Biology subjects

Eickmann, M.

Publications and source records attributed to Eickmann, M..

5 recordsLinked to original sources

bioRxiv2026

Lethal Sudan virus infection in IFNAR-/- mice reveals hallmarks of a cytokine storm

Sudan virus (SUDV) is a member of the family Filoviridae, which comprises highly pathogenic viruses associated with unusually high case fatality rates. The development of medical countermeasures against filoviruses, including antivirals, vaccines, and therapeutic antibodies, requires preclinical evaluation in suitable animal models. C57BL/6J IFNAR-/- mice, which lack the type I interferon (IFN-/{beta}) receptor, have been reported to be susceptible to filovirus infections, although their impaired innate immune response may represent a potential limitation of the model. Here, we show that IFNAR-/- mice constitute a suitable model for SUDV infection. Following infection, animals developed a clear clinical disease characterized by significant weight loss and pronounced changes in behaviour and appearance. Mice reached the predefined clinical endpoint 3-5 days post infection. Post mortem analysis of terminal samples revealed high viral loads and viral genome copies in all tested organs as well as in serum, indicating widespread systemic dissemination. Importantly, infection was associated with a marked increase in several key chemokines and cytokines linked to systemic inflammation, consistent with the development of a cytokine storm-like response. Together, these findings demonstrate that SUDV infection in IFNAR-/- mice induces systemic viral dissemination and a pronounced inflammatory response, supporting the suitability of this model for investigating filovirus pathogenesis and infection-associated immune dysregulation.

microbiology↗

bioRxiv2025

Side-by-side evaluation of two mouse models for Crimean-Congo Hemorrhagic Fever Virus infection.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of a severe hemorrhagic fever in humans, associated with case fatality rates ranging from 10 to 40%. Due to the lack of approved vaccines or specific antiviral treatments, CCHFV is classified as a biosafety level 4 (BSL4) pathogen in most countries and designated a priority pathogen by the World Health Organization (WHO). To facilitate the preclinical assessment of medical countermeasures, we have established two murine models using C57BL/6J IFNAR-/- mice, which lack the IFN/{beta} receptor, infected with the phylogenetically distinct CCHFV strains Afghanistan09-2990 (Afg09) and Kosovo Hoti (Hoti). Infection with both CCHFV strains in IFNAR-/- mice resulted in significant weight loss, with Afg09 infection leading to more severe clinical disease. Quantitative analysis of viral RNA revealed widespread viral dissemination across multiple organs in both models. Detection of infectious virus varied by organ and strain. These results confirm and extend previous findings, providing a deeper understanding of CCHFV strain-specific pathogenesis in IFNAR-/- mice. Thereby, these mouse models represent valuable tools for the evaluation of antiviral therapeutics and vaccine candidates, enabling the investigation of cross-lineage protection against genetically diverse CCHFV isolates.

microbiology↗

bioRxiv2024

Experimental Infection of greater white-toothed Shrews (Crocidura russula) with Borna disease virus 1: Insights into Viral Spread and Shedding

Numbers of human encephalitis cases caused by infection with Borna disease virus 1 (BoDV1) increase continuously in endemic areas. The reservoir host of BoDV1 is the bicoloured white-toothed shrew, albeit few naturally infected individuals of other shrew species have been detected. To establish a reliable experimental reservoir model, 15 greater white-toothed shrews were infected with a shrew-derived BoDV1 isolate by different inoculation routes (intracerebral, intranasal, oral, subcutaneous, intraperitoneal) and monitored up to 41 days. Except for the oral route all other animals (12/15) were successfully infected, and the majority of them displayed temporary reduced feed intake and loss of body weight but no inflammatory lesions. Infectious virus was isolated from 11/12 infected animals. Viral RNA was demonstrated by RT-qPCR in the central nervous system (CNS) and the majority of organs. Immunohistochemistry demonstrated BoDV1 antigen in neurons and astrocytes in the CNS and peripheral nerves. High viral loads in the CNS and the spinal cord points towards spread from periphery to the CNS to enhance viral replication, and subsequent centrifugal spread to organs capable of secretion and excretions. In general, successful experimental BoDV1 infection of shrews proves their usefulness as animal model, enabling further studies on maintenance, transmission, pathogenesis, and risk assessment for human spill-over infections.

pathology↗

bioRxiv2021

Intranasal administration of a monoclonal neutralizing antibody protects mice against SARS-CoV-2 infection

Despite recent availability of vaccines against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an urgent need for specific anti-SARS-CoV-2 drugs. Monoclonal neutralizing antibodies are an important drug class in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection and their potential to be used as both, prophylactic and therapeutic drugs. Clinically used neutralizing antibodies against respiratory viruses are currently injected intravenously, which can lead to suboptimal pulmonary bioavailability and thus to a lower effectiveness. Here we describe DZIF-10c, a fully human monoclonal neutralizing antibody that binds the receptor-binding domain of SARS-CoV-2 spike protein. DZIF-10c displays an exceptionally high neutralizing potency against SARS-CoV-2 and retains activity against the variants of concern B.1.1.7 and B.1.351. Importantly, not only systemic but also intranasal application of DZIF-10c abolished presence of infectious particles in the lungs of SARS-CoV-2 infected mice and mitigated lung pathology. Along with a favorable pharmacokinetic profile, these results highlight DZIF-10c as a novel human SARS-CoV-2 neutralizing antibody with high in vitro and in vivo antiviral potency. The successful intranasal application of DZIF-10c paves the way for clinical trials investigating topical delivery of anti-SARS-CoV-2 antibodies. Significance StatementMonoclonal neutralizing antibodies are important in the global fight against the SARS-CoV-2 pandemic due to their ability to convey immediate protection. However, their intravenous application might lead to suboptimal bioavailability in the lung. We here precisely characterize a new monoclonal neutralizing antibody (DZIF-10c) that binds to the receptor binding domain of the spike protein of SARS-CoV-2. DZIF-10c neutralizes SARS-CoV-2 with exceptionally high potency and maintains activity against circulating variants of concern. The antibody has a favorable pharmacokinetic profile and protects mice from SARS-CoV-2 infection. Importantly, we show that intranasal administration of DZIF-10c generates protective efficacy. These results not only identify DZIF-10c as a novel highly potent neutralizing antibody, but further pave the way for a topical application of anti-SARS-CoV-2 antibodies.

microbiology↗

bioRxiv2020

TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets

In December 2019, a novel coronavirus named SARS-CoV-2 first reported in Wuhan, China, emerged and rapidly spread to numerous other countries globally, causing the current pandemic. SARS-CoV-2 causes acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. Currently, there is no approved antiviral drug for treating COVID-19 patients and there is an urgent need for specific antiviral therapies and vaccines. In order for SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study we investigated which host cell proteases activate the SARS-CoV-2 S protein in Calu-3 human airway epithelial cells. We show that S can be cleaved by both the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2 site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 cells through antisense-mediated knockdown of TMPRSS2 expression. Further, we show that SARS-CoV-2 replication can be efficiently inhibited by two synthetic inhibitors of TMPRSS2 and also by the broad range serine protease inhibitor aprotinin. Additionally, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851. Combining various TMPRSS2 inhibitors with MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Our data demonstrate that both TMPRSS2 and furin are essential for SARS-CoV-2 activation in human airway cells and are promising drug targets for the treatment of COVID-19 either by targeting one of these proteases alone or by a combination of furin and TMPRSS2 inhibitors. Therefore, this approach has a high therapeutic potential for treatment of COVID-19.

microbiology↗