Intrinsic <scp>T</scp>‐ and <scp>B</scp>‐cell defects impair <scp>T</scp>‐cell‐dependent antibody responses in mice lacking the actin‐bundling protein <scp>L</scp>‐plastin

Todd, Elizabeth M.; Deady, Lauren E.; Morley, Sharon Celeste

doi:10.1002/eji.201242780

Cited by 21 publications

(29 citation statements)

References 23 publications

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“…Concurrent with this hypothesis, we observed a significant decrease in the lysosomal enzyme hexosaminidase B that plays a role in degradation of internalized Staphylococcus (106). Taken together, the regulatory systems described generate precise control of actin filament and network formation and participate in multiple aspects of pathogenesis (107)(108)(109)(110)(111)(112).…”

Section: Discussionsupporting

confidence: 68%

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

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A thorough understanding of the molecular details of the interactions between bacteria and host are critical to ultimately prevent disease. Recent technological advances allow simultaneous analysis of host and bacterial protein and metabolic profiles from a single small tissue sample to provide insight into pathogenesis. We used the chinchilla model of human otitis media to determine, for the first time, the most expansive delineation of global changes in protein and metabolite profiles during an experimentally induced disease. After 48 h of infection with nontypeable Haemophilus influenzae, middle ear tissue lysates were analyzed by high-resolution quantitative two-dimensional liquid chromatography-tandem mass spectrometry. Dynamic changes in 105 chinchilla proteins and 66 metabolites define the early proteomic and metabolomic signature of otitis media. Our studies indicate that establishment of disease coincides with actin morphogenesis, suppression of inflammatory mediators, and bacterial aerobic respiration. We validated the observed increase in the actin-remodeling complex, Arp2/3, and experimentally showed a role for Arp2/3 in nontypeable Haemophilus influenzae invasion. Direct inhibition of actin branch morphology altered bacterial invasion into host epithelial cells, and is supportive of our efforts to use the information gathered to modify outcomes of disease. The twenty-eight nontypeable Haemophilus influenzae proteins identified participate in carbohydrate and amino acid metabolism, redox homeostasis, and include cell wall-associated metabolic proteins. Quantitative characterization of the molecular signatures of infection will redefine our understanding of host response driven developmental changes during pathogenesis. These data represent the first comprehensive study of host protein and metabolite profiles in vivo in response to infection and show the feasibility of extensive characterization of host protein profiles during disease. Identification of novel protein targets and metabolic biomarkers will advance development of therapeutic and diagnostic options for treatment of disease. Molecular & Cellular Proteomics 15: 10.1074/mcp.M115.052498, 1117-1138, 2016.Our current understanding of the global changes that occur during infection is primarily based upon transcriptional profiles of either the host or the bacteria. However, a significant component of disease progression is dependent upon posttranscriptional processes. Recent advances in the application of two-dimensional tandem mass spectrometry have dramatically increased sensitivity to allow simultaneous analyses of multiple molecules from very small biological samples. In this study, we report the comprehensive proteomic and metabolomic profiling of middle ear tissues using samples that are smaller than those typically obtained from a human biopsy. Proteomic and metabolomic analyses of samples as small as biopsies will revolutionize the elucidation of the mechanisms From the

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Section: Discussionsupporting

confidence: 68%

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

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“…First, monocyte precursors relied on LPL for normal migration into alveoli. Although LPL was previously shown to be required for normal motility in lymphocytes, 17,18,47 it was dispensable for motility in neutrophils. 15 The defect in monocyte alveolar transmigration in LPL 2/2 mice was more profound than that of monocyte trafficking into the peritoneum, 46 suggesting that different tissues present distinct environments for cellular migration.…”

Section: Discussionmentioning

confidence: 99%

Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli

Todd¹,

Zhou²,

Szasz³

et al. 2016

Blood

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Key Points• A key transition from the prealveolar macrophage precursor to mature alveolar macrophage is impaired in neonatal mice lacking LPL.• Genetic impairment of neonatal alveolar macrophage development associates with impaired clearance of a pulmonary pathogen in adult animals. ) exhibited significant reductions in alveolar macrophages and failed to effectively clear pulmonary pneumococcal infection, showing that immunodeficiency results from reduced alveolar macrophage numbers. We next identified the phase of alveolar macrophage development requiring LPL. In mice, fetal monocytes arrive in the lungs during a late fetal stage, maturing to alveolar macrophages through a prealveolar macrophage intermediate. LPL was required for the transition from prealveolar macrophages to mature alveolar macrophages. The transition from prealveolar macrophage to alveolar macrophage requires the upregulation of the transcription factor peroxisome proliferatoractivated receptor-g (PPAR-g), which is induced by exposure to granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite abundant lung GM-CSF and intact GM-CSF receptor signaling, PPAR-g was not sufficiently upregulated in developing alveolar macrophages in LPL 2/2 pups, suggesting that precursor cells were not correctly localized to the alveoli, where GM-CSF is produced. We found that LPL supports 2 actin-based processes essential for correct localization of alveolar macrophage precursors: (1) transmigration into the alveoli, and (2) engraftment in the alveoli. We thus identify a molecular pathway governing neonatal alveolar macrophage development and show that genetic disruption of alveolar macrophage development results in immunodeficiency. (Blood. 2016;128(24):2785-2796

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“…In B cells, total levels of Pyk2 and Pyk2 phosphorylation are reduced in the absence of LPL , suggesting a possible function for LPL in linking integrins to downstream signaling moieties. While a similar requirement for LPL in the maintenance of Pyk2 protein expression has not been observed in T cells, work to determine whether LPL participates in integrin outside‐in signaling in T cells is ongoing .…”

Section: A Unified View Of Lpl In T Cells – Required For Integrin‐medmentioning

confidence: 98%

“…Impaired conjugate formation likely results in the failure to retain LPL −/− T cells at the site of antigen presentation . Germinal center formation and T‐dependent antibody formation has been recently reported to depend on LPL .…”

Section: Requirement For Lpl In T‐cell Activationmentioning

confidence: 99%

The actin‐bundling protein L‐plastin supports T‐cell motility and activation

Morley

2013

Immunological Reviews

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Summary Tight regulation of actin dynamics is essential for T-cell trafficking and activation. Recent studies in human and murine T cells reveal that T-cell motility and full T-cell activation require the hematopoietic-specific, actin-bundling protein L-plastin. T cells lacking L-plastin do not form fully mature synapses and thus demonstrate reduced cytokine production and proliferation. Reduction or loss of L-plastin expression also reduces the velocity of T cells and impairs thymic egress and intranodal motility. While dispensable for proximal T-cell receptor and chemokine receptor signaling, L-plastin is critical to the later stages of synapse maturation and cellular polarization. Serine phosphorylation, calcium, and calmodulin binding regulate the bundling activity and localization of LPL following T-cell receptor and chemokine receptor engagement. However, the interaction between these regulatory domains and resulting changes in local control of actin cytoskeletal structures has not been fully elucidated. Circumstantial evidence suggests a function for L-plastin in either the formation or maintenance of integrin-associated adhesion structures. As L-plastin may be a target of the commonly used immunosuppressive agent dexamethasone, full elucidation of the regulation and function of L-plastin in T-cell biology may illuminate new pathways for clinically useful immunotherapeutics.

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Intrinsic T‐ and B‐cell defects impair T‐cell‐dependent antibody responses in mice lacking the actin‐bundling protein L‐plastin

Cited by 21 publications

References 23 publications

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Alveolar macrophage development in mice requires L-plastin for cellular localization in alveoli

The actin‐bundling protein L‐plastin supports T‐cell motility and activation

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