Harvard Medical School Study Reveals How Cells Respond to Viral Infections

A new Harvard Medical School study uncovered a mechanism that cells use to rapidly respond to certain viral infections, a finding that researchers say could eventually improve vaccines and gene therapies.

The study revealed a key part of the interaction between viruses and hosts, showing that cells respond to enveloped viruses by releasing DNA into the cytoplasm, which is then sensed by an enzyme that triggers an immune response.

Enveloped viruses are a type of virus that has an outer lipid membrane, which often cloaks them from typical immune responses and allows them to infect host cells efficiently. But by understanding how cells respond to enveloped viruses could allow researchers to develop better therapies that make use of viruses to deliver drugs.

The paper was published on Aug. 18 in the Proceedings of the National Academy of Sciences as a joint project between HMS microbiology and molecular genetics professor David M. Knipe’s lab and a lab at Columbia University.

“Cells have a way of detecting virus infection very quickly after the virus basically just touches the cells and enters into them,” Knipe said.

“We’re finding more and more ways in which the cells are able to sense the virus, and so it was just surprising that it’s seen within an hour,” he added.

Researchers have known that a protein called cGAS senses DNA in the cytoplasm, but had not understood how or when cGAS could trigger an immune response. The protein accumulates in the cell’s nucleus when damage or blebbing — a bulging protrusion — occurs along the nuclear membrane.

Knipe said his lab originally thought cGAS was sensing viral DNA when it entered the cytoplasm, but the study showed that the viruses were actually causing small amounts of the cell’s DNA to leak out of the nucleus.

“As it turned out, it wasn’t viral DNA,” Knipe said. “It was cell DNA that was being kicked out to sort of upset things in the cell to turn on a signaling pathway.”

And the immune response was rapid.

Researchers observed DNA particles in the cytoplasm as early as one hour after infection. The group infected human fibroblasts with Herpes Simplex Virus, and found DNA had leaked into the cytoplasm in roughly 70 percent of infected cells.

Researchers observed cGAS clustered around the expelled DNA in the cytoplasm, activating a signaling pathway that spurs the production of interferon — a type of signaling protein heavily implicated in antiviral immune responses.

The team observed the same response when cells were infected with four different enveloped viruses that enter human fibroblasts through membrane fusion. But two non-enveloped viruses that entered cells through endocytosis did not trigger the same response.

The group focused on HSV as one of the most common enveloped viruses that affect humans. HSV is also used as a delivery vector for gene therapies because it is able to establish long-term, non-integrating latent infections — allowing the pathogen to remain in the host for an extended period of time without causing symptoms.

“Our work illustrates that nuclear DNA blebbing response is pivotal in the activation of interferon production in HSV infection,” wrote Nicolás Romero, the study’s first author.

But HSV-mediated therapies are often met with a strong immune system response, which can reduce how well the therapy works. But understanding what causes the immune response to these viruses can allow researchers to better design therapeutics to work around the mechanism.

They believe stopping the DNA from leaking out of the nucleus will block the signals that follow, which could make HSV-based gene therapies more effective.

“It’s something to be aware of when we’re using viruses as vaccines or as vectors,” Knipe said.

If researchers can identify the host-cell functions involved in releasing DNA from the nucleus, Knipe said they may eventually be able to reduce the immune response triggered by some gene therapy vectors.

The team now hopes to better understand the extent of the HSV-induced nuclear blebbing response by working to replicate the response with models that closely mirror conditions in the human body — like organoids and animal models.

Knipe said “it’s hard to know” when the findings could translate into clinical applications, but that the study is promising for the development of future treatments.

“It tells us that there are ways that viruses cause effects on cells that we didn’t know about, and that things like viral gene therapy vectors might induce the same response and induce the same alarm inside the cell — which you don’t want with a gene therapy vector,” he said.

“If we could figure out how to turn it off, it might help.” he added.