New Findings on How Initial SARS-CoV-2 Cell-Entry Route Influences Infection Outcomes

Quote Dr Richard Brown

Press Release

An international research team has gained new insights into the way SARS-CoV-2 enters cells and its downstream consequences. As an aid to the ACE2 surface protein, the TMPRSS2 serine protease plays an important role in enhancing cell infection: it boosts the resulting immune response, increases cell death, and drives virus evolution. In addition to the human version, TMPRSS2 proteins from diverse mammal species can also enhance infection. These findings may contribute to the development of future treatments and prevention strategies. Proceedings of the National Academy of Science (PNAS) reports on these results in its edition from 4 June 2024.

The SARS-CoV-2 coronavirus primarily uses the ACE2 surface receptor to gain entry into cells. The TMPRSS2 serine protease, which is also anchored in cell membranes, acts as a helper. Cells that carry both ACE2 and TMPRSS2 on their surface show higher rates of infection with SARS-CoV-2. It was previously unclear the extent to which the presence of TMPRSS2 improves cell entry, whether it applies equally to all virus variants, and whether it only applies to infections in humans.

The Influence of TMPRSS2-Mediated Cell Entry on Virus and Host

A research team investigated these questions under the leadership of Dr Richard Brown, former group leader and current visiting scientist in the "Research Veterinary Medicine" Section at the Paul-Ehrlich-Institut and researcher in Dr Daniel Todt's "Computational Virology" group at the Ruhr-Universität Bochum. The group infected cells with and without TMPRSS2 proteins on their cell surface with different virus variants and monitored both virus and host.

Improvement of virus particle uptake into the host cells could be observed using electron microscopy analyses. The research team also investigated whether TMPRSS2-associated cell entry influences the host's innate immune responses and the evolution of the viral genome. Last, but not least, the team looked into the question of whether the observed improvement in SARS-CoV-2 entry is a conserved property of TMPRSS2 from evolutionarily diverse nonhuman species.

The main findings from this study are:

• TMPRSS2-mediated virus uptake occurs via cellular vesicles (endosomes). It had been previously assumed that endosomes are bypassed when SARS-CoV-2 enters the cell using TMPRSS2.
• Equally new was the observation that newer variants such as Omicron also benefit from improvement in the virus uptake into the host cell mediated by TMPRSS2, although the protein is not required for cell entry.
• More efficient TMPRSS2-mediated virus uptake amplifies the infection. Genome replication (process of creating genome copies in the infected cells) is increased, as is the production of new infectious viruses. As a consequence, the immune reaction of infected cells is boosted and cell death occurs more quickly.
• Not only human TMPRSS2 proteins, but also those from other mammalian species, can enhance SARS-CoV-2 infection.

These findings highlight an intricate balance between viral uptake efficiency, cell immune responses, and infection-induced cell-death during infection by SARS-CoV-2.

Original Publication

Qu B, Miskey C, Gömer A, Kleinert RDV, Calvo Ibanez S, Eberle R, Ebenig A, Postmus D, Nocke MK, Herrmann M, Itotia TK, Herrmann ST, Heinen N, Höck S, Hastert FD, von Rhein C, Schürmann C, Li X, van Zandbergen G, Widera M, Ciesek S, Schnierle BS, Tarr AW, Steinmann E, Goffinet C, Pfaender S, Krijnse Locker J, Mühlebach MD, Todt D, Brown RJP (2024): TMPRSS2-mediated SARS-CoV-2 uptake boosts innate immune activation, enhances cytopathology and drives convergent virus evolution.
Proc Natl Acad Sci U S A 121: e2407437121.
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