TY  - JOUR
A1  - Häder, Antje
A1  - Schäuble, Sascha
A1  - Gehlen, Jan
A1  - Thielemann, Nadja
A1  - Buerfent, Benedikt C.
A1  - Schüller, Vitalia
A1  - Hess, Timo
A1  - Wolf, Thomas
A1  - Schröder, Julia
A1  - Weber, Michael
A1  - Hünniger, Kerstin
A1  - Löffler, Jürgen
A1  - Vylkova, Slavena
A1  - Panagiotou, Gianni
A1  - Schumacher, Johannes
A1  - Kurzai, Oliver
T1  - Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity
JF  - Nature Communications
N2  - Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.
KW  - antimicrobial responses
KW  - immunogenetics
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357441
VL  - 14
ER  - 
TY  - JOUR
A1  - Sánchez-Maldonado, Jose Manuel
A1  - Moñiz-Díez, Ana
A1  - ter Horst, Rob
A1  - Campa, Daniele
A1  - Cabrera-Serrano, Antonio José
A1  - Martínez-Bueno, Manuel
A1  - Garrido-Collado, María del Pilar
A1  - Hernández-Mohedo, Francisca
A1  - Fernández-Puerta, Laura
A1  - López-Nevot, Miguel Ángel
A1  - Cunha, Cristina
A1  - González-Sierra, Pedro Antonio
A1  - Springer, Jan
A1  - Lackner, Michaela
A1  - Alcazar-Fuoli, Laura
A1  - Fianchi, Luana
A1  - Aguado, José María
A1  - Pagano, Livio
A1  - López-Fernández, Elisa
A1  - Clavero, Esther
A1  - Potenza, Leonardo
A1  - Luppi, Mario
A1  - Moratalla, Lucia
A1  - Solano, Carlos
A1  - Sampedro, Antonio
A1  - Cuenca-Estrella, Manuel
A1  - Lass-Flörl, Cornelia
A1  - Canzian, Federico
A1  - Loeffler, Juergen
A1  - Li, Yang
A1  - Einsele, Hermann
A1  - Netea, Mihai G.
A1  - Vázquez, Lourdes
A1  - Carvalho, Agostinho
A1  - Jurado, Manuel
A1  - Sainz, Juan
T1  - Polymorphisms within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis: a two-stage case control study in the context of the aspBIOmics consortium
JF  - Journal of Fungi
N2  - Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4\(_{rs7526628T/T}\) genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4\(_{rs7526628T}\) allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2\(_{rs12137965G}\) allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2\(_{rs17013271T}\) allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2\(_{rs12137965G}\) allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2\(_{rs17013271T}\) allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.
KW  - invasive aspergillosis
KW  - TNFSF4
KW  - MAPKAPK2
KW  - genetic susceptibility
KW  - B cells
KW  - monocytes
KW  - serum biomarkers
KW  - TSLP
KW  - TNFSF14
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220107
SN  - 2309-608X
VL  - 7
IS  - 1
ER  -