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Tsan Xiao, Ph.D.
Building 4, Room 228B
4 Memorial Drive
Bethesda, MD 20892-0430
Phone: 301-402-9782
Fax: 301-480-1291
xiaot@niaid.nih.gov

Laboratory of Immunology

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Tsan "Sam" Xiao, Ph.D.

Photo of Dr. Tsan Sam Xiao

Chief, Structural Immunobiology Unit, LI

Major Areas of Research

  • Structural studies of innate immune receptors for nucleic acids
  • Mechanisms of inflammasome activation by ligands from host and microbial sources
  • Innate signaling mechanisms mediated by adapter molecules
 

Program Description

The research program at the Structural Immunobiology Unit (SIBU) is composed of two integrated themes: the mechanisms of nucleic acid recognition by innate immune receptors and the study of large macromolecular signaling platforms known as the “inflammasomes.” We use X-ray crystallography as the primary method to dissect the molecular details of innate receptors and signaling adapters, integrated with chemical tools that target these signaling pathways for potential therapeutic applications.

Nucleic acids are among the most potent stimulants for cells in the innate immune system that subsequently induce robust adaptive immunity. However, immune responses to nucleic acids, the universal genetic material, pose a unique challenge. By definition, pattern-recognition receptors (PRRs) from the host (self) typically recognize structural and chemical signatures that are specific for microorganisms (non-self). In contrast, innate DNA recognition is largely independent of sequences or modifications, and DNA from host, microbial, and synthetic sources are all known to induce inflammatory responses. Certain safeguards are therefore built into the nucleic acid sensing pathways, such as the compartmentalization of receptors in the cytosol or endolysosomes and the widespread presence of nucleases to prevent receptor activation under normal conditions.

However, these safeguards can be overwhelmed during infection or excessive tissue damage. For example, infections by intracellular pathogens such as Francisella tularensis, Listeria monocytogenes, vaccinia virus, and herpes simplex virus type 1 result in the presence of significant amount of cytosolic DNA. In autoimmune diseases such as systemic lupus erythematosus (SLE) and psoriasis, DNA is a major auto-antigen. We are working on a number of cytosolic and cell surface receptors that mediate immune responses to nucleic acids, with the goal of understanding the mechanisms of nucleic acid recognition and harnessing such knowledge for the prevention and treatment of infectious diseases and autoimmune disorders.

A subset of the NLR and PYHIN family of receptors form large macromolecular signaling scaffolds known as the “inflammasomes,” a concept introduced by the late Jürg Tschopp in 2002. Inflammasomes are large signaling platforms composed of the receptor (such as NLRP1, NLRP3, NLRP6, NLRP7, NLRC4/NAIP, AIM2, and IFI16), the adapter protein ASC, and the effector enzyme procaspase-1. Activation of the inflammasomes leads, at a minimum, to maturation of proinflammatory cytokines IL-1β and IL-18 and to “pyroptosis.” Blocking IL-1 activities using Food and Drug Administration-approved drugs Anakinra, Rilonacept, and Canakinumab has shown promise in the treatment of several inflammatory disorders, a testament to the physiological importance of the inflammasomes.

Because inflammasomes are implicated in a wide array of inflammatory processes in infectious diseases and autoimmunity, they are becoming one of the pillars of the innate immune system. A major unresolved issue in the field has been the lack of definitive evidence for direct receptor:ligand association for most inflammasomes: Seemingly unrelated stimuli are all capable of activating inflammasomes. Therefore, the true identities of the respective ligands and a unifying mechanism of inflammasome activation remain elusive. In contrast, double-stranded DNA (dsDNA) has been identified as the bona fide ligand for the AIM2 inflammasome. Our structural studies on the AIM2 inflammasome reveal the mechanisms of inflammasome activation through sequence-independent DNA recognition, the autoinhibition of the receptor via intramolecular domain-domain interactions, and the formation of the inflammasome through oligomerization at the multivalent DNA ligand. Building on our structural work, we are investigating mechanisms to modulate the function of the AIM2 and other inflammasomes for therapeutic applications.

Recognition of nucleir acids by the innate immune system.
Figure 1. Recognition of nucleic acids by the innate immune system. The innate immune system responds to the presence of nucleic acids on the cell surface, in the cytosol, and in the endolysosomal compartment. Such recognition events lead to the production of interferons, or the secretion of proinflammatory cytokines such as IL-1β and IL-18.

 

Activation mechanism of the AIM2 inflammasome
Figure 2. Activation mechanism of the AIM2 inflammasome. The AIM2 receptor resides in an autoinhibited state in the absence of DNA. Association of dsDNA with the AIM2 HIN domain leads to the release of the intramolecular inhibition and the assembly of the oligomeric AIM2 inflammasome through the multivalent DNA ligand.
 

Biography

Dr. Xiao received his Ph.D. in molecular biophysics from the University of Texas Southwestern Medical Center at Dallas, where he studied essential signal transducing molecules involved in Drosophila innate immunity and development. Following his postdoctoral research on integrins at the Harvard Medical School, he joined the Laboratory of Immunology in the spring of 2006.

Memberships

  • American Crystallographic Association
  • American Association of Immunologists
  • International Cytokine Society
  • American Chemical Society
  • Sigma Xi, the Scientific Research Society

Special Interest Groups

Immunology, Structural Biology, X-ray Diffraction

Research Group

Photo of Structural Immunobiology Unit Research Group Members
Photo of Structural Immunobiology Unit Research Group Members.
 

Members of the Structural Immunobiology Unit, April 2013

Watchalee Chuenchor, 301-402-7523
Jiansheng Jiang, 301-594-2097
Tengchuan Jin, 301-594-2114
Geoffrey Ravilious, 301-443-2125
Patrick T. Smith, 301-496-5070
Peter E. Hemenegildo, 301-594-2202

Selected Publications

Snyder GA, Cirl C, Jiang J, Chen K, Waldhuber A, Smith P, Römmler F, Snyder N, Fresquez T, Dürr S, Tjandra N, Miethke T, Xiao TS. Molecular mechanisms for the subversion of MyD88 signaling by TcpC from virulent uropathogenic Escherichia coli. Proc Natl Acad Sci U S A. 2013 Apr 8. Epub ahead of print.

Jin T, Perry A, Smith PT, Jiang J, Xiao TS. Structure of the AIM2 pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. J Biol Chem. 2013 Mar 25. Epub ahead of print.

Jin T, Curry J, Smith P, Jiang J, Xiao TS. Structure of the NLRP1 caspase recruitment domain suggests potential mechanisms for its association with procaspase-1. Proteins. 2013 Mar 18. Epub ahead of print.

Jin T, Perry A, Jiang J, Smith P, Curry JA, Unterholzner L, Jiang Z, Horvath G, Rathinam VA, Johnstone RW, Hornung V, Latz E, Bowie AG, Fitzgerald KA, Xiao TS. Structures of the HIN domain: DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity. 2012 Apr 20;36(4):561-71.

Xiao TS, Ting JP. NLRX1 has a tail to tell. Immunity. 2012 Mar 23;36(3):311-2.

Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirois CM, Jin T, Latz E, Xiao TS, Fitzgerald KA, Paludan SR, Bowie AG. IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol. 2010 Nov;11(11):997-1004.

Visit PubMed for a complete publication listing.

Structural Biology of Innate Immune Recognition

A postdoctoral fellow position is available at the Structural Immunobiology Unit (SIBU), Laboratory of Immunology, NIAID/NIH for a highly motivated individual to study the molecular mechanisms of innate immune recognition. Our research program is composed of two integrated themes: the mechanisms of nucleic acid recognition by innate immune receptors and the study of large macromolecular signaling platforms known as the “inflammasomes.” We use X-ray crystallography as the primary method to dissect the molecular details of innate receptors and signaling adapters, integrated with chemical tools that target these signaling pathways for potential therapeutic applications.

SIBU is well funded with state-of-the-art equipment for molecular biology, protein chemistry and crystallography, including participation in dedicated synchrotron beam time. There are numerous opportunities for collaboration and acquiring new skills at NIH with one of the leading scientific communities dedicated to immunology research.

We are seeking future career scientists capable of independent thinking and interested in learning new techniques. The ideal candidate must have a M.D. or Ph.D. degree with less than five years of postdoctoral experience. Strong skills in protein expression, purification and molecular biology are essential. Knowledge in protein crystallization and X-ray crystallography is desirable. The candidate must possess excellent written and oral communication skills, and will be expected to work in a diverse and collaborative environment.

Salary will be highly competitive and commensurate with experience, supplemented with excellent fringe benefits.

To apply, please send your curriculum vitae and names and addresses of three references to

T. Sam Xiao, Ph.D.
Chief, Structural Immunobiology Unit
Laboratory of Immunology
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Building 4, Room 228B
4 Memorial Drive
Bethesda, MD 20892-0430, USA
Phone: 301-402-9782
Fax: 301-480-1291
xiaot@niaid.nih.gov

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Last Updated April 18, 2013