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Using Expanded Natural Killer Cells as Therapy for Invasive Aspergillosis

Division of Infectious Diseases, University Medicine Cluster, National University Health System, Singapore 119228, Singapore
Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore 119074, Singapore
Department of Surgery and Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
Department of Biochemistry, National University of Singapore, Singapore117596, Singapore
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore
Department of Pathology, National University of Singapore, Singapore 117597, Singapore
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
Author to whom correspondence should be addressed.
J. Fungi 2020, 6(4), 231;
Received: 30 August 2020 / Revised: 30 September 2020 / Accepted: 14 October 2020 / Published: 17 October 2020
(This article belongs to the Special Issue Antifungal Immunity and Fungal Vaccine Development)
Invasive aspergillosis (IA) is a major opportunistic fungal infection in patients with haematological malignancies. Morbidity and mortality rates are high despite anti-fungal treatment, as the compromised status of immune system prevents the host from responding optimally to conventional therapy. This raises the consideration for immunotherapy as an adjunctive treatment. In this study, we evaluated the utility of expanded human NK cells as treatment against Aspergillus fumigatus infection in vitro and in vivo. The NK cells were expanded and activated by K562 cells genetically modified to express 4-1BB ligand and membrane-bound interleukin-15 (K562-41BBL-mbIL-15) as feeders. The efficacy of these cells was investigated in A. fumigatus killing assays in vitro and as adoptive cellular therapy in vivo. The expanded NK cells possessed potent killing activity at low effector-to-target ratio of 2:1. Fungicidal activity was morphotypal-dependent and most efficacious against A. fumigatus conidia. Fungicidal activity was mediated by dectin-1 receptors on the expanded NK cells leading to augmented release of perforin, resulting in enhanced direct cytolysis. In an immunocompromised mice pulmonary aspergillosis model, we showed that NK cell treatment significantly reduced fungal burden, hence demonstrating the translational potential of expanded NK cells as adjunctive therapy against IA in immunocompromised patients. View Full-Text
Keywords: Aspergillus; antifungal immunity; fungal infection; immune evasion; immune recognition; expanded natural killer cells Aspergillus; antifungal immunity; fungal infection; immune evasion; immune recognition; expanded natural killer cells
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Soe, W.M.; Lim, J.H.J.; Williams, D.L.; Goh, J.G.; Tan, Z.; Sam, Q.H.; Chotirmall, S.H.; Ali, N.A.B.M.; Lee, S.C.; Seet, J.E.; Ravikumar, S.; Chai, L.Y.A. Using Expanded Natural Killer Cells as Therapy for Invasive Aspergillosis. J. Fungi 2020, 6, 231.

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