The C-Type Lectin Receptor Mincle Binds to Streptococcus pneumoniae but Plays a Limited Role in the Anti-Pneumococcal Innate Immune Response (original) (raw)
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PLoS pathogens, 2016
Among various innate immune receptor families, the role of C-type lectin receptors (CLRs) in lung protective immunity against Streptococcus pneumoniae (S. pneumoniae) is not fully defined. We here show that Mincle gene expression was induced in alveolar macrophages and neutrophils in bronchoalveolar lavage fluids of mice and patients with pneumococcal pneumonia. Moreover, S. pneumoniae directly triggered Mincle reporter cell activation in vitro via its glycolipid glucosyl-diacylglycerol (Glc-DAG), which was identified as the ligand recognized by Mincle. Purified Glc-DAG triggered Mincle reporter cell activation and stimulated inflammatory cytokine release by human alveolar macrophages and alveolar macrophages from WT but not Mincle KO mice. Mincle deficiency led to increased bacterial loads and decreased survival together with strongly dysregulated cytokine responses in mice challenged with focal pneumonia inducing S. pneumoniae, all of which was normalized in Mincle KO mice reconst...
Journal of Infectious Diseases, 2013
Background. Nosocomial infections with Klebsiella pneumoniae are a frequent cause of Gram-negative bacterial sepsis. To understand the functioning of host innate immune components in this disorder, we examined a previously uninvestigated role of the C-type lectin receptor Mincle in pneumonic sepsis caused by K. pneumoniae. Methods. Disease progression in wild-type and Mincle −/− mice undergoing pulmonary infection with K. pneumoniae was compared. Results. Whereas the wild-type mice infected with a sublethal dose of bacteria could resolve the infection with bacterial clearance and regulated host response, the Mincle −/− mice were highly susceptible with a progressive increase in bacterial burden, despite their ability to mount an inflammatory response that turned to an exaggerated hyperinflammation with the onset of severe pneumonia. This correlated with severe lung pathology with a massive accumulation of neutrophils in their lungs. Importantly, Mincle −/− neutrophils displayed a defective ability to phagocytize nonopsonic bacteria and an impaired ability to form extracellular traps (NETs), an important neutrophil function against invading pathogens, including K. pneumoniae. Conclusion. Our results demonstrate protective role of Mincle in host defense against K. pneumoniae pneumonia by coordinating bacterial clearance mechanisms of neutrophils. A novel role for Mincle in the regulation of neutrophil NET formation may have implications in chronic disease conditions characterized by deregulated NET formation.
Proceedings of the National Academy of Sciences, 2002
The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.
The lectin-like domain of thrombomodulin hampers host defence in pneumococcal pneumonia
European Respiratory Journal, 2013
The lectin-like domain of thrombomodulin (TM) plays an important regulatory role in sterile inflammatory conditions, but its role in severe Gram-positive infectious disease is unknown. Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The aim of this study was to determine the role of the lectin-like domain of TM in murine pneumococcal pneumonia.
PLoS ONE, 2011
Natural killer (NK) cells serve as a crucial first line of defense against tumors, viral and bacterial infections. We studied the involvement of a principal activating natural killer cell receptor, natural cytotoxicity receptor 1 (NCR1), in the innate immune response to S. pneumoniae infection. Our results demonstrate that the presence of the NCR1 receptor is imperative for the early clearance of S. pneumoniae. We tied the ends in vivo by showing that deficiency in NCR1 resulted in reduced lung NK cell activation and lung IFNc production at the early stages of S. pneumoniae infection. NCR1 did not mediate direct recognition of S. pneumoniae. Therefore, we studied the involvement of lung macrophages and dendritic cells (DC) as the mediators of NK-expressed NCR1 involvement in response to S. pneumoniae. In vitro, wild type BM-derived macrophages and DC expressed ligands to NCR1 and co-incubation of S. pneumoniae-infected macrophages/DC with NCR1-deficient NK cells resulted in significantly lesser IFNc levels compared to NCR1-expressing NK cells. In vivo, ablation of lung macrophages and DC was detrimental to the early clearance of S. pneumoniae. NCR1-expressing mice had more potent alveolar macrophages as compared to NCR1-deficient mice. This result correlated with the higher fraction of NCR1-ligand high lung macrophages, in NCR1-expressing mice, that had better phagocytic activity compared to NCR1-ligand dull macrophages. Overall, our results point to the essential contribution of NK-expressed NCR1 in early response to S. pneumoniae infection and to NCR1-mediated interaction of NK and S. pneumoniae infected-macrophages and -DC.
Scientific Reports, 2019
trigger factor (tF) has a known cytoplasmic function as a chaperone. In a previous study we showed that pneumococcal TF is also cell-wall localized and this finding combined with the immunogenic characteristic of tF, has led us to determine the vaccine potential of tF and decipher its involvement in pneumococcal pathogenesis. Bioinformatic analysis revealed that tF is conserved among pneumococci and has no human homologue. Immunization of mice with recombinant (r)tF elicited a protective immune response against a pneumococcal challenge, suggesting that tF contributes to pneumococcal pathogenesis. Indeed, rtF and an anti-rtF antiserum inhibited bacterial adhesion to human lung derived epithelial cells, indicating that tF contributes to the bacterial adhesion to the host. Moreover, bacteria lacking tF demonstrated reduced adhesion, in vitro, to lung-derived epithelial cells, neural cells and glial cells. the reduced adhesion could be restored by chromosomal complementation. Furthermore, bacteria lacking TF demonstrated significantly reduced virulence in a mouse model. taken together, the ability of rtF to elicit a protective immune response, involvement of tF in bacterial adhesion, conservation of the protein among pneumococcal strains and the lack of human homologue, all suggest that rtF can be considered as a future candidate vaccine with a much broader coverage as compared to the currently available pneumococcal vaccines. The commensal bacterium Streptococcus pneumoniae continues to cause morbidity and mortality worldwide 1. Since the implementation of pneumococcal capsular polysaccharide vaccines 2,3 a substantial reduction in disease burden has been reported. While the 23 valent unconjugated pneumococcal polysaccharide vaccine (PPSV23) was found to be 45-65% effective in immunocompetent adult patients 2 , this vaccine, unfortunately, does not elicit an immune response in the group with the highest rate of pneumococcal disease burden, i.e., children younger than two years of age 4,5. The first commercial version of the pneumococcal conjugate vaccine (PCV), which included 5 capsular serotypes, has evolved over the last three decades to include up to 15 capsular polysaccharide serotypes 6,7. PCVs induce immune memory and a protective immune response in infants, but only protect against serotypes that are included in the vaccine 8,9. Limitations of the currently available polysaccharide vaccines and the continuous increase in antibiotic resistance to S. pneumoniae underscore the urgency of the need for pneumococcal vaccines with broader coverage 9-12 .
Immunity, 2013
Cord factor, also called trehalose-6,6 0-dimycolate (TDM), is a potent mycobacterial adjuvant. We herein report that the C-type lectin MCL (also called Clec4d) is a TDM receptor that is likely to arise from gene duplication of Mincle (also called Clec4e). Mincle is known to be an inducible receptor recognizing TDM, whereas MCL was constitutively expressed in myeloid cells. To examine the contribution of MCL in response to TDM adjuvant, we generated MCL-deficient mice. TDM promoted innate immune responses, such as granuloma formation, which was severely impaired in MCL-deficient mice. TDM-induced acquired immune responses, such as experimental autoimmune encephalomyelitis (EAE), was almost completely dependent on MCL, but not Mincle. Furthermore, by generating Clec4e gfp reporter mice, we found that MCL was also crucial for driving Mincle induction upon TDM stimulation. These results suggest that MCL is an FcRg-coupled activating receptor that mediates the adjuvanticity of TDM. Immunity MCL Is an FcRg-Coupled TDM Receptor