Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection.
Pattern recognition receptors (PRRs) engage microbial components in the lung, although their role in providing primary host defense against respiratory virus infection is not fully understood. We have previously shown that Gram-positive Lactobacillus plantarum (Lp) administered to the respiratory tract promotes full and sustained protection in response to an otherwise lethal mouse pneumovirus (PVM) infection, a robust example of heterologous immunity. While Lp engages PRRs TLR2 and NOD2 in ex vivo signaling assays, we found that Lp-mediated protection was unimpaired in single gene-deleted TLR2(-/-) and NOD2(-/-) mice. Here we demonstrate substantial loss of Lp-mediated protection in a double gene-deleted NOD2(-/-)TLR2(-/-) strain. Furthermore, we demonstrate protection against PVM infection by administration of the bi-functional NOD2-TLR2 agonist, CL-429. The bi-functional NOD2-TLR2 ligand CL-429 not only suppresses virus-induced inflammation, it is significantly more effective at preventing lethal infection than equivalent amounts of mono-molecular TLR2 and NOD2 agonists. Interestingly, and in contrast to biochemical NOD2 and/or TLR2 agonists, Lp remained capable of eliciting primary proinflammatory responses from NOD2(-/-)TLR2(-/-) mice in vivo and from alveolar macrophages challenged ex vivo. Taken together, we conclude that coordinate engagement of NOD2 and TLR2 constitutes a key step in the genesis of Lp-mediated protection from a lethal respiratory virus infection, and represents a critical target for modulation of virus-induced inflammatory pathology.
Inflammation Immunobiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
Tyler A
TA
Rice
Inflammation Immunobiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
Todd A
TA
Brenner
Inflammation Immunobiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
Caroline M
CM
Percopo
Inflammation Immunobiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
Michelle
M
Ma
Drug Discovery Infectious Diseases, GlaxoSmithKline, Research Triangle Park, NC 27709, United States.
Jesse D
JD
Keicher
Department of Pediatrics, Division of Infectious Diseases, SUNY Upstate Medical Center, Syracuse, NY 13210, United States.
Joseph B
JB
Domachowske
Inflammation Immunobiology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: hrosenberg@niaid.nih.gov.
Helene F
HF
Rosenberg
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism; D048191:Lactiplantibacillus plantarum / Q000276:immunology; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D029122:Murine pneumonia virus / Q000276:immunology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D018111:Pneumovirus / Q000276:immunology*; D018186:Pneumovirus Infections / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load
D016207:Cytokines; D018836:Inflammation Mediators; D008024:Ligands; D053473:Nod2 Signaling Adaptor Protein; D051192:Receptors, Pattern Recognition; D051195:Toll-Like Receptor 2
Cytokines; Inflammation; Pattern recognition receptors; Pneumovirus; Probiotic