A study by scientists of the University Medical Centre Ulm has investigated how well different variants of the coronavirus SARS-CoV-2 propagate in cultured human heart muscle cells. The results show that the original Omicron subvariant BA.1 spreads only to a very limited extent. The current BA.5 subvariant, however, can infect cardiomyocytes as effectively as the previous Delta variant. This is due to additional mutations – especially in the Spike protein, which increase the infectivity and cell-damaging effect of BA.5. The results have been published in the Nature journal 'Signal Transduction and Targeted Therapy'.
When healthy heart muscle cells are cultured and multiply, they start to beat spontaneously. 'This spontaneous "heartbeat" of cardiomyocytes is a good indicator of the health and function of the cells,' explains Professor Steffen Just, Head of the Section for Molecular Cardiology at the Department of Internal Medicine II. Together with virologist Professor Frank Kirchhoff, Just has launched a study on the pathogenic effects of various SARS-CoV-2 variants. 'For this purpose, we infected spontaneously beating heart muscle cells with different variants of the coronavirus and examined the respective proliferation rates and levels of cell-damaging effects,' explains Kirchhoff, who heads the Institute of Molecular Virology at the University Medical Centre Ulm. The more cytopathic a virus variant or subvariant is, the sooner the 'heartbeat' of the cells stops.
The researchers compared early SARS-CoV-2 variants, such as NL-02-2020 and Delta, with different subvariants of Omicron. As expected, the early Omicron subvariant BA.1 – generally considered less aggressive – was significantly less harmful to cardiomyocytes than the early variants NL-02-2020 and Delta. By contrast, the investigation of Omicron BA.5 revealed a different result: 'The heart muscle cells infected with BA.5 stopped beating much sooner than cultures infected with the early BA.1 Omicron subvariant. The result was similar to that of the Delta variant infection – the beats ceased after 3 to 5 days,' says Rayhane Nchioua, first author of the study and doctoral researcher at the Institute of Molecular Virology, who examined the heart cells together with Federica Diofano from the Section for Molecular Cardiology.
Cardiac muscle cells are particularly susceptible to SARS-CoV-2
Different cell types, tissues and organs are susceptible to SARS-CoV-2 to different extents. Heart muscle cells are particularly vulnerable because they present many ACE2 receptors, through which the virus infects the cells. This makes it easier for the virus to propagate and probably explains why cardiomyopathies and cardiac injury are common complications of COVID-19. Clinical symptoms include inflammation of the heart muscle in particular, but cardiac arrhythmias are seen as well. Autopsies of deceased COVID-19 patients also showed high levels of viral RNA and Spike proteins in cardiac muscle cells.
The research team in Ulm thus also analysed the different variants in terms of concentration of virus RNA and the proportion of Spike proteins in virally infected cardiomyocytes. They found that the heart muscle cells that were infected with the Delta variant or the late Omicron subvariant BA.5, showed particularly high concentrations of such viral traces.
A key conclusion of the study is that BA.5 is not only resistant to many neutralising antibodies of the adaptive immune response, but can also multiply very effectively in human cells. 'Our results indicate that BA.1's efficient circumvention of adaptive immune responses initially came at the expense of viral infectivity. Additional mutations in the Spike protein of BA.5, however, restored the full replication potential,' the researchers explain. Current studies with animal models also show a higher pathogenicity of BA.5 compared to BA.1, thus agreeing with the findings of the researchers in Ulm. Further investigations are needed to clarify whether this is also the case in humans.
The research project was funded by the German Research Foundation (DFG) as part of the Collaborative Research Centres 1279 and 1506. Further funding comes from the Fight-nCoV programme of the EU as well as from the Ministry of Science, Research and the Arts Baden-Württemberg, and the Federal Ministry of Education and Research.
Strong attenuation of SARS-CoV-2 Omicron BA.1 and increased replication of the BA.5 subvariant in human cardiomyocytes. Rayhane Nchioua, Federica Diofano, Sabrina Noettger, Pascal von Maltitz, Steffen Stenger, Fabian Zech, Jan Münch, Konstantin M. J. Sparrer, Steffen Just & Frank Kirchhoff. In: Signal Transduction and Targeted Therapy volume 7, article number: 395 (2022), 25 December 2022, https://doi.org/10.1038/s41392-022-01256-9
Prof. Frank Kirchhoff, Head of the Institute of Molecular Virology, University Medical Centre Ulm, eMail: frank.kirchhoff(at)uni-ulm.de
Prof. Steffen Just, Head of the Section for Molecular Cardiology at the Department of Internal Medicine II, University Medical Centre Ulm, eMail: steffen.just(at)uniklinik-ulm.de
Picture and video material
Video link 1
The video shows uninfected, spontaneously beating heart muscle cells from human cell culture, day 1 (source: https://doi.org/10.1038/s41392-022-01256-9)
Video link 2
The video shows spontaneously beating heart muscle cells from human cell culture infected with SARS-CoV-2 viruses, day 4 (source: https://doi.org/10.1038/s41392-022-01256-9)
Text and media contact: Andrea Weber-Tuckermann