Paul-Ehrlich-Institut

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Caught in the Act – Snapshots of early Infection with Hepatitis C

07 / 2021

Acute Hepatitis C (HCV) infections are often asymptomatic and remain undiagnosed. For this reason, little is known about cellular responses in the early phase of HCV infection. In a national research collaboration, the research team led by Dr Richard Brown at the Paul-Ehrlich-Institut has uncovered the signatures of host-virus interactions in early HCV infection and shed new light on the viral mechanisms used to evade elimination by the immune system, which may ultimately contribute to effective vaccine development. The Journal of Virology reports on the results in its online version of 3 March 2021.

Hepatitis C Virus (Quelle: Kateryna Kon/Shutterstock.com)

Around 71 million people are chronically infected with hepatitis C virus (HCV). Unlike acute virus infections, including common colds or influenza, where the immune system successfully eliminates the virus, HCV infections can become chronic and can cause liver failure and liver cancer. Currently, there is no vaccine against HCV. HCV infection initially causes immune reactions typical for viral infections: virus genetic material is sensed via various pattern recognition receptors (PRRs), which trigger multiple signalling cascades of the immune system. In this process, transcription factors trigger the expression of target genes into RNA, which is then translated into proteins, including interferons. Interferons are hormones that, among other things, exert their antiviral effect by activating the transcription of other genes. Gene transcriptional regulation is thus a vital step in controlling the functionality of the cell: genes are expressed in a coordinated manner by cells at any given time point and patterns of gene expression can change according to environmental stimuli. Knowledge of transcriptional processes thus provides valuable information on the processes ongoing at any point in time in the cell and on how they change under certain influences.

In a multi-centre collaboration with other research teams from Germany, Dr Richard Brown, head of the ‘Virus Tropism and Immunogenicity’ research group in the Division Veterinary Medicine at the Paul-Ehrlich-Institut, and his team, examined the early phase of HCV infection using “transcriptional profiling”. This method is based on next generation sequencing (NGS) of cellular RNAs and provides snapshots of virus-mediated cellular reprogramming. For their study, the research team used material from seven HCV-negative patients who, for medical reasons, had had part of their livers removed (liver resection). The liver cells (hepatocytes) were infected with HCV in the laboratory of Professor Thomas Pietschmann at TWINCORE in Hannover, and the resulting cellular transcriptional changes were analysed at different time points following infection.

The scientists report complex virus-induced footprints in the transcriptional landscape of the cells, which increased in magnitude over time. This gene dysregulation affected processes, which are known to be involved in both virus removal and virus persistence. This simultaneous antagonistic dysregulation of proviral and antiviral programs facilitates tolerance of the host towards the virus, keeping virus levels low in the liver and thus favouring progression to chronic infection. These findings reveal the signatures of host-virus interactions in early HCV infection and shed light on the mechanisms used by the hepatitis C virus to evade elimination by the immune system. These findings may contribute to the development of an effective vaccine.

Original Publication

Tegtmeyer B, Vieyres G, Todt D, Lauber C, Ginkel C, Engelmann M, Herrmann M, Pfaller CK, Vondran FWR, Broering R, Vafadarnejad E, Saliba AE, Puff C, Baumgärtner W, Miskey C, Ivics Z, Steinmann E, Pietschmann T, Brown RJP (2021): Initial HCV infection of adult hepatocytes triggers a temporally structured transcriptional program containing diverse pro- and anti-viral elements.
J Virology 95: e00245-21.
Online-Abstract

Updated: 31.03.2021