UNC scientists describe new protein?s role in immune response to pathogens

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CHAPEL HILL, NC ? The human immune system is a double-edged sword. While it is finely adapted to fighting potentially deadly viruses, such as the H1N1 influenza, the mechanisms it uses to fight pathogens can have negative effects such as inflammatory disorders or autoimmune diseases.

A new finding by UNC scientists provides a window into how the immune system initially reacts to a virus invader, as well as how a subgroup of proteins plays a role in returning the immune system to a normal surveillance function. Their pre-clinical findings were published in the June 24, 2011 online edition of Immunity.

Coy Allen, PhD, first author of the paper and a postdoctoral fellow at UNC Lineberger Comprehensive Cancer Center, explains, ?We knew that proteins called NLRs control the immune system?s initial response to an invading pathogen, such as influenza. However, we did not realize that a sub-group of these proteins actually functions to bring an overactive immune response back under control after the pathogen threat has been resolved. Our study showed that a newly identified NLR protein called NLRX1 is capable of shutting down an overreaction by the immune system during an influenza infection.?


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http://www.healthcanal.com/immune-s...-proteins-role-immune-response-pathogens.html

 

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Re: UNC scientists describe new protein?s role in immune response to pathogens

NLRX1 Protein Attenuates Inflammatory Responses to Infection by Interfering with the RIG-I-MAVS and TRAF6-NF-κB Signaling Pathways


Immunity, Volume 34, Issue 6, 854-865, 24 June 2011
Copyright ? 2011 Elsevier Inc. All rights reserved.
10.1016/j.immuni.2011.03.026

Refers to: NOD So Fast: NLRX1 Puts the Brake on Inf...
Authors
Irving C. Allen, Chris B. Moore, Monika Schneider, Yu Lei, Beckley K. Davis, Margaret A. Scull, Denis Gris, Kelly E. Roney, Albert G. Zimmermann, John B. Bowzard, Priya Ranjan, Kathryn M. Monroe, Raymond J. Pickles, Suryaprakash Sambhara, Jenny P.Y. Tingsend emailSee Affiliations

Highlights
NLRX1 attenuates IFN induction by preventing the interaction between RIG-I and MAVS
NLRX1 functions as a negative regulator of IFN-I and IL-6 during influenza infection
NLRX1 attenuates inflammation by intersecting the TRAF6 pathway to affect NF-κB

Summary

The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) proteins regulate innate immunity. Although the positive regulatory impact of NLRs is clear, their inhibitory roles are not well defined. We showed that Nlrx1−/− mice exhibited increased expression of antiviral signaling molecules IFN-β, STAT2, OAS1, and IL-6 after influenza virus infection. Consistent with increased inflammation, Nlrx1−/− mice exhibited marked morbidity and histopathology. Infection of these mice with an influenza strain that carries a mutated NS-1 protein, which normally prevents IFN induction by interaction with RNA and the intracellular RNA sensor RIG-I, further exacerbated IL-6 and type I IFN signaling. NLRX1 also weakened cytokine responses to the 2009 H1N1 pandemic influenza virus in human cells. Mechanistically, Nlrx1 deletion led to constitutive interaction of MAVS and RIG-I. Additionally, an inhibitory function is identified for NLRX1 during LPS activation of macrophages where the MAVS-RIG-I pathway was not involved. NLRX1 interacts with TRAF6 and inhibits NF-κB activation. Thus, NLRX1 functions as a checkpoint of overzealous inflammation.


http://www.cell.com/immunity/abstract/S1074-7613(11)00226-3