The major capsid proteins of the procapsid (left) and mature capsid of the herpes simplex virus type 1 form hexons (lighter blue) and pentons (darker blue) connected by triplexes (green). As the virus matures, the holes in the procapsid close to stabilize the mature capsid.
The Cost of Conflict Discovery

Research at HMS

Viral Regulation

Once herpes simplex infects a person, the virus takes up permanent residence inside nerve cells, periodically reigniting infection and causing cold sores or genital lesions to recur.

How the virus maintains this sleep-wake mode has been unknown. Now, HMS scientists in the Department of Microbiology and Immunobiology and the Department of Biological Chemistry and Molecular Pharmacology have used a mouse model to identify the molecular regulator of this viral lifestyle: a host cell protein called CTCF, or cellular CCCTC-binding factor.

The researchers found that CTCF enables herpes simplex to establish latent infections in the body’s sensory neurons. Preventing CTCF from binding to the viral DNA weakens the virus’s ability to rekindle infection and its associated symptoms.

Previous research at HMS showed that the virus’s sleep-wake cycle is regulated by the interaction of two sets of genes. Latency-associated transcript genes, or LATgenes, turn off the transcription of viral RNA, which induces viral latency, while a gene called ICP0 produces a protein that activates genes that stimulate viral replication, leading to active infection. Past studies have shown that the LATgene and the ICP0ngene can act in opposition, inducing the virus to alternate between dormant and active states, but can also act in concert to promote latency or reactivation. The genes also occupy overlapping sites on the viral genome.

In a series of experiments, the recent study identified the sites on the virus’s DNA where the CTCF protein binds and showed that deleting the CTCF binding sites weakened the virus’s ability to awaken from its dormant state, strong evidence that the CTCF protein is a key regulator of the sleep-wake cycle in herpes simplex infections.

Lee JS, et al., mBio, January/February 2018

colorized x-ray of a section of a human lung
Colorized x-ray of a section of a human lung
 

Immune Response

When the body is fighting infection, the immune system kicks into high gear. It may not be acting alone, however. Research by HMS scientists indicates that the nervous system may also be involved, particularly in deadly lung infections.

In work carried out in mice, scientists in the HMS departments of Microbiology and Immunobiology and Cell Biology, the Evergrande Center for Immunologic Diseases at HMS, Brigham and Women’s Hospital, and the University of Calgary in Alberta, Canada, found that neurons carrying nerve signals to and from the lungs suppress immune response during infection with Staphylococcus aureus. This bacterium, which is growing increasingly impervious to antibiotics, has emerged as a top killer of hospitalized patients.

In the lungs, sensory neurons detect mechanical pressure, inflammation, temperature change, and the presence of chemical irritants, then send an alert to the brain—a notification that can come in the form of pain, airway constriction, or a cough that expels harmful agents or particles from the airways.

This study, however, revealed that when mouse lungs are invaded by staph bacteria, sensory neurons reduce the lungs’ ability to summon several types of disease-fighting cells in response to infection. A second set of experiments showed that disabling these neurons in mice promoted immune-cell recruitment, increased the lungs’ ability to clear bacteria, and boosted survival in staph-infected mice.

According to the researchers, the results suggest that different classes of sensory neurons may be involved in restraining or promoting immune response. These  findings could pave the way to nonantibiotic therapies for bacterial pneumonia that would target neuroimmune signaling in the lungs.

Baral P, et al., Nature Medicine, March 2018

Images: Bernard Heymann, Ph.D., NIAMS Laboratory of Structural Biology Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (top); baona, iStock