TY  - JOUR
A1  - Tappe, Beeke
A1  - Lauruschkat, Chris D.
A1  - Strobel, Lea
A1  - Pantaleón García, Jezreel
A1  - Kurzai, Oliver
A1  - Rebhan, Silke
A1  - Kraus, Sabrina
A1  - Pfeuffer-Jovic, Elena
A1  - Bussemer, Lydia
A1  - Possler, Lotte
A1  - Held, Matthias
A1  - Hünniger, Kerstin
A1  - Kniemeyer, Olaf
A1  - Schäuble, Sascha
A1  - Brakhage, Axel A.
A1  - Panagiotou, Gianni
A1  - White, P. Lewis
A1  - Einsele, Hermann
A1  - Löffler, Jürgen
A1  - Wurster, Sebastian
T1  - COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds
JF  - Frontiers in Immunology
N2  - Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.
KW  - COVID-19
KW  - immune impairment
KW  - T cells
KW  - granulocytes
KW  - Aspergillus
KW  - Rhizopus
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283558
SN  - 1664-3224
VL  - 13
ER  - 
TY  - JOUR
A1  - Page, Lukas
A1  - Wallstabe, Julia
A1  - Lother, Jasmin
A1  - Bauser, Maximilian
A1  - Kniemeyer, Olaf
A1  - Strobel, Lea
A1  - Voltersen, Vera
A1  - Teutschbein, Janka
A1  - Hortschansky, Peter
A1  - Morton, Charles Oliver
A1  - Brakhage, Axel A.
A1  - Topp, Max
A1  - Einsele, Hermann
A1  - Wurster, Sebastian
A1  - Loeffler, Juergen
T1  - CcpA- and Shm2-Pulsed Myeloid Dendritic Cells Induce T-Cell Activation and Enhance the Neutrophilic Oxidative Burst Response to Aspergillus fumigatus
JF  - Frontiers in Immunology
N2  - Aspergillus fumigatus causes life-threatening opportunistic infections in immunocompromised patients. As therapeutic outcomes of invasive aspergillosis (IA) are often unsatisfactory, the development of targeted immunotherapy remains an important goal. Linking the innate and adaptive immune system, dendritic cells are pivotal in anti-Aspergillus defense and have generated interest as a potential immunotherapeutic approach in IA. While monocyte-derived dendritic cells (moDCs) require ex vivo differentiation, antigen-pulsed primary myeloid dendritic cells (mDCs) may present a more immediate platform for immunotherapy. To that end, we compared the response patterns and cellular interactions of human primary mDCs and moDCs pulsed with an A. fumigatus lysate and two A. fumigatus proteins (CcpA and Shm2) in a serum-free, GMP-compliant medium. CcpA and Shm2 triggered significant upregulation of maturation markers in mDCs and, to a lesser extent, moDCs. Furthermore, both A. fumigatus proteins elicited the release of an array of key pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-8, and CCL3 from both DC populations. Compared to moDCs, CcpA- and Shm2-pulsed mDCs exhibited greater expression of MHC class II antigens and stimulated stronger proliferation and IFN-γ secretion from autologous CD4\(^+\) and CD8\(^+\) T-cells. Moreover, supernatants of CcpA- and Shm2-pulsed mDCs significantly enhanced the oxidative burst in allogeneic neutrophils co-cultured with A. fumigatus germ tubes. Taken together, our in vitro data suggest that ex vivo CcpA- and Shm2-pulsed primary mDCs have the potential to be developed into an immunotherapeutic approach to tackle IA.
KW  - antigens
KW  - dendritic cells
KW  - cytokines
KW  - host defense
KW  - immunotherapy
KW  - Aspergillus
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239493
SN  - 1664-3224
VL  - 12
ER  -