As Mpox Spreads, CHOP Researchers Explore How the Virus Evades and Infects

Mpox (formerly monkeypox), a member of the orthopoxvirus family, has a unique ability to evade the body's defense systems.

By ingenol [at] chop.edu (Lauren Ingeno)

Two years after an mpox outbreak rattled the United States, health officials in August declared the spread of a deadlier strain of the virus a public health emergency. The new virus strain has infected patients in multiple African nations, and experts are warning that the disease could spill across international borders.

Mpox, camelpox, smallpox — all members of the orthopoxvirus family — are particularly virulent, meaning they have a unique ability to evade the body's defense systems.

Laurence "Ike" Eisenlohr, VMD, PhD

One evasion tactic that Laurence "Ike" Eisenlohr, VMD, PhD, and colleagues at Children's Hospital of Philadelphia Research Institute are investigating is the role of the B22 family of proteins, which are made by nearly all orthopoxviruses. Understanding exactly how these proteins interfere with the body's immune responses could provide key insights into orthopoxvirus virulence and lead to the development of new antivirals to fight these deadly diseases.

"Pox viruses aren't stealthy — they're gigantic, but they're destructive," said Dr. Eisenlohr, a professor of Pathology and Laboratory Medicine and co-leader of the Immunology and Infectious Disease Research Initiative at CHOP. "They have a whole armament of evasion-and subversion factors that give them the foothold they need to mount an infection."

With a grant from the National Institute of Allergy and Infectious Disease, the Eisenlohr Lab is focusing on the C15 protein, a member of the B22 family that is expressed by the ectromelia orthopoxvirus, the agent of mousepox and a considerable virulence factor.

Earlier studies from Dr. Eisenlohr and a team of researchers found that by knocking out the C15 protein in animal models, all animals were able to survive what is usually a lethal infection.

Their research has shown that C15 is able to inhibit the activation of T cells, components of the adaptive immune system. C15 also interferes with the ability of natural killer (NK) cells, components of the innate immune system, to destroy the virus, Dr. Eisenlohr and colleagues reported in a 2022 study published in iScience.

Now, Dr. Eisenlohr wants to find out the mechanisms by which the C15 protein and other members of the B22 family interfere with the immune system's ability to fight orthopoxviruses.

"This single protein takes on a big chunk of the host response all by itself," Dr. Eisenlohr said. "We're interested in figuring out how it does that, and we also want to know: What is the evolutionary advantage of packing all of these anti-host activities into a single protein?"

Enlisting the help of Nikolaos Sgourakis, PhD, an associate professor in CHOP's Center for Computational and Genomic Medicine, and Stephen Carro, a graduate student at the University of Pennsylvania, the Eisenlohr Lab will identify and map the functional activities of C15 and other B22 proteins to figure out how different parts of the proteins affect the immune system.

The project's wider implications include gaining deeper insights into how many other viruses operate, which aligns with one of Dr. Eisenlohr's "guiding philosophies."

"If you want to understand why the mammalian immune system is built the way it is, look to the pathogens it evolved to deal with," Dr. Eisenlohr said. "And if you want to understand why certain mammalian pathogens are built the way they are, look to the immune system they have to contend with."