MyD88-Dependent Responses Involving Toll-Like Receptor 2 Are Important for Protection and Clearance ofLegionella pneumophilain a Mouse Model of Legionnaires' Disease

Abstract

Legionella pneumophilais a gram-negative facultative intracellular parasite of macrophages. AlthoughL. pneumophilais the causative agent of a severe pneumonia known as Legionnaires' disease, it is likely that most infections caused by this organism are cleared by the host innate immune system. It is predicted that host pattern recognition proteins belonging to the Toll-like receptor (TLR) family are involved in the protective innate immune responses. We examined the role of TLR-mediated responses inL. pneumophiladetection and clearance using genetically altered mouse hosts in which the macrophages are permissive forL. pneumophilaintracellular replication. Our data demonstrate that cytokine production by bone marrow-derived macrophages (BMMs) in response toL. pneumophilainfection requires the TLR adapter protein MyD88 and is reduced in the absence of TLR2 but not in the absence of TLR4. Bacterial growth ex vivo in BMMs from MyD88-deficient mice was not enhanced compared to bacterial growth ex vivo in BMMs from heterozygous littermate controls. Wild-type mice were able to clearL. pneumophilafrom the lung, whereas respiratory infection of MyD88-deficient mice caused death that resulted from robust bacterial replication and dissemination. In contrast to an infection with virulentL. pneumophila, MyD88-deficient mice were able to clear infections withL. pneumophila dotAmutants, indicating that MyD88-independent responses in the lung are sufficient to clear bacteria that are unable to replicate intracellularly. In vivo growth ofL. pneumophilawas enhanced in the lungs of TLR2-deficient mice, which resulted in a delay in bacterial clearance. No significant differences were observed in the growth and clearance ofL. pneumophilain the lungs of TLR4-deficient mice and heterozygous littermate control mice. Our data indicate that MyD88 is crucial for eliciting a protective innate immune response against virulentL. pneumophilaand that TLR2 is one of the pattern recognition receptors involved in initiating this MyD88-dependent response.