UKE homepage?
DE
Protective early response patterns of innate cellular immune crosstalk in hemorrhagic fever virus infection
Summary
Viral hemorrhagic fevers (VHFs), including diseases like Ebola, are caused by dangerous viruses that can lead to high death rates and serious inflammation. These viruses affect people around the world and are considered top priorities for global health research. A key part of our immune defense against such viruses involves natural killer (NK) cells, which can destroy infected cells and regulate inflammation. However, we still need to understand more about how NK cells are activated and how they function during these infections.
Macrophages - another important immune cell type - play a dual role: they help activate NK cells but are also a major target for the virus. When NK cells don’t eliminate infected macrophages effectively, the virus can spread further and trigger dangerous immune reactions. This project investigates how early and strong NK cell activation might stop viral spread and reduce harmful inflammation, aiming to uncover mechanisms that could be used to improve treatments or vaccines.
Our Work Packages (WP):
WP1: Understanding why NK cells fail to kill virus-infected macrophages - this part of the project explores how and why NK cells may be unable to eliminate virus-infected macrophages during VHFs, leading to uncontrolled infection and inflammation.
WP2: Investigating how macrophages activate antiviral NK cell responses - we will study how macrophages can successfully trigger NK cell activity in order to strengthen early immune responses and prevent disease progression.
WP3: Exploring immune responses in different tissues using 3D human models - we will use advanced 3D human cell cultures to examine how macrophages and NK cells interact in various tissues, especially the brain, where inflammation is particularly harmful.
These work packages help us to unravel how the interaction between macrophages, NK cells, and microglia shapes the outcome of viral haemorrhagic fever infections and contributes to protective versus pathological immune responses.
Team
Prof. Angelique Hölzemer
Principal Investigator
E-mail address:
Research Group Hölzemer
The Research Group Infection & Immune Regulation is based at the University Medical Center Hamburg-Eppendorf (UKE).
Project related publications
Lin Y#, Bashirova A#, Viard M, …., Hoelzemer A, Gillespie GM, Garcia-Beltran WF, Carrington M. HLA class I signal peptide polymorphism determines the level of CD94/NKG2-HLA-E-mediated regulation of effector cell responses. Nat Immunol. 2023;24(7):1087-1097. doi: 10.1038/s41590-023-01523-z.
Mensching L, Hölzemer A, .NK Cells, Monocytes and Macrophages in HIV-1 Control: Impact of Innate Immune Responses. Front Immunol. 2022;13:883728. doi: 10.3389/fimmu.2022.883728.
Jung JM, Ching W, Baumdick ME, …, Bosse JB… Hölzemer A, …, Belderbos M, Dobner T, Bunders MJ. KIR3DS1 directs NK cell-mediated protection against human adenovirus infections. Sci Immunol. 2021;6(63):eabe2942. doi: 10.1126/sciimmunol.abe2942.
Garcia-Beltran WF#, St Denis KJ#, Hölzemer A, …, Iafrate AJ, Naranbhai V, Balazs AB. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2021;185(3):457-466.e4. doi:10.1016/j.cell.2021.12.033.
van Stigt Thans T#, Akko JI#, Niehrs A, …, Sauter D, Altfeld M, Hölzemer A. Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression. J Virol. 2019;93(20):e00719-19. doi: 10.1128/JVI.00719-19.
Körner C, Simoneau CR, Schommers P, …, Hölzemer A, …Kirchhoff F, Carrington M, Altfeld M. HIV-1-Mediated Downmodulation of HLA-C Impacts Target Cell Recognition and Antiviral Activity of NK Cells. Cell Host Microbe. 2017;22(1):111-119.e4. doi: 10.1016/j.chom.2017.06.008.
Dulberger CL, McMurtrey CP, Hölzemer A, … Altfeld M, Hildebrand WH, Adams EJ. Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors. Immunity. 2017;46(6):1018-1029.e7. doi: 10.1016/j.immuni.2017.06.002.
Garcia-Beltran WF, Hölzemer A, Martrus G,…, Jost S, Carrington M, Altfeld M. Open conformers of HLA-F are high-affinity ligands of the activating NK-cell receptor KIR3DS1. Nat Immunol. 2016;17(9):1067-74. doi: 10.1038/ni.3513.
Hölzemer A#, Thobakgale# CF, Jimenez Cruz CA, …, Zhou R, Ndung'u T, Altfeld M. Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. PLoS Med. 2015;12(11):e1001900; discussion e1001900. doi: 10.1371/journal.pmed.1001900.
#equally contributing authors