Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2014 May 20;111(20):E2110-9. doi: 10.1073/pnas.1322118111. Epub 2014 May 5.

NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein.

Author information

1
Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada H2X 2P2;
2
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada M5S 1A8;
3
Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN 38103; andDepartment of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-2794.
4
Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University Health Centre, McGill International TB Centre, Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada H2X 2P2; maziar.divangahi@mcgill.ca.

Abstract

To subvert host immunity, influenza A virus (IAV) induces early apoptosis in innate immune cells by disrupting mitochondria membrane potential via its polymerase basic protein 1-frame 2 (PB1-F2) accessory protein. Whether immune cells have mechanisms to counteract PB1-F2-mediated apoptosis is currently unknown. Herein, we define that the host mitochondrial protein nucleotide-binding oligomerization domain-like receptor (NLR)X1 binds to viral protein PB1-F2, preventing IAV-induced macrophage apoptosis and promoting both macrophage survival and type I IFN signaling. We initially observed that Nlrx1-deficient mice infected with IAV exhibited increased pulmonary viral replication, as well as enhanced inflammatory-associated pulmonary dysfunction and morbidity. Analysis of the lungs of IAV-infected mice revealed markedly enhanced leukocyte recruitment but impaired production of type I IFN in Nlrx1(-/-) mice. Impaired type I IFN production and enhanced viral replication was recapitulated in Nlrx1(-/-) macrophages and was associated with increased mitochondrial mediated apoptosis. Through gain- and loss-of-function strategies for protein interaction, we identified that NLRX1 directly bound PB1-F2 in the mitochondria of macrophages. Using a recombinant virus lacking PB1-F2, we confirmed that deletion of PB1-F2 abrogated NLRX1-dependent macrophage type I IFN production and apoptosis. Thus, our results demonstrate that NLRX1 acts as a mitochondrial sentinel protecting macrophages from PB1-F2-induced apoptosis and preserving their antiviral function. We further propose that NLRX1 is critical for macrophage immunity against IAV infection by sensing the extent of viral replication and maintaining a protective balance between antiviral immunity and excessive inflammation within the lungs.

KEYWORDS:

Nod-like receptor; innate immunity

PMID:
24799673
PMCID:
PMC4034189
DOI:
10.1073/pnas.1322118111
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center