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Disease and treatment

Where both herpes and COVID-19 attack the body

Researchers have identified the part of the immune system that both the herpes simplex virus and the COVID-19 virus need to neutralize to infect the body. In the long term, this discovery may help to prepare us for the pandemics of the future.

To infect the brain, the herpes simplex virus (HSV) must first neutralize a key part of the body’s immune system. Otherwise, the virus will be eliminated immediately.

Researchers from Aarhus University and other universities recently identified the part of the immune system that HSV attacks.

The virus that causes COVID-19 (SARS-CoV-2) and probably many other viruses attack the same part of the immune system, so if researchers can develop drugs that remove this primary weapon from the arsenal that viruses use, we may be better equipped to fight potentially all viruses and pandemics in the future.

“Viruses, including influenza, HSV and SARS-CoV-2, attack the body’s cells based on some general principles. Viruses need to inhibit the immune system to avoid being eliminated, and we have identified the location in the immune system that HSV attacks. Because this is also the location that SARS-CoV-2 attacks, this may be a very general strategy that may be interesting to examine in relation to developing drugs,” explains a researcher behind the new study, Søren Riis Paludan, Professor, Department of Biomedicine, Aarhus University.

The research has been published in the Journal of Experimental Medicine.

Neutralizes part of the immune system

The immune system comprises two components.

• Innate immunity responds immediately to external threats from viruses and other threats.

• Adaptive (acquired) immunity needs to identify the threat first.

Any virus must first bypass the innate immune system to have any chance of infecting a person.

In previous studies, researchers confirmed that the part of the innate immune system that deals with virus infections is called cGAS-STING (cyclic GMP-AMP synthase–stimulator of interferon genes), which could loosely be described as a cell police officer.

cGAS-STING works by detecting the presence of cytosolic DNA in our cells. The DNA of the cells is usually isolated in the cell nucleus and, if there is DNA outside the cell nucleus, this may be a sign that a virus has penetrated the cell.

cGAS-STING localizes the cytosolic DNA and initiates an immune response, which is the function the virus must neutralize.

“A virus cannot establish an infection if it does not block the innate immune system rapidly enough, and in this study we investigated exactly how HSV does this,” says Søren Riis Paludan.

Together with colleagues, Søren Riis Paludan had previously established this role of cGAS-STING in connection with an HSV infection, but the immune system’s police officer has the same function in all other viral infections.

Virus deactivates the cellular immune response

The researchers investigated HSV in cell cultures and in mouse brains.

HSV is best known as the virus that causes cold sores, but in rare cases it can also infect the brain.

The researchers hypothesized that, since cGAS-STING is so important in relation to the opportunities a virus has for infecting a cell, viruses will also have developed weapons targeting cGAS-STING – and the researchers verified this in the study.

First, the researchers created many HSV mutants with one or more genes knocked out to determine which genes play a role in the virus’ ability to bypass cGAS-STING.

They found that a mutant lacking the deubiquitinase activity of the VP1-2 protein activated the cell’s immune system to a much greater extent, which indicated that the mutant’s primary weapon had been destroyed.

“Deubiquitination works by removing ubiquitins from proteins, and in the case of cGAS-STING, the ubiquitins help to activate the immune system’s police officers,” explains Søren Riis Paludan.

Mechanism also applies to people’s brain cells

Further experiments with mice showed that the mutant HSV were also unable to infect mice.

A final experiment with mice that had the cGAS-STING removed showed that, once that part of the immune system was neutralized, even the viruses that had had their deubiquitinase destroyed could infect the mice.

Finally, the researchers carried out an experiment with cultured immune cells from human brains, and here too they found that infection with deubiquitinase-free HSV resulted in a very strong immune response.

“The primary result is that we have found the part of the immune system that HSV needs to neutralize to infect the brain – and we have also figured out how this takes place,” says Søren Riis Paludan.

Can be a universal therapeutic target

This new discovery has several perspectives.

Søren Riis Paludan indicates that both HSV and SARS-CoV-2 block cGAS-STING when they infect the body.

This shows that the attack mechanism may apply to a wide variety of viruses and is therefore a good place to start in creating medicine that can protect against more than just HSV or influenza viruses.

Further, the interaction between viruses and cGAS-STING has never been a therapeutic target.

Any medicine may potentially have two targets, but Søren Riis Paludan prefers one.

“The easiest approach would be to boost cGAS-STING, but this is too dangerous since it can activate inflammation throughout the body. The other option is to make medicine that targets the deubiquitinase that the virus uses to neutralize cGAS-STING. Fortunately, this is an enzyme, and we generally like to develop medicine against enzymes. Quite simply, one idea is to discover viral targets that are universally used to block the immune system. We may be able to benefit from these in combating future pandemics,” says Søren Riis Paludan.

HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection” has been published in the Journal of Experimental Medicine. In 2018, the Novo Nordisk Foundation awarded a grant to Søren Riis Paludan for the project Novel Mechanisms of Early Defense against Virus Infections.

Søren Riis Paludan
Professor
The early interactions between a pathogen (e.g. virus) and the immune system are of central importance for the eventual outcome – pathology and disease versus clearance and reestablishment of homeostasis. In my laboratory we are interested in understanding the early events that occur during immunological challenge, and to characterize the impact on the control of infections. The innate immune system utilizes pattern recognition receptors to sense infections and to induce antimicrobial responses. In the case of virus infections, the type I interferons are particularly well-described to have strong antiviral activity. However, type I interferon can also cause significant pathology, and there is increasing appreciation of antiviral activities, which are independent of type I interferon. We seek to understand the mechanisms involved in both interferon-dependent and –independent antiviral immunity, and the interactions between these activities. Since many immunological phenomena occurring during viral infections are also involved in the pathology of non-communicable diseases, e.g. autoinflammatory diseases, we are also interested in uncovering the immunological basis for a panel of human pathologies.