRNA expression, protein expression and functional studies were performed according with the findings to prove the causality. We also explored by ELISA the presence of anti-GM-CSF or anti-IFN-γ auto-Abs. RESULTS: We studied 53 Colombian patients from 49 unrelated kindreds presented with severe infectious diseases. Consanguinity was claimed in 4 kindred. We performed 42 WES and we found a disease-causing gene or disease-causing mechanism in 43% of the cohort (23/53). All variants were verified by sanger sequencing and X-linked (XL), autosomal dominant (AD) or autosomal recessive (AR) inheritance was confirmed. First, we studied 2 patients with invasive Ascomycetes fungal infections carrying biallelic CARD9 mutations (n=2) abolishing the CARD9 protein expression. Secondly, we found neutralizing GM-CSF autoantibodies in three patients suffering by disseminated cryptococcosis (n=3). Third, we deeply characterized 2 patients with invasive fungal (histoplasmosis and cryptococcosis), chronic cutaneous warts, and mycobacterial disease presenting with biallelic loss of function (LoF) mutations in IL7 (n=2). In addition, we found 4 patients with Mendelian susceptibility to mycobacterial diseases (MSMD) (n=4), 10 patients with chronic granulomatous diseases (CGD) (n=10), and 2 patients with tuberculosis and listeriosis carrying a biallelic TNF mutation (n=2). CONCLUSIONS: We characterize a cohort of Colombian patients with IEI underlying severe infectious diseases. We obtained important lessons studying fungal infections: First, we report biallelic CARD9 mutations in patients with invasive phaeohyphomicosis. Second, we identified a cohort of patients presenting disseminated cryptococcosis due to neutralizing antiGM-CSF autoantibodies. Third, we performed for the first-time a comprehensive and deep characterization of patients with inherited AR IL-7 deficiency. Fourth, we describe a cohort of MSMD and CGD patients from Colombia. Finally, we discovered, and we will report for the first time a TNF defect in patients presenting tuberculosis. The work performed during this thesis is the first complete characterization of Colombian patients with IEI underlying infections diseases based on WES or anti-cytokine auto-Abs screening.

• Autores: Arango Franco, Carlos Andrés
• Tipo de recurso: Doctoral thesis
• Fecha de publicación: 2023
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/35826
• Acceso en línea: https://hdl.handle.net/10495/35826
• Palabra clave: Enfermedad granulomatosa crónica; Granulomatous disease, chronic; Autoanticuerpos; Autoantibodies; Infecciones fúngicas invasoras; Invasive fungal infections; Inmunodeficiencia combinada grave; Severe combined immunodeficiency; Secuenciación del exoma; Exome sequencing; https://id.nlm.nih.gov/mesh/D006105; https://id.nlm.nih.gov/mesh/D001323; https://id.nlm.nih.gov/mesh/D000072742; https://id.nlm.nih.gov/mesh/D016511; https://id.nlm.nih.gov/mesh/D000073359
• Rights: embargoedAccess
• License: https://creativecommons.org/licenses/by-nc-sa/4.0/