Understanding the Role of Type I Interferon in Cell Death

Poltorak & Liu Spotlight

Sasha Poltorak & Caitlin Liu and an illustration of the pathway they are studying

Back to Previous Spotlights

In its constant battle with infectious microorganisms, the mammalian innate immune system developed two alternative responses that help to efficiently contain the infection at the systemic level. First, pathogens and their components are recognized by numerous receptors that are located inside and on the surface of a cell. Activated by these receptors, macrophages, monocytes and other myeloid cells release inflammatory mediators (cytokines) responsible for recruitment of other cells of the body – such as neutrophils - to the sites of inflammation thus eradicating the infectious microorganisms. An alternative response to infection by macrophages is undergoing cell death, for which several programs -such as apoptosis, necroptosis, and pyroptosis exist.

In spite of cell death, immune cells continue to release pro-inflammatory cytokines such as members of the Interleukin 1 family. Regulation of the balance between cell death and survival is not well understood. At what moment of infection the cells decide to die? What presets conditions for cell death? Therefore, understanding the balance between cells death and inflammatory responses is the fundamental question of immunology. In the particular case of pyroptosis that most frequently occurs upon infection with intracellular pathogens, macrophages recognize foreign danger signals within themselves, release pro-inflammatory cytokines, swell, and die.

When Caitlin Liu, an Immunology PhD student, joined Sasha Poltorak’s lab, she started off by investigating the role of type I Interferon (IFN-I) signaling in macrophage responses to Legionella pneumophila. To do that, she initiated a collaboration with Ralph Isberg, an expert in the field of Legionella pathogenesis. One of her early observations was that infection with cytosol-permeable bacteria was not accompanied by IFN-I signaling that was – based on the literature data – crucial for the release of bacteria into the cytosol and caspase-11-mediated pyroptosis. Instead, Caitlin identified host-intrinsic, constitutive, IFN-I signaling - rather than induced IFN-I - in facilitating disruption of cytosolic bacteria, thus releasing bacterial components to be sensed by host cytosolic surveillance mechanisms. In collaboration with others in the lab, she further identified cGAS/STING pathway to sustain levels of constitutive IFN-I signaling.

Caitlin’s findings, reviewed in the journal Cell Host and Microbe, show that factors mediating the release of bacterial components into the cytosol is controlled by pre-set host intrinsic IFN-I signaling prior to infection. Her utilization of IFNb1-deficient macrophages was instrumental to examining the role of constitutive vs. induced IFN-I. Indeed, several labs reported the role of IFN-I signaling in response to cytosolic bacteria relying primarily on IFN receptor deficient mice, which do not allow for evaluation of the effect of exogenously added IFN-I. A similar approach was successfully applied to studies on the role of constitutive IFN-I signaling in necroptosis, an alternative to apoptotic cell death that is currently investigated in the lab by another graduate student Joseph Sarhan. These studies provide strong rationale for further investigation of constitutive cytokine signaling in infection and disease. Going forward, the lab aims to generate a universal model of how sustained constitutive levels of IFN-I and other cytokines (such as TNF) made in rested cells help to activate programs of cell death and inflammatory responses, thereby facilitating biological function of macrophages in innate immunity.

Apply to the Sackler School

apply

The priority application deadlines are as follows:

December 1: Basic Science Division PhD Programs

February 15: Building Diversity in Biomedical Sciences

March 31: Post-Baccalaureate Research Program

May 1: Clinical & Translational Science, MS in Pharmacology & Drug Development

June 15: Online Certificate in Fundamentals of Clinical Care Research