The Infection Biology Unit is studying virus-host cell interactions and their contribution to viral spread and pathogenesis in the host.
Many viruses that cause severe diseases in primates are activated by host cell proteases. The responsible enzymes are potential targets for novel antivirals and are in the focus of our research efforts. Our recent studies provide evidence that the cellular protease TMPRSS2 is essential for influenza virus spread in mice and primate respiratory epithelium, and show that TMPRSS2 is used by other viruses to ensure their activation. Therefore, TMPRSS2-inhibitors might exert broad antiviral activity, similar to broadband antibiotics used to treat diverse bacterial infections.
The interferon system constitutes the first barrier against virus infection. A second focus of our studies is on the question how antiviral effector proteins of the interferon system inhibit viral spread and how viruses counter their antiviral activity. To answer this question, we employ siRNA and CRISPR/Cas9 approaches, life cell imaging, viruses with reporter function and ex vivo cultures of primate organs. Moreover, we are conducting, jointly with colleagues at DPZ, genetic analyses in order to reveal whether polymorphisms in genes encoding antiviral effectors impact disease development.
Another goal of the Infection Biology Unit is the diagnostic of viral infections of non-human primates. Transmission of herpes B virus from macaques to humans and transmission of herpes B-related viruses between non-human primates can result in fatal disease. Therefore, the Infection Biology Unit is developing herpes virus diagnostics. In addition, we offer diagnostic tests for several other viral infections, including chip-based antibody detection suitable for screening of non-human primate colonies.
Recent publications summarized in three sentences
VSV-G antagonizes tetherin in transfected cells
We show that the G protein of vesicular stomatitis virus (VSV-G) blocks the antiviral host cell factor tetherin, at least upon directed expression. However, our study failed to provide evidence that VSV-G-mediated tetherin antagonism is operative in infected cells.
Brinkmann et al. The glycoprotein of vesicular stomatitis virus promotes release of virus-like particles from tetherin-positive cells. PLoS One. 2017 Dec 7;12(12):e0189073
Inhibition of lectin-dependent enhancement of Ebola virus entry into cells
The cellular lectins DC-SIGN and DC-SIGNR bind to glycans present on Ebola virus and can augment viral entry into cells. This study shows that quantum dots (QD) displaying a dense array of glycans allow to dissect the multivalent protein-glycan interactions underlying ligand binding to DC-SIGN/R. Moreover, the research demonstrates that QDs can be used to block augmentation of Ebola virus cell entry by DC-SIGN/R.
Guo et al. Dissecting Multivalent Lectin-Carbohydrate Recognition Using Polyvalent Multifunctional Glycan-Quantum Dots. J Am Chem Soc. 2017 Aug 30;139(34):11833-11844.
Identification of amino acid residues in the SARS-CoV spike protein required for activation by TMPRSS2
We have previously demonstrated that the host cell protease TMPRSS2 activates the SARS coronavirus spike protein (SARS-S) and that a TMPRSS2 inhibitor blocks SARS-CoV spread and pathogenesis in a rodent model. However, the amino acid residues in SARS-S that are required for cleavage by TMPRSS2 were largely unknown. Here, we show that SARS-S residues R667 and R797 are important for cleavage and activation, respectively.
Reinke et al. Different residues in the SARS-CoV spike protein determine cleavage and activation by the host cell protease TMPRSS2. PLoS One. 2017 12(6):e0179177
pH dependence of influenza A viruses is linked to interferon- and IFITM3-sensitivity
Influenza A viruses (IAV) fuse with target cells upon exposure to acidic pH and fusion can be blocked by the interferon (IFN)-inducible antiviral host cell factor IFITM3. This study shows that the pH-optimum required for fusion determines IFN- and IFITM-sensitivity of IAV, i.e. viruses that have a low pH optimum are more sensitive to blockade by IFN/IFITM3 than viruses that have a high pH optimum.
Gerlach et al. pH Optimum of Hemagglutinin-Mediated Membrane Fusion Determines Sensitivity of Influenza A Viruses to the Interferon-Induced Antiviral State and IFITMs. J Virol. 2017 12;91(11).
TMPRSS2 of non-human primates activates influenza viruses
We show that non-human primate (NHP) orthologues of the cellular serine protease activate influenza A viruses (IAV) and that an inhibitor of TMPRSS2 and related proteases blocks viral spread in the respiratory epithelium of NHP ex vivo. These results and our previous work suggest that IAV might depend on TMPRSS2 activity for spread in diverse host species and that NHP might be a suitable model to study viral activation by TMPRSS2.
Zmora et al. Non-human primate orthologues of TMPRSS2 cleave and activate the influenza virus hemagglutinin. PLoS One. 2017 11;12(5).