Pathogens exploit a wide array of strategies to facilitate infection in mammalian hosts. For obligate intracellular pathogens, there is a constant need to manipulate signaling pathways in the host cell. We are particularly interested in the pathways used by intracellular organisms to exit host cells. This research encompasses the underlying molecular mechanisms of these processes and the illumination of how these strategies facilitate unique interactions with the host immune system, most notably for immune evasion.
RESEARCH OVERVIEWOur research focus is on how the intracellular pathogens Chlamydia and malaria manipulate cellular function in order to exit host cells and cause infectious disease. Collectively, diseases caused by Chlamydia and malaria are the among the most devastating and widespread to plague mankind; effective intervention strategies are sorely lacking. And remarkably, these two disparate pathogens have coevolved similar mechanisms for escaping their respective host cells and disseminating within human hosts. Our ultimate goal is to leverage a thorough understanding of these pathogenic mechanisms as a new, unexplored therapeutic platform.
We are interested in:
- How do intracellular pathogens subvert host cell signaling pathways from within a vacuole?
- How do intracellular pathogens exit host cells?
- How do pathogens disseminate within a host?
- How do particular exit pathways enable immune evasion by pathogens?
THE GREAT ESCAPEExit of intracellular pathogens from host cells Intracellular pathogens (including Chlamydia and malaria) have evolved numerous strategies for promoting their exit from host cells, consistent with its essential role in pathogenesis. Yet despite its fundamental importance, microbial exit remains an unexplored research area.
Our pioneering discoveries forged the current understanding of Chlamydia exit from host cells. Chlamydiae possess two mechanisms for accomplishing cellular escape that are mutually exclusive: extrusion and lysis. Malarial parasites employ the same two egress strategies – extrusion at the liver stage of infection and lysis from red blood cells.
The primary goals of our research are to expand our knowledge of the molecular basis of the extrusion and lysis exit mechanisms, discover how pathogens trigger each pathway independently, determine the functional roles of extrusion and lysis in Chlamydia and malarial pathogenesis in vivo, and investigate how these mechanisms are used to facilitate immune evasion.
NOVEL STRATEGIES FOR IMMUNE EVASIONThe extrusion paradigm of Chlamydia and malaria pathogenesis Extrusion is a packaged release of Chlamydia or malaria wherein the pathogens are pinched off from the host cell into a membrane-encased compartment, a process that leaves the original host cell intact and often with a residual vacuole (for Chlamydia). Extrusions are novel structures that serve as ‘stealth shuttles’ for the pathogens that reside within them. Extrusions possess intrinsic characteristics that allow them to interact with the host immune system in unique ways, such as to enable immune evasion or dissemination within the host.
At a molecular level, extrusion is the result of many complex interactions between intracellular pathogen and the host cell. We have demonstrated that extrusion of Chlamydia is mediated by manipulation of actin polymerization, myosin-based contraction and Rho GTPase signaling by the bacteria from within their vacuole. Mechanisms of malaria extrusion are poorly defined, and in this regard Chlamydia are a model system for studying the molecular aspects of extrusion. We are using forward-based biochemical approaches and cellular screens to identify and characterize the key host, chlamydial and malarial proteins that mediate signature steps in the extrusion pathway.
Extrusion represents a novel strategy for immune evasion. Malarial extrusions are key for allowing malaria to avoid hepatic macrophages and progress to the blood stage of infection. Chlamydial extrusions enable unique interactions with immune cells, which may be important for in vivo pathogenesis. In general, the extrusion exit strategy likely confers unique abilities for immune evasion, cell-to-cell spread, dissemination to distal tissues, transmission and the capacity to elicit chronic infection. These are fundamental, unanswered themes in pathogenesis which we aim to resolve.
LYSIS FROM WITHINInside-out lysis of the host cell by host and pathogen proteases Malaria and Chlamydia are also capable of escaping host cells by lysis of their resident vacuole and host plasma membranes, followed by subsequent release of free microorganisms into the extracellular milieu. For both pathogens, lysis is a biologic process that is mediated by cysteine proteases and other signaling pathways.
We are using novel small-molecule tools and proteomic methods to identify the bacterial and host cysteine proteases, and their proteolytic substrates, that are essential for the lysis exit pathway.
Other Areas of ResearchWe have additional interests in the broader arenas of microbial pathogenesis. Research topics of particular interest to our group are:
- Cellular and molecular biology of host – intracellular pathogen interactions
- Immune evasion strategies for intracellular pathogens
- Infectious disease modeling
- Genetic screens and mutagenesis strategies
- Therapeutic development
Ph.D. UC Berkeley
B.S. UC Berkeley
PhD Program in Infectious Diseases & Immunity
Molecular & Cell Biology
2011 Amgen Scholar
(via University of Maryland)
2012 Amgen Scholar
(via CSU Fullerton)
Actin recruitment to the Chlamydia inclusion is spatiotemporally regulated by a mechanism that requires host and bacterial factors
Chin E & Kirker K & Zuck M & James G & Hybiske K.
PLoS ONE, 7(10):e46949 (2012)
PLoS | PDF
Activation of two extrusions by intracellular Chlamydia trachomatis. Each extrusion contains bacteria that are released from the host cell.
Cellular exit of Chlamydia trachomatis from host cells by the extrusion mechanism.
Chlamydia-induced lysis of vacuole and host cell. This exit mechanism is mediated by bacterial and host cysteine proteases.
The Hybiske Lab is affiliated with the Division of Allergy and Infectious Diseases, Department of Medicine, at the University of Washington, Seattle. We will soon be located at the new South Lake Union campus, near downtown Seattle.
Lab location: 750 Republican Way
Office phone: (510) 642-9453
Join The Lab
The Hybiske lab is always interested in hearing from prospective graduate students, postdocs and fellows. We are part of a growing nexus of interdepartmental research in microbial pathogenesis, infectious diseases and global health at the University of Washington. We also promote collaborative interactions with STD groups, Global Health, Microbiology and investigators at other institutions.