THE PROBLEM
To fight pathogen infections, cells of the immune system must respond to products of invading microorganisms. Consequences of immune cell encounter with pathogen products include cell division and activation of “effector functions,” which are the activities of immune cells that will combat the pathogen infection. Understanding how signals from pathogen products trigger effector functions is fundamental to understanding how the immune system works. This type of knowledge is essential for the design of new drugs to suppress or stimulate the immune system, and for design of better vaccines. Our work is relevant for diverse human pathologies including infectious diseases, autoimmune diseases, immunodeficiency diseases and many types of cancer. This research area is broadly important for the health and welfare of DoD service members and civilians.
OUR APPROACH
Research in the Schaefer lab is focused on defining mechanisms by which the immune system is activated to combat infections and how immune cell signaling and activation mechanisms are perturbed in cancer. We investigate this problem in several ways, including defining molecular signaling mechanisms in purified immune cells, particularly T cells and macrophages. We also study immune responses at the whole organism level to better understand relationships between pathogen infection and initiation of immune responses. Our experimental approach combines cutting-edge imaging technologies with biochemistry, molecular biology, cell biology, and animal models.
"Cells of the immune system play a major role in the proper function of essentially every tissue and organ in the body. Understanding the cellular and molecular regulation of immune responses is key to generating medical interventions that specifically target pathological immune responses, while leaving required mechanisms of host protection intact."
RESULTS
ELUCIDATING THE MOLECULAR MECHANISMS AND SUBCELLULAR ORGANIZATION OF T CELL RECEPTOR (TCR)-REGULATED NF-ΚB SIGNALING INTERMEDIATES.
Our published studies have documented that TCR stimulation triggers the formation of a cytoplasmic signaling structure that we have named the “POLKADOTS signalosome.” We have shown that both signal transmission to NF-κB and limitation of this signal by a protein degradation process, called selective autophagy, occur at this site. Currently, we are using “super-resolution” microscopy and other cutting-edge techniques to define nanoscale features of this complex and to relate those features mechanistically to regulation of signaling. We are also beginning to investigate in more detail the biochemical pathway by which the TCR induces the autophagy of specific signaling proteins, such as Bcl10. Dr. Schaefer is currently overall PI of two multi-PI NIH grants, which fund the work on this project. Collaborating PIs on these grants are Dr. Wolgang Losert at the University of Maryland, Dr. You-Wen He at Duke University, and Dr. Thomas Conrads at the Women's Health Integrated Research Center. Additionally, Dr. Maria Traver, a scientist in Dr. Schaefer's lab, received the Cancer Research Institute Irvington Fellowship, a prestigious postdoctoral fellowship, to fund her work on this project.
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Ongoing Projects Here and Here
PRE-CLINICAL MODELS AND NOVEL THERAPEUTICS FOR INFECTIONS BY NEUROTROPIC VIRUSES.
In collaboration with Dr. Christopher Broder, we are investigating pathogenesis of neurotropic viruses at the cellular and organism level. We have established an in vivo infection model with Australian Bat Lyssavirus (ABLV), a rabies-like virus which can infect humans and livestock. We are using a luciferase-expressing form of this virus to track infection progression over time in individual animals and to determine the response of animals to antiviral therapy. A major goal is to understand how the immune response combats infections in the central nervous system and why such responses ultimately fail in the case of rabies and related viruses. A translational goal of this work is to develop novel, immune-based therapies for neurotropic virus infections, including ABLV and rabies. This project was originally funded by a USU Program Project grant to Drs. Schaefer and Broder and our collaborators in the USU Department of Radiology.
Oral presentation of this project at the 2017 Military Health System Research Symposium (MHSRS) earned graduate student Kate Zeigler a Young Investigator Award.
Additionally, through a sub-project of a NIH U19 grant awarded to Dr. Broder, we are also now developing an in vivo model for the study of the host response to Cedar virus, a non-pathogenic henipavirus. Similar to our work with ABLV, this project is focused on developing novel therapeutics for pathogenic henipaviruses (Hendra virus and Nipah virus), which cause lethal disease in humans.
DEFINING NOVEL MITOCHONDRIAL SIGNALING PATHWAYS, AND THEIR RELEVANCE IN NORMAL MACROPHAGE FUNCTION AND CANCER.
We have identified a novel mitochondrial protein, and we are attempting to define how this protein regulates the function of macrophages during immune responses. We are also investigating its possible role in a type of cancer called Acute Myeloid Leukemia (AML). This work is a collaborative effort with Dr. Igor Brodsky at the University of Pennsylvania and Dr. Yang (Dennis) Du in the USU Department of Pediatrics.