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An age-related deficiency of antiviral interferon proteins is likely to be a major reason why older people often fall seriously ill with SARS-CoV-2 / Study in mouse model shows cause and treatment option with approved drugs

Researchers at the Faculty of Medicine - University of Freiburg have discovered that an impaired immune response in old age, the production of antiviral interferons, may be responsible for older patients being more susceptible to severe courses of COVID-19. The study, published in the Journal of Experimental Medicine (JEM ) on September 21, 2022, shows that older mice infected with SARS-CoV-2 produce fewer interferons. Treatment with drug-induced interferons protected them from severe disease. This suggests that the clinical use of interferons in older COVID-19 sufferers could be very effective.

"We found that younger animals mount a very rapid and well-coordinated innate and adaptive immune response to effectively fight off the viral infection, while older animals showed a reduced, delayed and inefficient inflammatory response," explains study leader Dr. Daniel Schnepf from the Institute for Virology at the Medical Center University of Freiburg.

Interferons - conductors of the immune response

The immune system's response to SARS-CoV-2 is coordinated by a group of antiviral signaling proteins called interferons. These help to stop the virus from replicating. At the same time, they are involved in activating various immune cells that help to remove the virus from the body. There are three different types of interferon proteins, known as types I, II and III. It is estimated that up to 20 percent of SARS-CoV-2-related deaths are due to defects in interferon signaling, for example due to genetic mutations or autoantibodies that prevent the correct course of an interferon response.

Which age-related changes are responsible for the fact that older patients are much more susceptible to severe courses of COVID-19 was previously unclear.

To investigate this question, the team led by Schnepf and research group leader Prof. Dr. Martin Schwemmle from the Institute for Virology at the Medical Center - University of Freiburg has modified the SARS-CoV-2 virus so that it can cause severe disease in normal laboratory mice, in contrast to clinical virus isolates. This mouse-adapted variant, which is much less able to replicate in human cells, was particularly virulent in older mice: the virus replicated much more strongly and caused a severe, usually fatal, course of disease.

The Freiburg researchers found that the type I and type II interferon responses were greatly reduced in old mice, which in turn explained the uninhibited virus replication. They also showed that therapeutic treatment with type II interferon in combination with the particularly well-tolerated type III interferon could efficiently prevent severe disease progression in particularly vulnerable mice with advanced age and genetic immunodeficiencies.

"Our data show that an impaired interferon-mediated immune response may be responsible for the high SARS-CoV-2 mortality in older mice and possibly also in older humans," says Schnepf.

"Through our research, we have identified the age-dependent impairment of type I and type II interferon responses as a critical pathomechanism that makes SARS-CoV-2 particularly dangerous for old individuals," says Schwemmle. "We were able to successfully translate these findings into a treatment strategy that prevents mortality from SARS-CoV-2 in a highly sensitive disease model."

Original title of the study: Impaired immune response drives age-dependent severity of COVID-19

DOI: 10.1084/jem.20220621

Link to the study:https://doi.org/10.1084/jem.20220621

Contact:
Prof. Dr. Martin Schwemmle
martin.schwemmle@uniklinik-freiburg.de

Dr. Daniel Schnepf
daniel.schnepf@uniklinik-freiburg.de

Institute for Virology
Medical Center - University of Freiburg
Phone: 0761 203-6526