Protein 'tubules' free avian flu virus from immune recognition

November 06, 2008

A protein found in the virulent avian influenza virus strain called H5N1 forms tiny tubules in which it "hides" the pieces of double-stranded RNA formed during viral infection, which otherwise would prompt an antiviral immune response from infected cells, said Baylor College of Medicine researchers in an online report in the journal Nature.

Two domains or portions of the protein NS1 combine to form tiny tubules where double-stranded RNA is hidden from the immune system, said Dr. B. V. Venkataram Prasad, professor of biochemistry and molecular biology, molecular virology and microbiology at BCM and his student, Dr. Zachary A. Bornholdt (now of the Scripps Research Institute in La Jolla, California).

"Once we confirm the importance of this structural information, we should be able to design drugs to block this action," said Prasad. "There are other things the protein could do to interfere with different immune mechanisms. We don't know if this is the only mechanism or if there are others that also come into play during influenza virus infection."

The two researchers had already recognized the importance of the protein NS1 in the virulence of influenza viruses and particularly, H5N1, a form of avian flu associated with more than half the deaths in a 2004 "bird flu" outbreak that resulted in 50 human cases and 36 deaths in Vietnam, China and Thailand. In all but one case, experts ruled out human-to-human spread of the virus. In a previous report, Prasad and Bornholdt described the structure of an area of the protein called the effector domain. In this report, a series of elegant experiments designed and carried out over eight months by Bornholdt allowed the two scientists to "crystallize" the entire protein.

By doing this, they were able to determine its structure using a technique called X-ray crystallography. This technique enables scientists to determine the three-dimensional structure of proteins and other bio-molecules by scattering X-rays through a crystal of the molecule. They substantiated their structure with cryo-electron microscopy, which makes images of tiny frozen structures using an extremely powerful electron microscope.

That structure revealed a previously unsuspected idiosyncrasy of NS1 in H5N1 that could explain the virus' virulence. In most cases, when an infected cell is exposed to a virus, double-stranded RNA molecules are formed triggering a potent anti-viral response that involves production of interferon.

However, the two domains of NS1 in this H5N1 interact to form tiny tubules. The double-stranded RNA is hidden or sequestered in these structures. The cell never sees a significant length of the RNA and does not marshal its immune forces to the fight the virus. Prasad and Bornholdt believe also that cellular factor binding sites found on the surface of the tubules also play a role in fooling the immune system.

"This is only one structure," said Prasad. "We need to see if this holds up with other NS1 structures from other influenza viruses."

Bornholdt's technique for crystallizing the protein will prove valuable in pursuing this work, said Prasad.

"Is this a common mechanism for eluding the immune system?" he said. He said hopes to build a library to NS1 structures to facilitate future studies designed to fight influenza worldwide.

While H5N1 is not usually transmitted from human-to-human at this point, a small change in its genetic structure - perhaps an exchange of genes with a more easily transmitted flu virus - could change that, he said. Developing drugs to fight the virus could prove life-saving in a pandemic.

Baylor College of Medicine

Expression of the Interleukin (IL)-23 p19 subunit during innate anti-viral immune responses: Cell signaling and promoter analysis.
by Fahd Al-Salleeh (Author)

IL-23 p19/p40, produced by macrophages and dendritic cells during innate immunity, is critical for development of TH17 cells, a subset of T helper (TH) cells that produce the proinflammatory cytokine, IL-17. The IL-23/IL-17 axis has been shown to play a major role in several autoimmune and chronic inflammatory diseases caused by pathogens. Theiler's murine encephalomyelitis virus (TMEV) infects macrophages of mice, establishes a persistent infection in certain strains of mice, and causes a demyelinating inflammatory disease in these strains of mice. IL-23 is expressed by macrophages in response to TMEV, which provide an excellent model to analyze the cell signaling necessary to induce IL-23 during viral infections associated with autoimmune and chronic inflammatory diseases. In this...

Interferon: The 50th Anniversary (Current Topics in Microbiology and Immunology)
by Paula M. Pitha (Editor)

A vital text for researchers and clinicians in the fields of virology and oncology alike, this book is a comprehensive guide to one of medicine’s most important tools that covers the most recent research. Important insights have been made in recent months that are challenging the accepted concept of the critical role of dsRNA in IFN induction. Recent work with genetically modified mice seems to confirm the original idea that interferon is the first cellular defense against viral infection.

Viral Proteins Counteracting Host Defenses
by U.H. Koszinowski (Editor), H. Hengel (Editor)

Since the first observations of viral interference with antigen presentation in the MHC class-I pathway, the field has advanced to a detailed analysis. We know numerous genes and for some of them we have profound information on their mechanistic function. The antigen presentation pathway is affected at all stages starting from proteasomal degradation of an antigenic viral protein, as shown for EBV, transfer of the proteasomal cleavage products as peptides in the ER by specific transporters, the loading of the nascent MHC class-I molecule, and finally the transport of the complex to the surface and presentation in a normal or deranged form. All these different steps of the MHC class-I antigen presentation pathway are targets for viral proteins. Not only MHC class-I but also MHC class-II...

Control of Innate and Adaptive Immune Responses during Infectious Diseases
by Julio Aliberti (Editor)

Upon infection the host needs to mount vigorous immune response against pathogen in order to successfully control its replication. However, once the infectious agent is controlled or eliminated, host cells need to signal the immune system to slow or cease its activities. While vast knowledge has been accumulated through the years on the mechanisms involved in the initiation and effector phases of the immune responses, the pathways triggered in order to modulate or end innate and acquired immunity are becoming more evident as evidence for its relevance comes to surface. Due to its biological power, evidence has surfaced indicating that eventually pathogens may take advantage of such regulatory pathways in order to escape effector mechanisms and progress to persistence. This book will...

West Nile Encephalitis Virus Infection: Viral Pathogenesis and the Host Immune Response (Emerging Infectious Diseases of the 21st Century)
by Michael S. Diamond (Editor)

West Nile virus has emerged globally as a significant cause of viral encephalitis in humans. Infection of humans is associated with a febrile illness that can progress to meningitis and encephalitis with symptoms including cognitive dysfunction and flaccid paralysis. Following its introduction to the United States in 1999, West Nile virus rapidly disseminated across North America. Outbreaks of West Nile virus fever and neuroinvasive disease now occur annually in the United States, with about 23,000 diagnosed human cases between 1999 and 2006. The emergence of West Nile virus in the Western hemisphere and the corresponding increase in disease burden has been accompanied by intensive study. West Nile Encephalitis Virus Infection: Viral Pathogenesis and the Host Immune Response focuses on...

Mathematical Modelling of Immune Response in Infectious Diseases (Mathematics and Its Applications (closed))
by Guri I. Marchuk (Author)

This is the first monograph to present a unified approach to using mathematical models in the study of qualitative and quantitative regularities of immune response dynamics in infectious diseases within individual organisms. These mathematical models are formulated as systems of delay- differential equations. Simple mathematical models of infectious diseases, antiviral immune response and antibacterial response were developed and applied to the study of hepatitis B, influenza A, infectious bacterial pneumonia, and mixed infections. Particular attention was paid to the development of efficient computational procedures for solving the initial value problem for stiff delay-differential equations and to the parameter identification problem. Adjoint equations and the...

Analyzing T Cell Responses: How to analyze cellular immune responses against tumor associated antigens
by Dirk Nagorsen (Editor), Francesco M. Marincola (Editor)

This book reviews, describes, categorizes and provides a critical assessment of all assays that have been used for the monitoring of antigen-specific immune responses. In particular, it emphasizes a global approach to the analysis of T cell mediated target/host interactions at the systemic and the peripheral level when such interactions are supposed to occur. In addition, the tools described here could be utilized for the search of surrogate biomarkers predictive of treatment responsiveness and/or clinical outcome that are of interest to the biotechnology industry. In detail, this book provides an overview of antigen-specific immune biology in human models of tumor and viral disease, discusses modulation of such responses through immune escape and presents cellular assays (cytoxicity,...

Antivirals Against AIDS
by Unger/Kreuter/r (Author)

This volume, devoted specifically to antiviral therapy, describes current practices used to treat HIV-infected patients, clarifies the use and suitability of animal model systems for the study and evaluation of drug performance, and reveals novel treatments and vaccines in early developmental stages. Highlights gene therapy and nanoparticle technology! Including more than 1375 references that encourage and facilitate further research, Antivirals Against AIDS · addresses problems encountered with resistance to antiretroviral treatments · details second- and third-generation approaches to anti-HIV therapies targeting HIV reverse transcriptase and protease proteins · examines inhibiting the spread of HIV by pinpointing appropriate receptors for entry into cells · considers unique...

Immunology of Gene Therapy
by Roland W. Herzog (Author)

Summarises and reviews the important field of genetic therapy with respect to the latest immunological advances in the lab and clinicUnique treatment of immunology and immunotherapy in gene - approached from a vector and target organ point of view rather than from the perspective a specific diseasesBroad appeal - applicable for immunology and genetics / gene therapy, recombinant DNA studies, transplantation, virology, cancer research and tumor research

Negative Co-Receptors and Ligands (Current Topics in Microbiology and Immunology, Vol. 350)
by Rafi Ahmed (Editor), Tasuku Honjo (Editor)

Adaptive immune responses serve as a key defense mechanism for the control of infections in vertebrates. Immune responses must be of sufficient strength to contain invading pathogens, antigen specific responses require regulatory mechanisms to ensure termination or downmodulation to avoid excessive damage to the host tissue. For both branches of the adaptive immune system, regulatory molecules i.e. coreceptors and ligands have been identified that control the signaling cascades initiated by engagement of the T cell and B cell antigen receptors. This book describes biological functions as well as molecular mechanisms of these molecules.