Scientists Reveal New Mechanism Adenovirus Uses to Sabotage Immune System

Adenovirus, a common human virus that usually affects the lungs and causes respiratory tract infections, is an old friend to virologists. They have long studied how this virus interacts with host cells to understand cellular processes and reveal key regulators of cellular functions. But even your closest friends may have hidden secrets, as scientists at The Children’s Hospital of Philadelphia revealed when they identified a surprising way that adenovirus works to subvert a host’s immune system and allow the infection to spread.

Daphne C. Avgousti, PhD, first author of the study that appeared in Nature and a postdoctoral fellow in the lab of Matthew Weitzman, PhD, a CHOP virologist, found a new mechanism by which a viral protein, called protein VII, sequesters an important danger signal, called HMGB1, that host cells use to alarm the immune system. When it is normally released as an “alarmin,” HMGB1 is like a scout that travels beyond the cell to recruit an inflammatory response during an infection or injury.

“What we’ve discovered is that this viral protein, which normally packages DNA, actually retains the danger signal,” said Dr. Weitzman, who also is an associate professor of Pathology, Pediatrics and Microbiology at the Perelman School of Medicine at the University of Pennsylvania. “It prevents these alarmins from getting out of the cell, which results in abrogation of the immune response. It was a completely unexpected role for this viral protein.”

Adenovirus uses protein VII to compact its genome within virus particles, similarly to how histone proteins condense a cell’s DNA into chromosomes, collectively called chromatin. Because protein VII resembles histones, the study group tested whether protein VII could manipulate cellular chromatin by mimicking histones and disrupting chromatin structure. They found that protein VII alters cellular chromatin in cell culture, in human lung tissue in the laboratory, and in mouse models.

Dr. Weitzman pointed out that a Nature paper, from back in 1977, was the first to describe how protein VII was histone-like. Another Nature paper published in 2002 described how HMBG1 is a potent mediator of inflammation when released. The latest paper ties these findings together and combines the fields of virology, immune signaling, and chromatin biology. Establishing these new connections within the context of a classic virus opens a new area of basic scientific research to determine the extent to which other viral proteins mimic histones.

“The implication is other viruses probably do something similar, but nobody had known to even look,” said Dr. Avgousti, who had the idea when she came to Dr. Weitzman’s lab three years ago to view protein VII through a new lens by applying the same research techniques and principles that are used to study histones.

The study team also plans to do more investigations to see how they could possibly exploit their findings about protein VII’s dual role in both viral and host DNA. For example, now that they understand how protein VII traps HMGB1 in the cell nucleus to suppress immune responses, they want to see if knowledge of this process could somehow benefit patients in other cases by leading to new ways to control unwanted inflammation in diseases such as cancer and severe infections such as sepsis.

Many experts contributed to this discovery of adenovirus’ novel immune evasion mechanism, including CHOP neonatology researcher G. Scott Worthen, MD, and biochemists Ben Black, PhD, and Benjamin Garcia, PhD, of Penn. The study team also relied on insights from their colleagues in virology, pulmonology, and proteomics.

“We had access to a large number of collaborators and were able to harness their knowledge for this project,” Dr. Weitzman said. “Penn-CHOP has a great community that is highly collaborative and really allows you to move into new areas.”