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  - 
TY  - JOUR
A1  - Dichtl, Karl
A1  - Forster, Johannes
A1  - Ormanns, Steffen
A1  - Horns, Heidi
A1  - Suerbaum, Sebastian
A1  - Seybold, Ulrich
A1  - Wagener, Johannes
T1  - Comparison of β-D-Glucan and galactomannan in serum for detection of invasive aspergillosis: retrospective analysis with focus on early diagnosis
JF  - Journal of Fungi
N2  - The early diagnosis of invasive aspergillosis (IA) relies mainly on computed tomography imaging and testing for fungal biomarkers such as galactomannan (GM). We compared an established ELISA for the detection of GM with a turbidimetric assay for detection of the panfungal biomarker β-D-glucan (BDG) for early diagnosis of IA. A total of 226 serum specimens from 47 proven and seven probable IA cases were analysed. Sensitivity was calculated for samples obtained closest to the day of IA-diagnosis (d0). Additional analyses were performed by including samples obtained during the presumed course of disease. Most IA cases involved the respiratory system (63%), and Aspergillus fumigatus was the most frequently isolated species (59%). For proven cases, sensitivity of BDG/GM analysis was 57%/40%. Including all samples dating from –6 to +1 weeks from d0 increased sensitivities to 74%/51%. Sensitivity of BDG testing was as high as or higher than GM testing for all subgroups and time intervals analysed. BDG testing was less specific (90–93%) than GM testing (99–100%). Combining BDG and GM testing resulted in sensitivity/specificity of 70%/91%. Often, BDG testing was positive before GM testing. Our study backs the use of BDG for diagnosis of suspected IA. We suggest combining BDG and GM to improve the overall sensitivity.
KW  - BDG
KW  - beta-D-glucan
KW  - GM
KW  - galactomannan
KW  - IA
KW  - invasive aspergillosis
KW  - biomarker
KW  - fungal antigens
KW  - serology
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216298
SN  - 2309-608X
VL  - 6
IS  - 4
ER  - 
TY  - JOUR
A1  - Seif, Michelle
A1  - Einsele, Hermann
A1  - Löffler, Jürgen
T1  - CAR T cells beyond cancer: hope for immunomodulatory therapy of infectious diseases
JF  - Frontiers in Immunology
N2  - Infectious diseases are still a significant cause of morbidity and mortality worldwide. Despite the progress in drug development, the occurrence of microbial resistance is still a significant concern. Alternative therapeutic strategies are required for non-responding or relapsing patients. Chimeric antigen receptor (CAR) T cells has revolutionized cancer immunotherapy, providing a potential therapeutic option for patients who are unresponsive to standard treatments. Recently two CAR T cell therapies, Yescarta® (Kite Pharma/Gilead) and Kymriah® (Novartis) were approved by the FDA for the treatments of certain types of non-Hodgkin lymphoma and B-cell precursor acute lymphoblastic leukemia, respectively. The success of adoptive CAR T cell therapy for cancer has inspired researchers to develop CARs for the treatment of infectious diseases. Here, we review the main achievements in CAR T cell therapy targeting viral infections, including Human Immunodeficiency Virus, Hepatitis C Virus, Hepatitis B Virus, Human Cytomegalovirus, and opportunistic fungal infections such as invasive aspergillosis.
KW  - infectious diseases
KW  - mAb engineering
KW  - CAR T cells
KW  - HIV
KW  - HCV
KW  - CMV
KW  - invasive aspergillosis
KW  - HBV
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195596
SN  - 1664-3224
VL  - 10
IS  - 2711
ER  - 
TY  - JOUR
A1  - Dix, Andreas
A1  - Czakai, Kristin
A1  - Springer, Jan
A1  - Fliesser, Mirjam
A1  - Bonin, Michael
A1  - Guthke, Reinhard
A1  - Schmitt, Anna L.
A1  - Einsele, Hermann
A1  - Linde, Jörg
A1  - Löffler, Jürgen
T1  - Genome-Wide Expression Profiling Reveals S100B as Biomarker for Invasive Aspergillosis
JF  - Frontiers in Microbiology
N2  - Invasive aspergillosis (IA) is a devastating opportunistic infection and its treatment constitutes a considerable burden for the health care system. Immunocompromised patients are at an increased risk for IA, which is mainly caused by the species Aspergillus fumigatus. An early and reliable diagnosis is required to initiate the appropriate antifungal therapy. However, diagnostic sensitivity and accuracy still needs to be improved, which can be achieved at least partly by the definition of new biomarkers. Besides the direct detection of the pathogen by the current diagnostic methods, the analysis of the host response is a promising strategy toward this aim. Following this approach, we sought to identify new biomarkers for IA. For this purpose, we analyzed gene expression profiles of hematological patients and compared profiles of patients suffering from IA with non-IA patients. Based on microarray data, we applied a comprehensive feature selection using a random forest classifier. We identified the transcript coding for the S100 calcium-binding protein B (S100B) as a potential new biomarker for the diagnosis of IA. Considering the expression of this gene, we were able to classify samples from patients with IA with 82.3% sensitivity and 74.6% specificity. Moreover, we validated the expression of S100B in a real-time reverse transcription polymerase chain reaction (RT-PCR) assay and we also found a down-regulation of S100B in A. fumigatus stimulated DCs. An influence on the IL1B and CXCL1 downstream levels was demonstrated by this S100B knockdown. In conclusion, this study covers an effective feature selection revealing a key regulator of the human immune response during IA. S100B may represent an additional diagnostic marker that in combination with the established techniques may improve the accuracy of IA diagnosis.
KW  - human biomarker
KW  - invasive aspergillosis
KW  - allogeneic stem cell transplantation
KW  - gene expression data
KW  - fungal infection
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165386
IS  - 7
ER  -