Ruslan M Medzhitov, PhD

David W. Wallace Professor of Immunobiology; Investigator, Howard Hughes Medical Institute

Research Interests

Biochemistry; Immunobiology; Immunology; Innate Immunity; Toll Receptors

Research Summary

Research in this laboratory focuses on many aspects of innate immunity and includes the following areas:

• Molecular mechanisms of innate immune recognition: Identification and analysis of receptors involved in innate immune recognition (Pattern Recognition Receptors) and signaling pathways activated by these receptors. Of particular interest is the recently identifiedfamily of Toll-like receptors, which plays an essential role in innate immune recognition in both mammals and insects.

• Control of adaptive immune responses by innate immune recognition. Signals induced upon innate immune recognition (co-stimulatory molecules, cytokines and chemokines) are necessary both for the initiation of adaptive immune responses and the control of effector functions. We are interested in molecular mechanisms that translate the signals recognized by Pattern Recognition Receptors into signals that control the activation of naive lymphocytes and their differentiation into effector cells.

•  Mechanisms of autoimmunity and allergy. Inflammation is a normal component of the host response to infection. However, excessive inflammation, or inflammation in the absence of infection, may lead to a variety of pathological states, including autoimmunity and allergy. We are studying the cellular and molecular basis of inflammatory disorders that are caused by the dysfunctions of the innate immune system.

Extensive Research Description

Innate immune recognition

The innate immune system relies on several distinct strategies of recognition, including pattern recognition and missing self recognition. We are interested in defining cellular and molecular mechanisms of innate immune sensing and signaling. There are several different classes of receptors involved in innate immune recognition. We are interested in the general design of the recognition and signaling modules of the innate immune system, their functional relationships, their roles in host defense and in control of adaptive immunity, and their contributions to immunopathology.

Host-Pathogen interactions

The disease state caused by microbial infection is a result of either microbial virulence or immunopathology (the host response to infection), or in some cases both. Thus immune sensing and responsiveness to infection are adjusted during evolution to achieve an optimal balance to maximize protection from infection, and to minimize the pathology caused by an overzealous immune response. This balance can presumably vary depending on infection. We are interested in studying the mechanisms (both hard-wired and adaptive) that allow for an optimal trade-off between these two conflicting goals. We are interested in understanding the role of virulence in host-pathogen interactions and the effect of microbial virulence on innate and adaptive immunity. We are also studying the affect of infection on the immune system and how the immune system handles co-infections.

Inflammation

Inflammation is a fundamental physiological process that underlies a multitude of normal and pathological conditions. We are studying both the basic biology of inflammation and the regulatory mechanisms that control initiation, quality and intensity of inflammatory responses. In particular, we are studying the links between inflammation and metabolism, inflammation and aging, and inflammation and cancer.

Control of adaptive immunity

Innate immune recognition plays a critical role in the control of adaptive immune responses. Multiple mechanisms underlie the connections between innate and adaptive immune systems, and most of them are poorly understood. We are studying basic mechanisms that couple innate immune recognition with activation and differentiation of adaptive immune responses. We are also studying the links between innate immune system and peripheral tolerance.

Cell biology of signal transduction

Most of what we know about cell signaling is based on biochemical and genetic studies. While these approaches provide essential information about the composition of signaling pathways, much less progress has been made in understanding the functional organization of signaling pathways, especially in the context of basic cell biological processes, such as protein sorting and vesicular trafficking. We are interested in basic principles that govern the cell biology of signaling transduction pathways.

Control of gene expression

Stimulation of macrophages through TLRs leads to changes in the expression (induction and suppression) of hundreds of genes. These changes are effected through a diversity of mechanisms. Gene regulation occurs at multiple levels (activation of trasnscription factors, chromatin remodeling and histone modifications) and has both signal-specific and gene-specific components. Different subsets of TLR-inducible genes are subject to differential regulatory influences, which are dependent on the function of the products they encode. We are interested in the basic principles of inducible gene expression, which are currently poorly characterized.

Cancer biology

We are studying the mechanisms whereby cancer cells can sense their 'oncogenic state' and communicate it to other cells of the host. We are also studying the role of inflammation and tissue repair in tumor progression.

Selected Publications