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Prof. Percy Knolle and his team at the Institute of Molecular Immunology / Experimental Oncology.
Prof. Percy Knolle (middle) and his team at the Institute of Molecular Immunology / Experimental Oncology. (Photo: Heddergott / TUM)
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Researchers discover immune factor that allows viral infections to become chronic“Master switch” for chronic infections

Certain viral diseases have a tendency to become chronic – HIV being a notable example. The patient’s immune response is simply not effective enough to eliminate the virus permanently. Researchers at the University of Bonn working with colleagues from the Technical University of Munich (TUM) and the University of Cologne have now identified an important immune factor which is partially responsible for this immune response. Their results give rise to hopes for new treatment approaches. Their work is being published in the renowned journal Nature Immunology.

The HIV virus triggers the immunodeficiency disease AIDS. The infection is chronic in nature as the immune system is not able to get rid of the pathogen. This is due, among other things, to the fact that the virus directly attacks and destroys certain immune cells known as helper T cells.

Many helper T cells are not actually infected by the virus themselves. Nonetheless, their function is impaired in the case of AIDS. Normally, helper T cells secrete inflammatory messengers during an infection. As a result of this chemical distress call, killer T cells – the body’s own defense troops – are mobilized and deployed to the battle site. By contrast, in AIDS and other chronic infections, the helper T cells remain silent. As a result, the killer T cells also remain inactive and no longer fight infection. But why is that?

T cells become silent

To answer this question, the researchers first identified the active genes in the silent helper T cells of HIV patients. In cases of chronic inflammation, the immune function of the helper T cells is inhibited by various signaling pathways. The researchers have now discovered that all of these signaling pathways are apparently controlled by a single molecule known as tumor necrosis factor (TNF). If this is present, the helper T cells become silent.

“TNF seems to function as a kind of ‘master switch’. This is a very important discovery for us, because we will be able to use this factor to change multiple signaling pathways at the same time,” declares Prof. Percy Knolle of TUM.

The researchers used this discovery to re-activate the helper cells in cases of chronic infection. “We investigated mice suffering from a chronic viral infection similar to HIV and deactivated the TNF molecule in them,” explains Dr. Marc Beyer from the Life and Medical Sciences Institute (LIMES) of the University of Bonn. “As a result, the helper T cells worked normally once again. After ten days, the animals had completely eliminated the virus; they were healthy.”

Misdirected protective function

Paradoxically, TNF has exactly the opposite effect in acute viral attacks. It fully mobilizes the immune system, additionally ensuring that cells infected with the virus destroy themselves. “In an acute infection, large quantities of TNF are formed very rapidly,” comments Beyer. “In chronic infections, on the other hand, the body secretes small amounts of TNF over a long period of time. This appears to cause the helper T cells to shut down to some extent.”

The researchers suspect that this response is attributable to a self-defense mechanism. A prolonged strong immune reaction can, in fact, destroy healthy tissue as well – with life-threatening consequences. “We assume that TNF is acting as a kind of overarching emergency brake which monitors other signaling pathways at what are known as checkpoints. This is the body’s very effective way of preventing an excessive immune reaction, but in chronic infections it also has the effect of preventing healing,” sums up Percy Knolle. Exactly how TNF works at a molecular level is still largely unknown. The researchers involved now want to examine this question in detail.

The results may establish new treatment options in the medium term. There are drugs which inhibit the effect of TNF. Up to now, these TNF blockers have been used in the treatment of autoimmune disorders such as rheumatism, for example. Their purpose is to prevent defense cells from attacking the body itself. “Our findings on the role of TNF in chronic infections will bring new hope for sufferers of autoimmune disorders, too. Among other things, we want to investigate what effects these drugs have in rheumatic patients who are additionally suffering from a chronic viral infection,” says Marc Beyer.

Publication: Tumor necrosis factor impairs CD4+ T cell-mediated immune control in chronic viral infection; Nature Immunology; DOI: 10.1038/ni.3399

Prof. Percy Knolle
Institute of Molecular Immunology / Experimental Oncology
Klinikum rechts der Isar, Technical University of Munich
Tel.: +49 89 4140 6921

Corporate Communications Center

Technical University of Munich

Article at tum.de

Percy Knolle, Professor für Molekulare Immunologie an der TUM, untersucht die Ursachen des Leberversagens. (Bild: A. Heddergott / TUM)

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