The Alveolar Epithelial Cell Chemokine Response to Pneumocystis Requires Adaptor Molecule MyD88 and Interleukin-1 Receptor but Not Toll-Like Receptor 2 or 4

Abstract

ABSTRACTPneumocystisis an opportunistic fungal pathogen that causes pneumonia in a variety of clinical settings. An early step inPneumocystisinfection involves the attachment of organisms to alveolar epithelial cells (AECs). AECs produce chemokines in response toPneumocystisstimulation, but the upstream host-pathogen interactions that activate AEC signaling cascades are not well-defined. MyD88 is an adaptor molecule required for activation of proinflammatory signaling cascades following Toll-like receptor (TLR)-dependent recognition of conserved molecular patterns on pathogens. To determine whether the TLR/MyD88 pathway is required for the AEC chemokine response toPneumocystis, wild-type (WT) and MyD88-deficient AECs were incubated withPneumocystis. As expected, WT AECs produced CCL2 and CXCL2 followingPneumocystisstimulation. In contrast, MyD88-deficient AECs were severely impaired in their ability to respond toPneumocystis. MyD88-deficient AECs did not displayPneumocystis-induced Jun N-terminal protein kinase activation and produced much less chemokine thanPneumocystis-stimulated WT AECs. Using a panel of TLR agonists, primary murine AECs were found to respond vigorously to TLR2 and TLR4 agonists. However, the AEC chemokine response toPneumocystisdid not require TLR2 or TLR4. Surprisingly, the interleukin-1 receptor (IL-1R) was required for an AEC chemokine response toPneumocystis. The role of MyD88 in early responses duringPneumocystisinfection was supported byin vivostudies demonstrating that MyD88-deficient mice showed impairedPneumocystis-stimulated chemokine production and impaired inflammatory cell recruitment. These data indicate an important role for MyD88 in the AEC inflammatory response toPneumocystis.