Advisory Committee Chair
David D Chaplin
Advisory Committee Members
T Prescott Atkinson
David E Briles
Laura Timares
Casey T Weaver
Document Type
Dissertation
Date of Award
2009
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Several reports have suggested that Mycoplasma pneumoniae (Mp) can contribute importantly to the expression of symptoms in asthmatic human subjects. As a foundation for understanding the interactions between Mp and asthma susceptibility, we first studied the mechanisms by which the host normally eliminated Mp. Mice were inoculated with 4x106 Mp intranasally. Twenty-four hours after inoculation with Mp, subpopulations of CD11b+ macrophages/monocytes had been recruited into the lungs. The clearance of Mp was impaired both in macrophage-depleted and in macrophage-deficient mice. Furthermore, mice deficient in MyD88, a major adaptor for TLR signaling, showed dramatically defective clearance of Mp, associated with reduced activation and recruitment of macrophages into the lungs. Incubation of bone marrow derived macrophages (BMM) in vitro with Mp induced activation and ii nuclear translocation of NFκB, and clearance of YFP-labeled Mp from the cultures. These responses were significantly impaired in cultures of MyD88-deficient BMM. Together these data indicate that TLR-MyD88-NFκB signaling is essential for the host response to Mp. We then focused on the role of TLR signaling in the macrophage response to this microbe. Several mycoplasma lipoproteins have been shown to activate macrophages via TLR2, through the TLR1/2 and TLR2/6 heterodimers. Interestingly, we found enhanced clearance of Mp from TLR2-/- mice, but modestly reduced clearance of Mp from TLR1-/- or TLR6-/- mice. The enhanced clearance in TLR2-/- mice is dependent on both TLR4 signaling and the presence of macrophages. These data suggest that there are interactions between TLR2 and TLR4 in the anti-Mp response. We extended these studies in vitro by infecting cultures of BMM with Mp. After infection with Mp, TLR2-/- BMM showed increased phosphorylation of IRF3 and NFκB, and up-regulated expression of IFN-β and IL-6 mRNA, compared to Mp-infected wild type BMM. These effects were all TLR4-dependent. Altogether, these data indicate a dual role of TLR2 signaling that contributes to the host response to Mp, and also down-regulates TLR4 signaling in the macrophage response to Mp.
Recommended Citation
Lai, Jen-Feng, "The Essential Role of Macrophages and TLR Signaling in the Host Response to Mycoplasma Pneumoniae" (2009). All ETDs from UAB. 226.
https://digitalcommons.library.uab.edu/etd-collection/226