Protective Role of Mincle in Bacterial Pneumonia by Regulation of Neutrophil Mediated Phagocytosis and Extracellular Trap Formation

Sharma, Atul; Steichen, Anthony L.; Jondle, Christopher Ned; Mishra, Bibhuti B.; Sharma, Jigyasa

doi:10.1093/infdis/jit820

Cited by 80 publications

(76 citation statements)

References 45 publications

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“…This suggests that MCL potentially contributes to immunity against all pathogens that are recognized by Mincle, such as fungi and bacteria as well as mycobacteria (3,14,19,26), although we cannot exclude Mincleindependent MCL function. In line with this idea, MCL-deficient mice show high susceptibility to infection by Klebsiella pneumonia, Candida albicans, and Mycobacterium bovis bacillus CalmetteGuérin (6,16,27), all of which are reported to be poorly eliminated in Mincle-deficient mice (5,26,28). As Mincle also recognizes dead cells (18) as well as microorganisms, MCL may also participate in inflammatory responses against damaged tissue.…”

Section: Discussionmentioning

confidence: 82%

C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

Miyake

Oh‐hora

Yamasaki

2015

The Journal of Immunology

112

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C-type lectin receptors expressed in APCs are recently defined pattern recognition receptors that play a crucial role in immune responses against pathogen-associated molecular patterns. Among pathogen-associated molecular patterns, cord factor (trehalose-6,6′-dimycolate [TDM]) is the most potent immunostimulatory component of the mycobacterial cell wall. Two C-type lectin receptors, macrophage-inducible C-type lectin (Mincle) and macrophage C-type lectin (MCL), are required for immune responses against TDM. Previous studies indicate that MCL is required for TDM-induced Mincle expression. However, the mechanism by which MCL induces Mincle expression has not been fully understood. In this study, we demonstrate that MCL interacts with Mincle to promote its surface expression. After LPS or zymosan stimulation, MCL-deficient bone marrow–derived dendritic cells (BMDCs) had a lower level of Mincle protein expression, although mRNA expression was comparable with wild-type BMDCs. Meanwhile, BMDCs from MCL transgenic mice showed an enhanced level of Mincle expression on the cell surface. MCL was associated with Mincle through the stalk region and this region was necessary and sufficient for the enhancement of Mincle expression. This interaction appeared to be mediated by the hydrophobic repeat of MCL, as substitution of four hydrophobic residues within the stalk region with serine (MCL4S) abolished the function to enhance the surface expression of Mincle. MCL4S mutant failed to restore the defective TDM responses in MCL-deficient BMDCs. These results suggest that MCL positively regulates Mincle expression through protein–protein interaction via its stalk region, thereby magnifying Mincle-mediated signaling.

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Section: Discussionmentioning

confidence: 82%

C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

Miyake

Oh‐hora

Yamasaki

2015

The Journal of Immunology

112

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“…2B and Dataset S3). The pattern of up-regulated inflammatory cytokines/chemokine receptors and strong enrichment of neutrophil-specific transcripts (e.g., stefin A/cystatin A, prokineticin 2, Schlafen 4, Fpr1, and Clec4e) involved in neutrophil mobilization, neutrophil-mediated phagocytosis, and neutrophil extracellular traps formation (24)(25)(26) highlight that the host immune response is dominated by infiltrating neutrophils (Dataset S3). This finding is consistent with previous observations that the number of neutrophils within murine Peyer's patches increases ∼100-fold (14).…”

Section: Resultsmentioning

confidence: 99%

Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host–pathogen transcriptomes

Nuss

Beckstette

Пименова

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

138

117

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Pathogenic bacteria need to rapidly adjust their virulence and fitness program to prevent eradication by the host. So far, underlying adaptation processes that drive pathogenesis have mostly been studied in vitro, neglecting the true complexity of host-induced stimuli acting on the invading pathogen. In this study, we developed an unbiased experimental approach that allows simultaneous monitoring of genome-wide infection-linked transcriptional alterations of the host and colonizing extracellular pathogens. Using this tool for Yersinia pseudotuberculosis-infected lymphatic tissues, we revealed numerous alterations of host transcripts associated with inflammatory and acute-phase responses, coagulative activities, and transition metal ion sequestration, highlighting that the immune response is dominated by infiltrating neutrophils and elicits a mixed T H 17/T H 1 response. In consequence, the pathogen's response is mainly directed to prevent phagocytic attacks. Yersinia up-regulates the gene and expression dose of the antiphagocytic type III secretion system (T3SS) and induces functions counteracting neutrophil-induced ion deprivation, radical stress, and nutritional restraints. Several conserved bacterial riboregulators were identified that impacted this response. The strongest influence on virulence was found for the loss of the carbon storage regulator (Csr) system, which is shown to be essential for the up-regulation of the T3SS on host cell contact. In summary, our established approach provides a powerful tool for the discovery of infection-specific stimuli, induced host and pathogen responses, and underlying regulatory processes.tissue dual RNA-seq | host-pathogen interaction | host-adapted metabolism | noncoding RNAs | Yersinia

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“…Once neutrophils are present in infected tissues, they employ the numerous effector functions in their arsenal to combat K. pneumoniae infection. Studies using both human neutrophils and mouse models of K. pneumoniae infection have noted the neutrophilic use of a number of processes to contain K. pneumoniae (22,(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171). These processes include phagocytosis/opsonophagocytosis, the production of inflammatory cytokines, and the release of antimicrobial compounds and structures, such as reactive oxygen species, serine proteases (e.g., neutrophil elastase), lactoferrin, lipocalin-2, myeloperoxidase, and neutrophil extracellular traps (NETs), to contain the bacteria and mediate clearance (22,(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171).…”

Section: K Pneumoniae and Host Immune Defensesmentioning

confidence: 99%

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

Paczosa

Mecsas

2016

Microbiol Mol Biol Rev

1,364

1,345

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SUMMARYKlebsiella pneumoniaecauses a wide range of infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Historically,K. pneumoniaehas caused serious infection primarily in immunocompromised individuals, but the recent emergence and spread of hypervirulent strains have broadened the number of people susceptible to infections to include those who are healthy and immunosufficient. Furthermore,K. pneumoniaestrains have become increasingly resistant to antibiotics, rendering infection by these strains very challenging to treat. The emergence of hypervirulent and antibiotic-resistant strains has driven a number of recent studies. Work has described the worldwide spread of one drug-resistant strain and a host defense axis, interleukin-17 (IL-17), that is important for controlling infection. Four factors, capsule, lipopolysaccharide, fimbriae, and siderophores, have been well studied and are important for virulence in at least one infection model. Several other factors have been less well characterized but are also important in at least one infection model. However, there is a significant amount of heterogeneity inK. pneumoniaestrains, and not every factor plays the same critical role in all virulentKlebsiellastrains. Recent studies have identified additionalK. pneumoniaevirulence factors and led to more insights about factors important for the growth of this pathogen at a variety of tissue sites. Many of these genes encode proteins that function in metabolism and the regulation of transcription. However, much work is left to be done in characterizing these newly discovered factors, understanding how infections differ between healthy and immunocompromised patients, and identifying attractive bacterial or host targets for treating these infections.

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Protective Role of Mincle in Bacterial Pneumonia by Regulation of Neutrophil Mediated Phagocytosis and Extracellular Trap Formation

Cited by 80 publications

References 45 publications

C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

Tissue dual RNA-seq allows fast discovery of infection-specific functions and riboregulators shaping host–pathogen transcriptomes

Klebsiella pneumoniae: Going on the Offense with a Strong Defense

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