Munck-Pfefferkorn and Beyond

Since 2016, the Munck-Pfefferkorn Grant Awards have supported faculty investigators launching new and innovative yearlong projects. Named in honor of Geisel School of Medicine late emeritus professors Elmer Pfefferkorn, PhD, and Allan Munck, PhD—scientists and mentors who inspired generations of researchers and physicians—the Elmer R. Pfefferkorn & Allan U. Munck Education and Research Fund Novel and Interactive Grant Initiative provides seed funding for research projects that have high potential to lead future sponsored projects or programs that encourage collaborations among and across Geisel faculty. 

As a result of this important seed funding, a number of Geisel researchers have been able to transition novel ideas into federally funded, long term projects. 

Virologists and modelers of disease 

David Leib, PhD. Photo by Rob Strong

With a shared interest in neonatal herpes, David Leib, PhD, and Margaret (Margie) Ackerman, PhD, began collaborating in 2016. Herpes simplex virus type-1 (HSV) is a common infection of the nervous system that is prevalent in adults, and generally not a problem, but causes devastating disease in newborn babies.  

The scientific paring of Leib, a professor and chair of microbiology and immunology, and Ackerman, a professor of engineering at Thayer, is a perfect match.  

As Leib says, “Our collaboration evolved when my lab discovered that certain types of antibodies are very protective against this disease. Margie is an engineer of antibodies. We are the virologists and animal modelers of disease, so we developed a mouse model to test the therapeutics that she is producing.” 

Margaret (Margie) Ackerman, PhD. Photo by John Sherman

His research has shown that maternal immunizations are effective in preventing neonatal herpes infections. As work in testing new vaccines and antibody approaches against neonatal HSV disease and probing the specificity and mechanisms of protection of these antibodies continues, their work caught the attention of one of Ackerman’s collaborators, a company that produces antibodies. They provided the duo with an antibody sample to test in the lab—it performed very well in the mouse model.  

Leib and Ackerman are now in the process of designing a phase 1 clinical trial of that antibody with company collaborators and clinicians. 

“This is very exciting and it’s all because of the Munck-Pfefferkorn grant,” Leib says. “Two years of Munck-Pfefferkorn funding provided much-needed support, leading to funding of two National Institutes of Health grants, and then to a clinical trial.” 

What’s interesting about research, Leib notes, is that you never know where you are going to end up and may find something surprising along the way.  “You start down one path of experimentation then discover something more interesting than when you started, which is the case here. 

“What we discovered through the federally funded part of our research, is that this work has implications beyond neonatal herpes,” he says. “Mice infected with HSV when very young, and not protected by either the antibody or vaccine, go on to develop neurodegeneration—we have clear evidence of that. If they are protected with either the antibodies we’ve developed or the vaccines we’ve been testing, they no longer develop neurodegeneration or behavioral problems.” 

Considering the predominance of neurodegeneration, and the cost of memory care worldwide, Leib says, “If I were to think of an area of future focus for us, this would be it.” 

Keeping fungal disease at bay 

Josh Obar, PhD. Photo by Kurt Wehde

Aspergillus fumigatus—the greenish grey mold that forms on bread or other foods is key to the decomposition and carbon cycle in the environment. The problem with it, according to Josh Obar, PhD, is that it’s become a modern medicine problem. 

Spores float through the air to disperse in nature. “Every day we are breathing in spores of the Aspergillus but normal healthy animals and humans clear them away without any detrimental effects,” the associate professor of microbiology and immunology explains. “For people who are extremely immunosuppressed it becomes problematic because they are unable to inhibit the spores’ growth causing invasive lung disease.” 

Patients undergoing either bone marrow transplants or solid organ transplants are particularly susceptible to these mold aspergillus infections that are very difficult to treat.  

The mortality rate among patients who develop these infections is from 30 – 50 percent, a far lower rate than a few decades ago because of earlier and prophylactic use of antifungal drugs. But patients with these infections have prolonged ICU level care at a high cost.  

Obar says our understanding of how the immune system keeps fungal infections at bay in immune competent individuals remains ill-defined. “Currently, there is a critical gap in understanding the early interactions between fungal conidia and tissue-resident phagocytes that are necessary for fungal clearance and host resistance.”  

His research focuses on the immune pathways that protect healthy humans and how he can use that information to provide better outcomes for patients who are at risk for these infections. 

“When immunosuppressed patients breathe in those spores and they start to grow, how does that compare to how healthy immune systems detect and clear the spore,” he says. “If we can learn which of these pathways are important, we can look at patients undergoing transplants to see whether or not they have the protein variants we know are key in preventing these fungal infections. 

“By understanding that, we can know what’s not working in immune compromised patients to either boost their response to further prevent those infections or give them a window of time to get through that stage of immunosuppression and fight off the infection.” 

Without a doubt, the Munck-Pfefferkorn funding enabled Obar and his team to collaborate with other researchers to gather the preliminary data needed to reach a fundable level. His project is now funded by the National Institutes of Health through 2023. 

Tapping the power of T cell memory 

Edward Usherwood, PhD. Photo by Kurt Wehde

Edward Usherwood, PhD, has a long-standing interest in T cell immune surveillance in both persistent viruses and tumors. His long-term goal is to develop next-generation immunotherapies that can harness the power of T cell memory to effect long-term protection against cancer and prevent disease associated with persistent infections. 

Much of the population is infected by multiple persistent viruses. In many cases infection is clinically silent, and the infected individual suffers no adverse effects. Evidence suggests persistent infection may be beneficial in aiding the immune response to repel other infections—a dynamic equilibrium between the virus and the immune response.  

“One of our missions is to understand this interplay, and how the T cell response persists in keeping infection under control,” says Usherwood, a professor of microbiology and immunology. 

“We looked at memory T cells and did genomic studies to identify genes differentially expressed in infection groups that may be promoting the ability of T cells to persist in the host, then drew up a list of genes we wanted to pursue further,” he explains. “One of the wonderful things about the Munck-Pfefferkorn grant is that it allowed us to investigate each of those genes individually to see what they do in a broad sense. It was great to have that kind of freedom to explore.” 

A few surprises emerged—the gene Zbtb20, a transcription factor (key proteins that decode the information in our genome to express a precise and unique set of proteins and RNA molecules in each cell type in our body) proved interesting throughout the course of the studies.  

“We decided to pursue it further and found a connection between Zbtb20 and T cell metabolism that was interesting,” Usherwood says. “Previous research indicates it is important in controlling metabolic pathways in the liver and pancreas, but nothing was known about it in T cells. When we deleted Zbtb20, we detected increased mitochondrial metabolism and increased glycolytic metabolic metabolism; these two types of metabolism are quite important in differentiation of the T cells—mitochondrial is crucial for T cells to become memory cells, and metabolic to elaborate infection functions that enable T cells to kill target cells—an infected or a tumor cell.” Importantly, T cells lacking Zbtb20 were better able to control tumors in mice, compared to mice with intact Zbtb20. 

He says it is unusual to find a transcription factor that regulates both of those pathways together. Most tend to turn one off and the other one on or the inverse. By exploring one of the mechanisms by which Zbtb20 controls the T cell metabolism and certain target genes that it affects, Usherwood hopes to understand which precise metabolic steps are being affected and how the switching works.  

This project “has enabled us to explore an initial finding with Zbtb20 and take it to both in a translational direction, and to understand the basic science of metabolic wiring of the T cells by taking a deeper look at T cell metabolism,” he says. 

“Science rarely moves in a linear direction and in this case, it led to a lot of interesting findings. I want to say how very appreciative we are to have the Munck-Pfefferkorn grant. It is a unique mechanism that allows Geisel researchers to pursue exploratory work that may not get funded on a federal level.”