title: Nitric oxide increases susceptibility of Toll-like receptor-activated macrophages to spreading Listeria monocytogenes.
abstract: Toll-like receptor (TLR) stimulation activates macrophages to resist intracellular pathogens. Yet, the intracellular bacterium Listeria monocytogenes (Lm) causes lethal infections in spite of innate immune cell activation. Lm uses direct cell-cell spread to disseminate within its host. Here, we have shown that TLR-activated macrophages killed cell-free Lm but failed to prevent infection by spreading Lm. Instead, TLR signals increased the efficiency of Lm spread from "donor" to "recipient" macrophages. This enhancement required nitric oxide (NO) production by nitric oxide synthase-2 (NOS2). NO increased Lm escape from secondary vacuoles in recipient cells and delayed maturation of phagosomes containing membrane-like particles that mimic Lm-containing pseudopods. NO also promoted Lm spread during systemic in vivo infection, as shown by the fact that inhibition of NOS2 with 1400W reduced spread-dependent Lm burdens in mouse livers. These findings reveal a mechanism by which pathogens capable of cell-cell spread can avoid the consequences of innate immune cell activation by TLR stimuli.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cole
authors.forename: Stacey
authors.initials: S
authors.lastname: Thomas
authors.forename: Holly
authors.initials: H
authors.lastname: Filak
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.forename: Laurel L
authors.initials: LL
authors.lastname: Lenz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007113:Immunity, Innate / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology* / Q000378:metabolism; D008088:Listeriosis / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000276:immunology / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D051193:Toll-Like Receptors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse