Danish researchers discover new initial layer of the immune response

Breaking new ground 26. jan 2021 4 min Professor Søren Riis Paludan, Professor MSO Trine Mogensen Written by Kristian Sjøgren

New Danish research reveals that the innate immune system constantly operates at a low level to combat viral infections without activating the full immune response.

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When a virus enters the human body, the immune system must eliminate it rapidly before it multiplies too much and create major problems.

For the past two decades, researchers were convinced that a part of the immune system called pattern recognition receptors is the immune system’s initial response to a viral infection. Now, however, new Danish research shows that the immune system has another innate layer that fights viral infections earlier than the pattern recognition receptors.

This discovery advances researchers’ knowledge about the immune system in general and offers the potential for designing better vaccines or medicines for people with immunodeficiencies.

“We already know many compounds that can stimulate what we have identified as the immune system’s very first response. If we can stimulate these mechanisms, it could be an interesting way to treat viral infections,” explains a researcher behind the discovery, Søren Riis Paludan, Professor, Department of Biomedicine, Aarhus University.

The research, carried out in collaboration with Trine Hyrup Mogensen, another Professor at the Department of Biomedicine, and others, has been published in Nature Reviews Immunology and Science Immunology.

Most infections do not make us ill

The pattern recognition receptors are a cornerstone of an effective immune response.

These receptors are located on the surface of and inside the immune system’s virus-fighting cells and recognize viruses entering the body. Then the immune system goes on alert and fights off the infection. If the infection gets established, you may feel that you are infected (ill) because the immune system is at work.

Søren Riis Paludan explains that an earlier response to viral infections than the pattern recognition receptors therefore makes good sense.

The immune response through these receptors is powerful, and researchers have not been able to get this to fit their understanding of how the body defends itself.

“Most viral infections do not make us ill. Our immune system eliminates them without us noticing. Therefore, we have long wondered whether the immune system might have a layer that fights viral infections more surreptitiously, so that the immune system can avoid deploying its cannons to shoot sparrows every time our bodies encounter a virus,” says Søren Riis Paludan.

Immune wall keeps infections at bay

Søren Riis Paludan and his colleagues reviewed several hundred articles to find evidence of an early immune response. He explains that the literature is full of data that have not previously been viewed from this perspective but can be used to gain new insight.

Trawling through the existing literature made clear that a constant low-grade background immune response inhibits viral infections.

According to Søren Riis Paludan, this subtle immune response can be compared to a sea wall that keeps the viral infections at bay.

When the infections are not especially threatening, the sea wall solves the problems, but when a tsunami of infection arrives, the pattern recognition receptors must act, and then we become ill.

“The pattern recognition receptors function by recognizing something and then accelerating the immune response. Conversely, the innate layer of the immune system does not strengthen anything but handles minor infections,” explains Søren Riis Paludan.

Identifying a palette of new immune mechanisms

This newly discovered layer of the immune system involves various proteins that recognize virus particles and bind to them immediately. These proteins are present in the body all the time and are not produced until, for example, the common cold virus or herpesvirus invades the body.

The proteins are generally quite broad in recognizing viruses, but some are also very specific and bind to only one type of virus.

The researchers found 15–20 mechanisms that meet several criteria for being the constitutive (initial) layer of the immune system.

“We have collected these many proteins and mechanisms, which only individual studies have identified so far, under a common umbrella and described them as a constitutive layer of the immune system acting before the pattern recognition receptors. It was not known that the pattern recognition receptors are a layer in the immune system two decades ago, but now the general principle has been identified,” says Søren Riis Paludan.

Identifying immune mechanisms among people with rare diseases

The literature review is just one part of the researchers’ new findings. In another study, the researchers examined 15 people with Mollaret’s meningitis, a very rare type triggered by herpesvirus in the central nervous system. This disease returns again and again as the virus reactivates. Most of us have herpesviruses laying dormant in our clls, and the immune system keeps the virus in check so we do not get ill, but not people with Mollaret’s meningitis.

The researchers mapped these people’s genomes and found that Mollaret’s meningitis results from a genetic defect that prevents autophagy, a mechanism for removing unnecessary and dysfunctional components from cells, including protein residues and other waste and thus also virus particles.

When autophagy functions, viruses are eliminated easily, but malfunctioning autophagy can trigger Mollaret’s meningitis.

The researchers replaced the damaged genes encoding for autophagy in cell samples from the participants, and the repaired cells were again able to eliminate the herpesvirus.

“Autophagy is a primary mechanism in the palette we identified in the constitutive layer of the immune system,” says Trine Hyrup Mogensen, who led the autophagy research.

Discovery may help people with immunodeficiencies

The discovery of the new layer of the immune system has implications for both basic research and drug development.

In the future, basic research can equip researchers to rationally develop drugs for people with Mollaret’s meningitis and other diseases and disorders.

Specifically, substances are already known that can stimulate autophagy, and according to Trine Hyrup Mogensen, these might be used to keep viral infections at bay.

Trine Hyrup Mogensen also thinks that there may be interesting perspectives in determining whether people with immunodeficiencies can stimulate the constitutive layer of the immune system and thus avoid being pummelled by viral infections all the time.

“Returning to the sea wall, perhaps we can raise the height slightly for these people so that their immune system does not continually drown. Our discovery also has perspectives in vaccine development. The previous immune response plays a major role in how well a vaccine works and for how long. Our discovery gives vaccine developers an extra tool for developing vaccines,” says Søren Riis Paludan.

Constitutive immune mechanisms: mediators of host defence and immune regulation” has been published in Nature Reviews Immunology, and “Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans” has been published in Science Immunology. In 2018, the Novo Nordisk Foundation awarded a grant to Søren Riis Paludan for the project Novel Mechanisms of Early Defence Against Virus Infections. In 2015, the Foundation awarded a grant to Trine Hyrup Mogensen for the project Identification of Novel Primary Immunodeficiencies Conferring Susceptibility to Viral Infections.

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