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Mycoplasma pneumoniae and Streptococcus pneumoniae are the most common bacterial causes of pneumonia in children. The clinical characteristics of pneumonia differ significantly between the two bacteria. We aimed to elucidate the differences in pathogenesis between M. pneumoniae and S. pneumoniae by characterizing the respiratory epithelial cell immune response to both pathogens. Using primary human bronchial epithelial cells in air-liquid interface cultures, we observed lower production of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in response to M. pneumoniae than to S. pneumoniae. In contrast to the differences in proinflammatory cytokine production, Toll-like receptor 2 (TLR2)-mediated signaling in response to M. pneumoniae was stronger than to S. pneumoniae. This difference largely depended on TLR1 and not TLR6. We found that M. pneumoniae, but not S. pneumoniae, also induced signaling of TLR10, a coreceptor of TLR2 that has inhibitory properties. M. pneumoniae-induced TLR10 signaling on airway epithelial cells was partially responsible for low IL-8 production, as blocking TLR10 by specific antibodies increased cytokine production. M. pneumoniae maintained Th2-associated cytokine production by epithelial cells, which concurs with the known association of M. pneumoniae infection with asthma. M. pneumoniae left IL-33 levels unchanged, whereas S. pneumoniae downregulated IL-33 production both under homeostatic and Th2-promoting conditions. By directly comparing M. pneumoniae and S. pneumoniae, we demonstrate that M. pneumoniae avoids induction of proinflammatory cytokine response despite its ability to induce robust TLR2 signaling. Our new findings suggest that this apparent paradox may be partially explained by M. pneumoniae-induced signaling of TLR2/TLR10.

Antibody responses to Mycoplasma pneumoniae correlate with pulmonary M. pneumoniae clearance. However, M. pneumoniae -specific IgG antibodies can cross-react with the myelin glycolipid galactocerebroside (GalC) and cause neurological disorders. We assessed whether antiglycolipid antibody formation is part of the physiological immune response to M. pneumoniae We show that antibodies against M. pneumoniae proteins and glycolipids arise in serum of M. pneumoniae -infected children and mice. Although antibodies to M. pneumoniae glycolipids were mainly IgG, anti-GalC antibodies were only IgM. B-1a cells, shown to aid in protection against pathogen-derived glycolipids, are lacking in Bruton tyrosine kinase (Btk)-deficient mice. M. pneumoniae -infected Btk-deficient mice developed M. pneumoniae -specific IgG responses to M. pneumoniae proteins but not to M. pneumoniae glycolipids, including GalC. The equal recovery from M. pneumoniae infection in Btk-deficient and wild-type mice suggests that pulmonary M. pneumoniae clearance is predominantly mediated by IgG reactive with M. pneumoniae proteins and that M. pneumoniae glycolipid-specific IgG or IgM is not essential. These data will guide the development of M. pneumoniae -targeting vaccines that avoid the induction of neurotoxic antibodies., (Copyright © 2019 American Society for Microbiology.)