With two new research projects, the Institute of Molecular Virology at Ulm University's Medical Centre contributes to a deeper understanding of the characteristics and spread of the novel coronavirus (SARS-CoV-2). Following the funding call of the Federal Ministry of Education and Research (BMBF) for research on COVID-19 in the wake of the SARS CoV 2 outbreak, institute director Professor Frank Kirchhoff and Dr. Daniel Sauter have acquired over 900,000 euros in funding.
In the project 'Restrict SARS-CoV-2', researchers led by Professor Frank Kirchhoff are investigating the interaction of different coronaviruses with the body's own immune response: How do the stimulation of the innate immune response and the activation of inflammatory reactions influence the replication and spread of coronaviruses? Coronaviruses differ considerably in their pathogenicity, i.e. in their disease-causing properties. The effects of an infection range from a mild cold to life-threatening lung diseases such as those caused by the MERS pathogen and, in rare cases, SARS-CoV-2. These different courses of disease can, it seems, be traced back to the characteristics of the individual viruses and to the immune response of the infected hosts. Accordingly, the researchers are investigating both the ability of coronaviruses to manipulate the body's own immune response as well as the defence mechanisms of the target cells. 'Some coronaviruses initially succeed in suppressing the immune reaction of their host in such a way that they can replicate without much interference. A delayed and excessive immune reaction of the infected person due to the high viral load, however, might lead to a severe and sometimes fatal disease course,' explains Professor Kirchhoff.
Comparison of different corona viruses
The project focuses on the current pandemic virus SARS-CoV-2, the SARS pathogen, MERS-CoV and some relatively harmless coronaviruses that infect humans or animals. First goal of the project is a deeper understanding of the biological basis of various coronaviruses. What characteristics enable the pathogens to switch off the antiviral immune response of their hosts? Why can some coronaviruses cross the species barrier from animal to human? The researchers will also look at how SARS-CoV-2 adapts to humans during the pandemic. Above all, the group wants to find out whether the body's own immune response can be modulated to the extent where it becomes possible to reliably control SARS-CoV-2. These findings could lay the foundation for an immunotherapy against SARS coronaviruses. The project funding for 'Immune activation and inhibition of SARS-CoV-2' (Restrict SARS-CoV-2) by the BMBF amounts to more than 542,000 euros for 1.5 years.
How can the reproduction cycle of SARS-CoV-2 be inhibited?
So-called spike proteins are the focus of the project 'protACT', which was initiated by Dr. Daniel Sauter. These proteins in the virus envelope grant coronaviruses access to the target cells in which they multiply. This 'key' to the new host, however, must be activated in advance by 'cutting' it with cellular proteases. The new coronavirus SARS-CoV-2 seems to have an advantage over other pathogens in this regard. 'With its polybasic interface for the common protease furin it has a master key, so to speak. This could make it easier for the virus to spread and amplify its disease-causing properties,' explains Daniel Sauter. In this new project, he wants to investigate the exact role of furin and other proteases in the activation of the spike protein of SARS-CoV-2. A comparison of different coronaviruses in particular – including those found in bats and pangolins – is hoped to show how a polybasic interface affects infectivity. The researchers will also analyse mutations that occur in the course of the current COVID-19 pandemic.
Hope for new therapeutic targets
The project aims to gain new insights into the activation of SARS-CoV-2. The team around Sauter also hopes to find new therapeutic targets. Is it possible to inhibit the replication cycle and thus the spread of the new coronavirus by inhibiting furin? The BMBF funding for the project 'Activation and therapeutic inhibition of the SARS-CoV-2 spike protein' (protACT) amounts to about 367,000 euros. Daniel Sauter collaborates with researchers from the Universities of Tübingen (Germany) and Tokyo (Japan) and the German Primate Center (DPZ) in Göttingen, among others.
The two new research projects complement the EU project 'Fight-nCoV', which is also based at the Institute of Molecular Virology in Ulm and focuses on the testing of antiviral drugs against the new coronavirus. Leibniz Prize winner Professor Frank Kirchhoff is considered a leading expert on the HIV/AIDS pandemic, the best-researched zoonosis: Findings on the origin of HIV and how the pathogen has adapted to humans are also relevant to a better understanding of the coronavirus pandemic.
Text and Mediacontact: Annika Bingmann