top of page

What we study


This image is from a review by former lab member Annelise Snyder depicts the interconnected cell death phenomena of apoptosis, pyroptosis, and necroptosis. We are seek to understand how these cell death programs are activated, the immunological signals they generate, and the consequences of these events for the organism. 

Programmed cell death—cellular suicide—is a fundamental process required for embryonic development, tissue homeostasis, tumor suppression and immunity. We now understand that cells can die in several different ways: in addition to the well-studied process of apoptosis, cells can activate other suicide programs, such as pyroptosis and necroptosis. Importantly, apoptotic cells are rapidly cleared from the body by phagocytes, and apoptosis is generally considered a non-inflammatory or immunosuppressive event. In contrast, cells dying by pyroptosis or necroptosis release both their contents and specific cytokine signals into surrounding tissues, activating immune cells and promoting both inflammation and adaptive immunity. Pathogen infection may trigger any of these cell death programs (depending on the bug), and various viruses and bacteria encode specific inhibitors of cell death effectors. Oncogenic transformation can also lead to inhibition of cell death signaling, and re-engagement of cell death within tumors is a major goal of cancer therapies. These observations lead to one of the central hypotheses on which the Oberst lab focuses: That how a cell dies—not simply whether it dies—is a key determinant of the innate and adaptive immune response that follows

Some of our questions:

What are the determinants of the immune response to necroptotic cells?

Necroptosis is a form of cellular suicide involving both lytic cell death and the production of inflammatory cytokines (Yatim et al., Science 2015). This is an odd finding, since inflammatory transcription is an active process, while cell death is a terminal event. We are investigating how these two immunogenic events are linked, in both engineered cellular models and viral infection.

How does cell death impact the immune response to cancer? 



This figure is taken from the review Comparing the effects of different cell death programs in tumor progression and immunotherapy, on which lab members Dr. Michelle Messmer and Annelise Snyder are co-first authors. 

The unregulated proliferation associated with tumor growth also causes abundant cell death within the tumor microenvironment. Furthermore, the goal of all tumor therapies is to cause the death of cancer cells. Notably though, in many cases this death is via apoptosis, which may actually dampen the immune responses that have the potential to control tumor growth. We've shown that inducing necroptosis within the tumor microenvironment beneficially re-programs tumor-associated phagocytes. We're now working to expand on this finding by creating reagents that can induce specific cell death and inflammatory programs within tumors. 

We are also investigating the converse phenomenon, by studying how apoptotic cells can promote tumor growth and metastasis by altering the function of tumor-associated myeloid cells. 

How does the "necroptotic" pathway protect the brain from viral infection?

Necroptotic cell death probably evolved to protect us from viral infection; consistent with this idea, several herpesviruses encode specific inhibitors of necroptosis. We have found that the "necroptotic" pathway is also essential for the control of brain infection by the flaviruses West Nile virus and Zika virus, but that this protection is independent of the induction of cell death. Rather, components of the necroptotic pathway drive beneficial cytokine production and metabolic reprogramming within the CNS. Current work focuses on understanding how neurons resist cell death upon activation of "necroptosis", how the necroptotic pathway drives inflammatory transcriptional responses, and how neurons that survive WNV infection differ from their uninfected counterparts. 

Activation of inflammation and cell death by "self" nucleic acids

ADAR1 is an enzyme that edits our own RNA to keep it from activating innate immune sensors in our own cells. Mutations in ADAR1 cause damaging autoinflammation, in both humans and in mouse models. We recently found that ZBP1, a nucleotide sensor that can activate both necroptosis and apoptosis, is responsible for the pathology in a mouse model of ADAR1 mutation. Unexpectedly, ZBP1 caused pathology even in ADAR1 mutant mice lacking inducers of apoptosis and necroptosis, implying that ZBP1 is doing this in a manner independent of the induction of programmed cell death. We're now working to understand how this process works, and whether there are other settings in which ZBP1 is activated by self-encoded nucleic acids. 

bottom of page