Influenza viruses pose a global health threat, particularly to infants and the elderly. The viruses constantly change. As a consequence, vaccines have to be constantly adapted and therapeutics may cease to be effective. Therefore, we seek to develop novel influenza therapies. One focus of our work is on the host cell protease TMPRSS2 since we obtained evidence that TMPRSS2 depend on the protease for acquisition of infectivity and spread in the host. Moreover, we are investigating how defective interfering particles (DIPs) can be generated in the absence of infectious virus and how DIPs inhibit influenza virus infection.
Emerging viruses that are transmitted from animals to humans may cause severe disease. Outbreaks frequently occur abroad but the responsible viruses might be imported into Germany due to infected travelers. We are investigating how emerging viruses interact with host cells and cause disease. A recently started project focuses on lymphocytic choriomeningitis virus (LCMV). LCMV is related to the highly pathogenic Lassa virus, circulates globally and is responsible for outbreaks of lethal hepatitis in marmoset colonies. Moreover, LCMV may cause severe disease in immunosuppressed patients and can constitute a threat to pregnant woman and their unborn children. In addition to LCMV and Ebola virus we are also investigating MERS coronavirus. The aim of our research is to develop cell culture systems that allow predicting transmissibility and thus pandemic potential of novel MERS coronavirus variants.
Another focus of our research is on primate herpesviruses. The transmission of herpes B virus from macaques to humans as well as transmission of related viruses among non-human primates can cause serve disease. We are investigating which viral and host factors determine whether infection will result in severe disease. Moreover, we are developing diagnostics for herpesvirus infections of non-human primates. Finally, we are offering diagnostics for many other viral infections of non-human primates, including a chip-based antibody detection system useful for screening of non-human primate colonies.
Recent publications summarized in three sentences
Identifikation of a cell line that is not susceptible to Ebola virus entry
The highly pathogenic Ebola virus (EBOV) exhibits an extremely broad cell tropism. Zapatero-Belinchón and colleagues demonstrate that the cell line SH-SY5Y is not susceptible to EBOV entry due to lack of factors that promote viral attachment. Therefore, SH-SY5Y cells can by used as tools to identify novel EBOV attachment factors and to characterize known ones.
Zapatero-Belinchón et al, Characterization of the Filovirus-Resistant Cell Line SH-SY5Y Reveals Redundant Role of Cell Surface Entry Factors. Viruses. 2019 Mar 19;11(3).
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A system for production of defective interfering particles
Defective interfering particles (DIP) inhibit influenza virus infection and are being developed for influenza therapy. However, so far, DIPs can only be produced joinlty with infectious virus, which is associated with safety concerns. Here, we report that a cell line stably expressing the viral protein PB2 is suitable for production of segment 1-based DIPs in the absence of infectious virus.
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Focal epithelial hyperplasia and papillomavirus infection in a bonobo
In a biopsie of a bonobo with focal epithelial hyperplasia (FEH) the Pan paniscus papillomavirus 1 (PpPV1) was detected. The animal was part of a bonoboa cohort in which FEH and PpPV1 infection were already detected in the 1980s and comparison of viral genome sequences revealed that the present genomic sequence different in 23 positions for the sequence detected in the 19180s. This finding indicates that either the animal was infected twice with different variants of PpPV1 or that the PpPV1 sequence changed more profound during the course of infection than expected from published data.
Hoffmann et al Disease Manifestation and Viral Sequences in a Bonobo More Than 30 Years after Papillomavirus Infection. Pathogens. 2019 Jan 26;8(1). pii: E13. doi: 10.3390/pathogens8010013.
Ebola and Nipah virus cause severe disease in humans but not fruit bats and it is unclear whether the antiviral host cell factor tetherin contributes to control of viral infection in fruit bat cells. Our study shows that tetherin efficiently blocks Nipah virus spread in fruit bat cells, suggesting that it may contribute to viral control in infected animals. In contrast, inhibition of Ebola virus spread by tetherin was modest and it is at present unclear whether this is due to tetherin counteraction by the viral glycoprotein.
A mutation protects MERS coronavirus against antibodies
The MERS coronavirus causes severe disease and there is concern that the virus might mutate and spread globally. Our work shows that a MERS coornavirus variant emerged during a large outbreak in South Korea that was partially protected against antibody responses raised in infected patients. Our results show that the virus can adapt to more efficient spread in infected patients and suggest that usage of single antíbodies for MERS therapie mgiht not be effective.
Kleine Weber et al. Mutations in the spike protein of MERS-CoV transmitted in Korea increase resistance towards antibody-mediated neutralization. J Virol. 2018 Nov 7. pii: JVI.01381-18.
Impact of protease cleavage sites in the spike protein on MERS-coronavirus entry
The spike protein of MERS-coronavirus mediates host cell entry. For this, the spike protein must be cleaved by cellular proteases. We showed that the S1/S2 cleavage site is required for entry into certain cell lines while the S2’ site is universally required
Kleine-Weber et al. Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein. Sci Rep. 2018 Nov 9;8(1):16597.
Enveloped viruses depend on activation by host cell proteases for acquisition of infectivity. Zmora and colleagues show that the cellular serine protease TMPRSS11A activates influenza A viruses and MERS coronavirus. Moreover, they provide evidence that TMPRSS11A is not blocked by the cellular protease inhibitor HAI-I.
Zmora et al, TMPRSS11A activates the influenza A virus hemagglutinin and the MERS coronavirus spike protein and is insensitive against blockade by HAI-1. J Biol Chem. 2018 Jul 5. pii: jbc.RA118.001273
Hoffmann and Pöhlmann comment on the finding that influenza A viruses use a cellular sialylated Ca++ channel as receptor for host cell entry.
The Ebola virus glycoprotein antagonizes the antiviral host cell factor tetherin. González-Hernández and colleagues show that a GXXXA motif within the transmembrane domain of the Ebola virus glycoprotein is required for inhibiton of tetherin. This finding should help to define the contribution of tetherin antagonism to Ebola virus spread and pathogenesis in the host.