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1.
J Exp Med ; 220(5)2023 05 01.
Article in English | MEDLINE | ID: mdl-36880831

ABSTRACT

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.


Subject(s)
COVID-19 , Myeloid Differentiation Factor 88 , Child , Humans , Adaptor Proteins, Signal Transducing , COVID-19/complications , Myeloid Differentiation Factor 88/genetics , SARS-CoV-2 , Toll-Like Receptor 7
2.
J Infus Nurs ; 43(1): 20-22, 2020.
Article in English | MEDLINE | ID: mdl-31876770

ABSTRACT

Long-term subcutaneous hydration has not been described in pediatrics. A case of a 4-year-old born prematurely with subsequent intestinal failure, large vessel thrombi, and repeated central line-associated bloodstream infections prompting catheter removal is discussed. Chronic dehydration ensued and was managed with long-term subcutaneous fluid infusions with no serious complications.


Subject(s)
Dehydration/therapy , Hypodermoclysis , Intestinal Diseases , Pediatrics , Child, Preschool , Humans , Male , Premature Birth , Time Factors
3.
Cell ; 139(2): 337-51, 2009 Oct 16.
Article in English | MEDLINE | ID: mdl-19837035

ABSTRACT

Golgi membranes, from yeast to humans, are uniquely enriched in phosphatidylinositol-4-phosphate (PtdIns(4)P), although the role of this lipid remains poorly understood. Using a proteomic lipid-binding screen, we identify the Golgi protein GOLPH3 (also called GPP34, GMx33, MIDAS, or yeast Vps74p) as a PtdIns(4)P-binding protein that depends on PtdIns(4)P for its Golgi localization. We further show that GOLPH3 binds the unconventional myosin MYO18A, thus connecting the Golgi to F-actin. We demonstrate that this linkage is necessary for normal Golgi trafficking and morphology. The evidence suggests that GOLPH3 binds to PtdIns(4)P-rich trans-Golgi membranes and MYO18A conveying a tensile force required for efficient tubule and vesicle formation. Consequently, this tensile force stretches the Golgi into the extended ribbon observed by fluorescence microscopy and the familiar flattened form observed by electron microscopy.


Subject(s)
Golgi Apparatus/metabolism , Membrane Proteins/metabolism , Actins/metabolism , Animals , Gene Knockdown Techniques , Golgi Apparatus/chemistry , HeLa Cells , Humans , Hydrophobic and Hydrophilic Interactions , Membrane Proteins/analysis , Membrane Proteins/genetics , Myosins/metabolism , Phosphatidylinositol Phosphates/metabolism , Transport Vesicles/metabolism
4.
Biol Lett ; 3(6): 607-10, 2007 Dec 22.
Article in English | MEDLINE | ID: mdl-17711815

ABSTRACT

In Drosophila melanogaster, accessory gland proteins (Acps) that a male transfers during mating affect his reproductive success by altering the female's behaviour and physiology. To test the role of male condition in the expression of Acps, we manipulated the pre-adult environment and examined adult males for relative transcript abundance of nine Acps, and for post-copulatory traits that Acps influence. Larval culture density had no effect on any measured trait. Larval nutrient availability impacted the number of sperm transferred and stored, the male's ability to induce refractoriness in his mate, but relative transcript abundance of only a single Acp (Acp36DE). Reduced male body size due to low yeast levels affected sperm competition. Our data indicate that some female-mediated post-copulatory traits (induced refractoriness and sperm transfer and storage) might be influenced by the male's developmental environment, but relative expression of most Acps and some traits they influence (P1') are not.


Subject(s)
Drosophila melanogaster/physiology , Spermatozoa/physiology , Animals , Body Size , Breeding/methods , Copulation , Drosophila Proteins/metabolism , Drosophila Proteins/physiology , Drosophila melanogaster/growth & development , Drosophila melanogaster/metabolism , Feeding Behavior , Female , Larva/metabolism , Male , Phenotype , RNA, Messenger/metabolism
5.
Mol Cell Biol ; 27(17): 6012-25, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17562858

ABSTRACT

K63 polyubiquitin chains spatially and temporally link innate immune signaling effectors such that cytokine release can be coordinated. Crohn's disease is a prototypical inflammatory disorder in which this process may be faulty as the major Crohn's disease-associated protein, NOD2 (nucleotide oligomerization domain 2), regulates the formation of K63-linked polyubiquitin chains on the I kappa kinase (IKK) scaffolding protein, NEMO (NF-kappaB essential modifier). In this work, we study these K63-linked ubiquitin networks to begin to understand the biochemical basis for the signaling cross talk between extracellular pathogen Toll-like receptors (TLRs) and intracellular pathogen NOD receptors. This work shows that TLR signaling requires the same ubiquitination event on NEMO to properly signal through NF-kappaB. This ubiquitination is partially accomplished through the E3 ubiquitin ligase TRAF6. TRAF6 is activated by NOD2, and this activation is lost with a major Crohn's disease-associated NOD2 allele, L1007insC. We further show that TRAF6 and NOD2/RIP2 share the same biochemical machinery (transforming growth factor beta-activated kinase 1 [TAK1]/TAB/Ubc13) to activate NF-kappaB, allowing TLR signaling and NOD2 signaling to synergistically augment cytokine release. These findings suggest a biochemical mechanism for the faulty cytokine balance seen in Crohn's disease.


Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Nod2 Signaling Adaptor Protein/metabolism , Polyubiquitin/metabolism , Signal Transduction/physiology , Toll-Like Receptors/metabolism , Animals , Crohn Disease/immunology , Enzyme Activation , Genes, Reporter , Humans , Immunity, Innate/physiology , Intracellular Signaling Peptides and Proteins/genetics , Mice , Mice, Knockout , NF-kappa B/genetics , NF-kappa B/metabolism , Nod2 Signaling Adaptor Protein/genetics , Polyubiquitin/genetics , RNA, Small Interfering , Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , TNF Receptor-Associated Factor 6/genetics , TNF Receptor-Associated Factor 6/metabolism , Toll-Like Receptors/genetics
6.
Proc Natl Acad Sci U S A ; 104(19): 8077-82, 2007 May 08.
Article in English | MEDLINE | ID: mdl-17483449

ABSTRACT

Inflammatory cell activation by chemokines requires intracellular signaling through phosphoinositide 3-kinase (PI3-kinase) and the PI3-kinase-dependent protein serine/threonine kinase Akt. Atherosclerosis is a chronic inflammatory process driven by oxidatively modified (atherogenic) lipoproteins, chemokines, and other agonists that activate PI3-kinase. Here we show that macrophage PI3-kinase/Akt is activated by oxidized low-density lipoprotein, inflammatory chemokines, and angiotensin II. This activation is markedly reduced or absent in macrophages lacking p110gamma, the catalytic subunit of class Ib PI3-kinase. We further demonstrate activation of macrophage/foam cell PI3-kinase/Akt in atherosclerotic plaques from apolipoprotein E (apoE)-null mice, which manifest an aggressive form of atherosclerosis, whereas activation of PI3-kinase/Akt was undetectable in lesions from apoE-null mice lacking p110gamma despite the presence of class Ia PI3-kinase. Moreover, plaques were significantly smaller in apoE-/-p110gamma-/- mice than in apoE-/-p110gamma+/+ or apoE-/-p110gamma+/-mice at all ages studied. In marked contrast to the embryonic lethality seen in mice lacking class Ia PI3-kinase, germ-line deletion of p110gamma results in mice that exhibit normal viability, longevity, and fertility, with relatively well tolerated defects in innate immune and inflammatory responses that may play a role in diseases such as atherosclerosis and multiple sclerosis. Our results not only shed mechanistic light on inflammatory signaling during atherogenesis, but further identify p110gamma as a possible target for pharmacological intervention in the primary and secondary prevention of human atherosclerotic cardiovascular disease.


Subject(s)
Atherosclerosis/prevention & control , Phosphatidylinositol 3-Kinases/physiology , Animals , Apolipoproteins E/physiology , Gene Deletion , Lipoproteins, LDL/pharmacology , Mice , Mice, Inbred C57BL , Oxidative Stress , Phosphatidylinositol 3-Kinases/genetics , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-akt/physiology
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