David W. Dorward's research while affiliated with National Institute of Allergy and Infectious Diseases and other places
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Publications (105)
Scanning electron microscopy (SEM) remains distinct in its ability to allow topographical visualization of structures. Key elements to consider for successful examination of biological specimens include appropriate preparative and imaging techniques. Chemical processing induces structural artifacts during specimen preparation, and several factors n...
Next-generation SARS-CoV-2 vaccines are needed that induce systemic and mucosal immunity. Murine pneumonia virus (MPV), a murine homolog of respiratory syncytial virus, is attenuated by host-range restriction in nonhuman primates and has a tropism for the respiratory tract. We generated MPV vectors expressing the wild-type SARS-CoV-2 spike protein...
Lymphocyte depletion is a distinctive feature of Ebola virus (EBOV) disease. The ectodomain of EBOV glycoprotein (GP) is cleaved off the surface of infected cells into circulation as shed GP. To test the hypothesis that shed GP induces lymphocyte death, we cultured primary human B, NK, or T cells with shed GP in vitro. We found that shed GP dependa...
The alternative sigma factor RpoS plays a central role in the critical host-adaptive response of the Lyme disease spirochete, Borrelia burgdorferi . We previously identified bbd18 as a negative regulator of RpoS but could not inactivate bbd18 in wild-type spirochetes. In the current study we employed an inducible bbd18 gene to demonstrate the essen...
Current vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are administered parenterally and appear to be more protective in the lower versus the upper respiratory tract. Vaccines are needed that directly stimulate immunity in the respiratory tract, as well as systemic immunity. We used avian paramyxovirus type 3 (APMV3)...
Monocyte dysfunction in helminth infection is one of the mechanisms proposed to explain the diminished parasite antigen-specific T cell responses seen with patent filarial infection. In fact, monocytes from filariae-infected individuals demonstrate internalized filarial antigens and, as a consequence, express inhibitory surface molecules and have d...
Pf bacteriophage (phage) are filamentous viruses that infect Pseudomonas aeruginosa and enhance its virulence potential. Pf virions can lyse and kill P. aeruginosa through superinfection, which occurs when an already infected cell is infected by the same or similar phage.
Chlamydia trachomatis infection causes severe inflammatory disease resulting in blindness and infertility. The pathophysiology of these diseases remains elusive but myeloid cell-associated inflammation has been implicated. Here we show NLRP3 inflammasome activation is essential for driving a macrophage-associated endometritis resulting in infertili...
The vector-borne flaviviruses (VBFVs) are well known for causing great misery and death in humans worldwide. The VBFVs include those transmitted by mosquitos, such as Zika virus (ZIKV), dengue virus; and those transmitted by ticks including the tick-borne flavivirus serocomplex and Powassan virus (POWV). Two of our recent reports showed that intrac...
Chlamydia are obligate intracellular Gram-negative bacteria distinguished by a unique developmental biology confined within a parasitophorous vacuole termed an inclusion. The chlamydial plasmid is a central virulence factor in the pathogenesis of infection. Plasmid gene protein 4 (Pgp4) regulates the expression of plasmid gene protein 3 (Pgp3) and...
We have previously shown that the microfilarial (mf) stage of Brugia malayi can inhibit the mammalian target of rapamycin (mTOR; a conserved serine/threonine kinase critical for immune regulation and cellular growth) in human dendritic cells (DC) and we have proposed that this mTOR inhibition is associated with the DC dysfunction seen in filarial i...
Significance
Interleukin 15 (IL-15) is essential for natural killer (NK) cell survival and proliferation. The IL-15 receptor consists of 3 subunits: the α chain and the β and common γ (γ c ) chains, which are shared with the IL-2 receptor. NK cells express the β-γ c chains and are activated in trans by cells presenting IL-15 bound to IL-15Rα, such...
Human RSV is the leading viral cause of severe pediatric respiratory illness. An RSV vaccine is not yet available. The RSV attachment protein G is an important protective and neutralization antigen. G contains a conserved fractalkine-like CX3C motif and is expressed in mG and sG forms. sG and the CX3C motif are thought to interfere with host immune...
Regulatory T cells (Treg cells) can activate multiple suppressive mechanisms in vitro after activation via the T cell antigen receptor, resulting in antigen-independent suppression. However, it remains unclear whether similar pathways operate in vivo. Here we found that antigen-specific Treg cells activated by dendritic cells (DCs) pulsed with two...
Activation of CD4+ T cells to proliferate drives cells toward aerobic glycolysis for energy production while using mitochondria primarily for macromolecular synthesis. In addition, the mitochondria of activated T cells increase production of reactive oxygen species, providing an important second messenger for intracellular signaling pathways. To be...
Background
Artemisinin-resistant Plasmodium falciparum has been reported throughout the Greater Mekong subregion and threatens to disrupt current malaria control efforts worldwide. Polymorphisms in kelch13 have been associated with clinical and in vitro resistance phenotypes; however, several studies suggest that the genetic determinants of resista...
Early secretion of IL-12 by mouse dendritic cells (DCs) instructs T cells to make IFN-g.However, only activated, but not naive T cells are able to license DCs for IL-12 production. We hypothesized that it might be due to different levels of CD40L expression on the surface of these cells, as CD40 signals are required for IL-12 production. Using quan...
B cells are activated by two temporally distinct signals, the first provided by the binding of antigen to the B cell antigen receptor (BCR), and the second provided by helper T cells. Here we found that B cells responded to antigen by rapidly increasing their metabolic activity, including both oxidative phosphorylation and glycolysis. In the absenc...
Key events in T cell-dependent antibody responses, including affinity maturation, are dependent on the B cell's presentation of antigen to helper T cells at critical checkpoints in germinal-center formation in secondary lymphoid organs. Here we found that signaling via Toll-like receptor 9 (TLR9) blocked the ability of antigen-specific B cells to c...
In most human and animal prion diseases the abnormal disease-associated prion protein (PrPSc) is deposited as non-amyloid aggregates in CNS, spleen and lymphoid organs. In contrast, in humans and transgenic mice with PrP mutations which cause expression of PrP lacking a glycosylphosphatidylinositol (GPI)-anchor, most PrPSc is in the amyloid form. I...
Granulibacter bethesdensis is a Gram-negative bacterium that infects patients with Chronic Granulomatous Disease (CGD), a primary immunodeficiency marked by a defect in NOX2, the phagocyte nicotinamide adenine dinucleotide phosphate oxidase. Previous studies have shown that NOX2 is essential for killing of G. bethesdensis by neutrophils and monocyt...
High-resolution microscopy techniques have advanced our understanding of lymphocyte biology. An emerging focus in the field of immunometabolism on activation-induced metabolic reprogramming and its effects on immune cell function will require in-depth analyses of mitochondria. However, even with newer imaging technologies, obtaining super-resolutio...
Tregs can employ numerous mechanisms for inhibiting immune responses. Antigen-specific Tregs exhibit enhanced capacity to suppress compared to polyclonal Tregs, but unique suppressor mechanisms used by antigen-specific Tregs have not been elucidated. We first compared the interaction of antigen-specific induced Tregs (iTregs) and antigen-specific T...
Klebsiella pneumoniae is a prominent cause of nosocomial infections worldwide. Bloodstream infections caused by carbapenem-resistant K. pneumoniae , including the epidemic lineage known as multilocus sequence type 258 (ST258), are difficult to treat and mortality is high. Thus, it is imperative that we gain a better understanding of host defense ag...
Cellular prion protein (PrPC) is a mammalian glycoprotein which is usually found anchored to the plasma membrane via a glycophosphatidylinositol (GPI) anchor. PrPC misfolds to a pathogenic isoform PrPSc, the causative agent of neurodegenerative prion diseases. The precise function of PrPC remains elusive but may depend upon its cellular localizatio...
The Zika virus (ZIKV) pandemic is a global concern due to its role in the development of congenital anomalies of the central nervous system. This mosquito-borne flavivirus alternates between mammalian and mosquito hosts, but information about the biogenesis of ZIKV is limited. Using a human neuroblastoma cell line (SK-N-SH) and an Aedes albopictus...
Importance:
Human respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are major viral agents of acute pediatric bronchiolitis and pneumonia wordwide that lack vaccines. A bivalent intranasal RSV/HPIV3 vaccine candidate consisting of a chimeric bovine/human PIV3 (rB/HPIV3) expressing RSV fusion (F) protein previously was...
The inhibitory function of killer cell immunoglobulin-like receptors (KIR) that bind HLA-C and block activation of human natural killer (NK) cells is dependent on zinc. We report that zinc induced the assembly of soluble KIR into filamentous polymers, as detected by electron microscopy, which depolymerized after zinc chelation. Similar KIR filament...
Carbapenem-resistant Klebsiella pneumoniae strains classified as multilocus sequence type 258 (ST258) are among the most widespread multidrug resistant hospital pathogens.
Treatment of infections caused by these organisms is difficult and mortality is high. The basis for the success of ST258 outside
of antibiotic resistance remains incompletely det...
Human prion diseases can have acquired, sporadic or genetic origins, each of which result in the conversion of prion protein (PrP) to transmissible, pathological forms. The genetic prion disease Gerstmann-Straussler-Scheinker (GSS) syndrome can arise from point mutations of prolines 102 or 105. However, the structural effects of these two prolines,...
Prion infections target neurons and lead to neuronal loss. However, the role of non-neuronal cells in the initiation and spread of infection throughout the brain remains unclear despite the fact these cells can also propagate prion infectivity. To evaluate how different brain cells process scrapie prion protein (PrPres) during acute infection, we e...
Primary normal human bronchial/tracheal epithelial (NHBE) cells, derived from the distal-most aspect of the trachea at the bifurcation, have been used for a number of studies in respiratory disease research. Differences between the source tissue and the differentiated primary cells may impact infection studies based on this model. Therefore, we exa...
The structure of the infectious form of prion protein, PrP(Sc), remains unclear. Most pure recombinant prion protein (PrP) amyloids generated in vitro are not infectious and lack the extent of the protease-resistant core and solvent exclusion of infectious PrP(Sc), especially within residues ~90-160. Polyanionic cofactors can enhance infectivity an...
In prion-infected hosts, PrPSc usually accumulates as non-fibrillar, membrane-bound aggregates. Glycosylphosphatidylinositol
(GPI) anchor-directed membrane association appears to be an important factor controlling the biophysical properties of PrPSc
aggregates. To determine whether GPI anchoring can similarly modulate the assembly of other amyloid-...
Staphylococcus aureus secretes numerous virulence factors that facilitate evasion of the host immune system. Among these molecules are pore-forming cytolytic toxins, including Panton-Valentine leukocidin (PVL), leukotoxin GH (LukGH; also known as LukAB), leukotoxin DE, and γ-hemolysin. PVL and LukGH have potent cytolytic activity in vitro, and both...
Unlabelled:
The majority of human Yersinia pestis infections result from introduction of bacteria into the skin by the bite of an infected flea. Once in the dermis, Y. pestis can evade the host's innate immune response and subsequently disseminate to the draining lymph node (dLN). There, the pathogen replicates to large numbers, causing the pathog...
of a paper presented at Microscopy and Microanalysis 2013 in Indianapolis, Indiana, USA, August 4 – August 8, 2013.
The chlamydial inclusion membrane is extensively modified by the insertion of type III secreted effector proteins. These inclusion membrane proteins (Incs) are exposed to the cytosol and share a common structural feature of a long, bi-lobed hydrophobic domain but little or no primary amino acid sequence similarity. Based upon secondary structural p...
Bhanja virus (BHAV) and its antigenically close relatives Forecariah (FORV), Kismayo (KISV) and Palma (PALV) viruses, are thought to be members of the family Bunyaviridae; but they have not been assigned to a genus or species. Despite their broad geographical distribution and reports that BHAV causes sporadic cases of febrile illness and encephalit...
Background
Leptospires lack many of the homologs for oxidative defense present in other bacteria, but do encode homologs of the Bacteriodes aerotolerance (Bat) proteins, which have been proposed to fulfill this function. Bat homologs have been identified in all families of the phylum Spirochaetes, yet a specific function for these proteins has not...
Distribution of bat genes in the Spirochaetes. Arrangement of bat genes in representative members of the Spirochaetes are shown compared to that found in B. fragilis. Gene fusions are denoted by *, and batE of T. denticola is significantly longer than in any other species examined (+), but does not appear to be a fusion with batD. (PDF 82 kb)
LGTV TP21-induced structures in acutely infected ISE6 cells. Animation through a z-series and 3D surface rendering of a semi-thick section of an acutely infected ISE6 cell. ER is depicted in green and vesicles & tubules in blue. Vesicles and tubules are contained within proliferated ER. Tubules are short in length, only reaching approximately twice...
LGTV TP21-induced structures in persistently infected ISE6 cells. Animation through a z-series and 3D surface rendering of a semi-thick section of a persistently infected ISE6 cell. ER is depicted in green and vesicles & tubules in blue. Numerous long tubules are seen in a large bundle; however, smaller tubules and round vesicles are also seen. The...
Tick-borne flaviviruses (TBFV) are sustained in nature through cycling between mammalian and tick hosts. In this study, we used African green monkey kidney cells (Vero) and Ixodes scapularis tick cells (ISE6) to compare virus-induced changes in mammalian and arthropod cells. Using confocal microscopy, transmission electron microscopy (TEM), and ele...
LGTV TP21-induced structures in acutely infected Vero cells. Animation through a z-series and 3D surface rendering of a semi-thick section of an acutely infected Vero cell. ER is depicted in green, vesicles in blue, and virions in red. Both virions and vesicles are contained within a network of proliferated ER. The images were aligned using Inspect...
Mammalian prions are thought to consist of misfolded aggregates (protease-resistant isoform of the prion protein [PrPres]) of the cellular prion protein (PrPC). Transmissible spongiform encephalopathy (TSE) can be induced in animals inoculated with recombinant PrP (rPrP) amyloid
fibrils lacking mammalian posttranslational modifications, but this in...
Scanning electron microscopy (SEM) remains distinct in its ability to allow topographical visualization of structures. Key elements to consider for successful examination of biological specimens include appropriate preparative and imaging techniques. Chemical processing induces structural artifacts during specimen preparation, and several factors n...
Binding of antigen to the B cell antigen receptor (BCR) triggers both BCR signaling and endocytosis. How endocytosis regulates BCR signaling remains unknown. Here we report that BCR signaling was not extinguished by endocytosis of BCRs; instead, BCR signaling initiated at the plasma membrane continued as the BCR trafficked intracellularly with the...
Mammalian prion diseases involve conversion of normal prion protein, PrP(C), to a pathological aggregated state (PrP(res)). The three-dimensional structure of PrP(res) is not known, but infrared (IR) spectroscopy has indicated high, strain-dependent β-sheet content. PrP(res) molecules usually contain a glycophosphatidylinositol (GPI) anchor and lar...
of a paper presented at Microscopy and Microanalysis 2010 in Portland, Oregon, USA, August 1 – August 5, 2010.
Mechanisms underlying the enhanced virulence phenotype of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) are incompletely defined, but presumably include evasion of killing by human polymorphonuclear leukocytes (PMNs or neutrophils). To better understand this phenomenon, we investigated the basis of rapid PMN lysis after...
Chlamydia trachomatis strains are obligate intracellular human pathogens that share near genomic synteny but have distinct infection and disease
organotropisms. The genetic basis for differences in the pathogen-host relationship among chlamydial strains is linked to
a variable region of chlamydial genomes, termed the plasticity zone (PZ). Two group...
Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres). PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen), a prote...
The intracellular pathogen Francisella tularensis is the causative agent of tularemia, a zoonosis that can affect humans with potentially lethal consequences. Essential to
Francisella virulence is its ability to survive and proliferate within phagocytes through phagosomal escape and cytosolic replication.
Francisella spp. encode a variety of acid p...
Coxiella burnetii infects mononuclear phagocytes, where it directs biogenesis of a vacuolar niche termed the parasitophorous vacuole (PV). Owing to its lumenal pH (approximately 5) and fusion with endolysosomal vesicles, the PV is considered phagolysosome-like. However, the degradative properties of the mature PV are unknown, and there are conflict...
Anthrax lethal toxin (LT) induces vascular insufficiency in experimental animals through unknown mechanisms. In this study, we show that neuronal nitric oxide synthase (nNOS) deficiency in mice causes strikingly increased sensitivity to LT, while deficiencies in the two other NOS enzymes (iNOS and eNOS) have no effect on LT-mediated mortality. The...
Echocardiography of LT-treated nNOS−/− and WT mouse heart. Mice were treated with LT (100 µg IP) and echocardiography performed at 24–28 h post toxin administration. Each symbol represents measurements for one mouse and the mean for each group is also shown. Panels show the following parameters as measured for LT-treated and untreated knockout and...
We generated a new live-attenuated vaccine against Ebola virus (EBOV) based on a chimeric virus HPIV3/DeltaF-HN/EboGP that contains the EBOV glycoprotein (GP) as the sole transmembrane envelope protein combined with the internal proteins of human parainfluenza virus type 3 (HPIV3). Electron microscopy analysis of the virus particles showed that the...
Dysregulation of professional APC has been postulated as a major mechanism underlying Ag-specific T cell hyporesponsiveness in patients with patent filarial infection. To address the nature of this dysregulation, dendritic cells (DC) and macrophages generated from elutriated monocytes were exposed to live microfilariae (mf), the parasite stage that...
Fluorescent tagging is a powerful tool for imaging proteins in living cells. However, the steric effects imposed by fluorescent tags impair the behavior of many proteins. Here, we report a novel technique, Instant with DTT, EDT, And Low temperature (IDEAL)-labeling, for rapid and specific FlAsH-labeling of tetracysteine-tagged cell surface proteins...
Using a combination of atomic force, scanning and transmission electron microscopy, we found that avian erythrocytes infected with the avian malaria parasite Plasmodium gallinaceum develop approximately 60 nm wide and approximately 430 nm long furrow-like structures on the surface. Furrows begin to appear during the early trophozoite stage of the p...
Synergistic engagement of the B cell receptor (BCR) and Toll-like receptor 9 (TLR9) in response to DNA-containing antigens underlies the production of many autoantibodies in systemic autoimmune diseases. However, the molecular basis of this synergistic engagement is not known. Given that these receptors are spatially segregated, with the BCR on the...
Electron microscopy of bacterial pathogens and interactions between bacteria and host cells and tissues provides valuable insights into structural and molecular properties and processes involved in pathogenesis. Applications for electron microscopy in bacterial pathogenesis range from discovering etiologic agents and following chronological events...
Methicillin-resistant Staphylococcus aureus (MRSA) remains a major human pathogen. Traditionally, MRSA infections occurred exclusively in hospitals and were limited to immunocompromised patients or individuals with predisposing risk factors. However, recently there has been an alarming epidemic caused by community-associated (CA)-MRSA strains, whic...
![Figure 4: Seeding rPrP-PMCA with CSF.(a) Aliquots (2 |[mu]|l) of CSF...](profile/Ryuichiro-Atarashi/publication/6195721/figure/fig2/AS:279228693139463@1443584716169/Seeding-rPrP-PMCA-with-CSFa-Aliquots-2-mul-of-CSF-taken-from-normal-hamsters-n_Q320.jpg)
The scrapie prion protein isoform, PrPSc, is a prion-associated marker that seeds the conformational conversion and polymerization of normal protease-sensitive prion protein (PrP-sen). This seeding activity allows ultrasensitive detection of PrPSc using cyclical sonicated amplification (PMCA) reactions and brain homogenate as a source of PrP-sen. H...
Human polymorphonuclear leukocytes (PMN) are a first line of defense against fungal infections. PMN express numerous pattern recognition receptors (PRR) that facilitate identification of invading microorganisms and ultimately promote resolution of disease. Dectin-1 (beta-glucan receptor) is a PRR expressed on several cell types and has been studied...
The ongoing outbreak of highly pathogenic avian influenza virus (HPAIV) in birds, the incidence of transmission to humans with a resulting high mortality rate, and the possibility of a human pandemic warrant the development of effective human vaccines against HPAIV. We developed an experimental live-attenuated vaccine for direct inoculation of the...
Methicillin‐resistant Staphylococcus aureus (MRSA) remains a major problem in hospitals, and it is now spreading in the community. A single toxin, Panton‐Valentine leukocidin
(PVL), has been linked by epidemiological studies to community‐associated MRSA (CA‐MRSA) disease. However, the role that PVL
plays in the pathogenesis of CA‐MRSA has not been...
Chronic granulomatous disease (CGD) is an inherited immune deficiency characterized by increased susceptibility to infection
with Staphylococcus, certain gram-negative bacteria, and fungi. Granulibacter bethesdensis, a newly described genus and species within the family Acetobacteraceae, was recently isolated from four CGD patients residing in geog...
The neurovirulent retroviruses FrCasE and Moloney MLV-ts1 cause noninflammatory spongiform neurodegeneration in mice, manifested clinically by progressive spasticity and paralysis. Neurons have been thought to be the primary target of toxicity of these viruses. However the neurons themselves appear not to be infected, and the possible indirect mech...
Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system causing defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections. We identified a novel gram-negative rod in excised lymph nodes from a patient with CGD. Gram-negative rods g...
Members of the genus Chlamydia are obligate intracellular pathogens that have a unique biphasic developmental cycle and interactions with host cells. Many
genes that dictate host infection tropism and, putatively, pathogenic manifestations of disease are clustered in a hypervariable
region of the genome termed the plasticity zone (PZ). Comparative...
This study demonstrates a strict temporal requirement for a virulence determinant of the Lyme disease spirochete Borrelia burgdorferi during a unique point in its natural infection cycle, which alternates between ticks and small mammals. OspC is a major surface
protein produced by B. burgdorferi when infected ticks feed but whose synthesis decrease...
Polymorphonuclear leukocytes (PMNs, or neutrophils) are critical for human innate immunity and kill most invading bacteria. However, pathogens such as Staphylococcus aureus avoid destruction by PMNs to survive, thereby causing human infections. The molecular mechanisms used by pathogens to circumvent killing by the immune system remain largely unde...
Borrelia burgdorferi sensu stricto is an etiological agent of Lyme disease. The lack of an adequate ex vivo system for human tissue infection
is an obstacle to fully understanding the molecular mechanisms of invasion of tissue by B. burgdorferi and its adaptation within the human host. Here, we report on the development of such a system. We inocula...
Type IV pili (Tfp) play central roles in prokaryotic cell biology and disease pathogenesis. As dynamic filamentous polymers, they undergo rounds of extension and retraction modelled as pilin subunit polymerization and depolymerization events. Currently, the molecular mechanisms and components influencing Tfp dynamics remain poorly understood. Using...
Invasion of the nervous system and neuronal spread of infection are critical, but poorly understood, steps in the pathogenesis of transmissible spongiform encephalopathies or prion diseases. To characterize pathways for the uptake and intraneuronal trafficking of infectious, protease-resistant prion protein (PrP-res), fluorescent-labeled PrP-res wa...
Group A Streptococcus (GAS) evades polymorphonuclear leukocyte (PMN) phagocytosis and killing to cause human disease, including pharyngitis and necrotizing fasciitis (flesh-eating syndrome). We show that GAS genes differentially regulated during phagocytic interaction with human PMNs comprise a global pathogen-protective response to innate immunity...
The LIM domain-binding protein 1 (Ldb1) is found in multi-protein complexes containing various combinations of LIM-homeodomain, LIM-only, bHLH, GATA and Otx transcription factors. These proteins exert key functions during embryogenesis. Here we show that targeted deletion of the Ldb1 gene in mice results in a pleiotropic phenotype. There is no hear...
Staphylococcus aureus preferentially catabolizes glucose, generating pyruvate, which is subsequently oxidized to acetate under aerobic growth conditions. Catabolite repression of the tricarboxylic acid (TCA) cycle results in the accumulation of acetate. TCA cycle derepression coincides with exit from the exponential growth phase, the onset of aceta...
Streptococcal inhibitor of complement (Sic) is a secreted protein made predominantly by serotype M1 Group A Streptococcus (GAS), which contributes to persistence in the mammalian upper respiratory tract and epidemics of human disease. Unexpectedly, an isogenic sic-negative mutant adhered to human epithelial cells significantly better than the wild-...
![Fig. 5. The [ 35 S]DRM conversion product is PrP. Conversion reactions](profile/Gerald-Baron-2/publication/11493758/figure/fig5/AS:281845452296193@1444208600586/The-35-SDRM-conversion-product-is-PrP-Conversion-reactions_Q320.jpg)
Prion protein (PrP) is usually attached to membranes by a glycosylphosphatidylinositol-anchor that associates with detergent-resistant membranes (DRMs), or rafts. To model the molecular processes that might occur during the initial infection of cells with exogenous transmissible spongiform encephalopathy (TSE) agents, we examined the effect of memb...
The ability of bacteria to establish complex communities on surfaces is believed to require both bacterial-substratum and bacterial-bacterial interactions, and type IV pili appear to play a critical but incompletely defined role in both these processes. Using the human pathogen Neisseria gonorrhoeae, spontaneous mutants defective in bacterial self-...
Dickkopf1 (Dkk1) is a secreted protein that acts as a Wnt inhibitor and, together with BMP inhibitors, is able to induce the formation of ectopic heads in Xenopus. Here, we show that Dkk1 null mutant embryos lack head structures anterior of the midbrain. Analysis of chimeric embryos implicates the requirement of Dkk1 in anterior axial mesendoderm b...
In vitro studies have demonstrated direct interactions between Borrelia burgdorferi and human B and T cells. However, largely because disseminated infections typically occur at very low density, little is known about associations between spirochetes and mammalian host cells in vivo. To assess whether spirochetes interact directly with lymphocytes i...
Citations
... We previously generated an MPV vaccine vector based on a recombinant version of MPV strain 15 with the L ORF encoding the MPV polymerase partially codon-pair optimized for efficient expression in humans 4,6 . Here, we evaluated a version of this MPV vector expressing the prefusion-stabilized SARS-CoV-2 S protein (S-2P; derived from strain Wuhan-1) in rhesus macaques. ...
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... Given EBOV severity in disease, it is prudent to consider that adaptive immune systems can vary by age. For example, thymic T cell development is only mainly documented during and after cytomegalovirus (CMV) infection [135]. ...
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... As a vector-borne pathogen, B. burgdorferi relies on the differential expression of several outer surface lipoproteins to transmit from its tick vector to a vertebrate host [7]. As such, a large fraction of the B. burgdorferi genome encodes outer membrane lipoproteins, mostly carried on the plasmids [6,8,9]. ...
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... The mechanisms of such suppression are diverse. They include binding the co-stimulation molecules CD80/86 on the dendritic cell by means of CTLA-4 (69); removing Ag-MHC-II from the DC surface by trans-endocytosis, in which case the DC remains capable of presenting other antigens (70)(71)(72); and a CTLA-4-mediated increase in IDO expression in the DC, which lowers the concentration of tryptophan necessary for T effectors to proliferate (73). In general, these mechanisms disrupt Ag presentation, cause T effector anergy, or trigger Ag-specific pTreg induction. ...
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... The avian paramyxovirus type 3 (APMV3) virus, which is not infective to humans, was utilized to express S in a prefusion-stabilized conformation, and then used to immunize hamsters [73]. A single intranasal vaccination elicited (i) high levels of neutralizing IgG and IgA in serum, (ii) detectable variant-transcending neutralization, and (iii) undetectable or low replication of challenging SARS-CoV-2 in the URT and LRT. ...
... Regulation of host immune cells, including monocyte/macrophage and T/B cells, is common in helminth infection. Brugia malayi can drive monocyte dysfunction via induction of indoleamine 2,3-dioxygenase, IFN-γ, or autophagy, and increase of M2 phenotype [29]. Trichinella spiralis can also inhibit polarization of M1 monocyte/macrophage [30]. ...
... We tested the possibility that HHQ present in the AQ-rich aggregates might be linked with Pf4 phage to promote localized regions of phage-mediated cell death. We examined colony biofilms of an isogenic ΔintF4 mutant strain, which lacks the integrase necessary for Pf4 bacteriophage excision-this strain is a lytic deficient mutant (50,51). Biofilms for the ΔintF4 were indistinguishable from wild type by the production of aggregates, levels of cell death, and regions of biofilm clearing (Fig. S7) and birefringence (Fig. S6). ...
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... of reducing the levels of bacterial DNA in epithelial cells and macrophages infected by Chlamydia, for example, at the same time that it increases the immune response through the activation of the NLRP3 inflammasome and the release of IL-1β [42]. However, this receptor acts in fungal infections as well, where the blockage of this receptor reduces the levels of IL-1β in polymer matrix composites infected by Candida albicans [42]. ...
... [37][38][39] Agonists of LXRs have been shown to attenuate RNA virus replication (HCV, HIV, POWV (Powassan virus), ZIKV, and CHIKV (Chikungunya virus)) via upregulation of ABCG1 and/or ABCA1 expression. 40,41 The LXR pathway is known to modulate lipid metabolism and innate immune response along with the reduction of inflammation in multiple human and mouse cells. 42,43 Likewise, our results demonstrate that induction of LXRs attenuates ZIKV replication in RPE cells and mice retinal tissue which corroborates with a recent study wherein ZIKV infection in human neuroblastoma cells was inhibited by LXR-623. ...
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... Some bacteria can evade the clearance of the immune system by inducing immune tolerance through the effectors secreted by secretion systems, and some effectors can also trigger the inflammatory response of the host. In addition, the secretion system can deliver effector proteins into host cells, causing apoptosis [114,115]. For example, T3SS manipulates P. aeruginosa to release inflammatory responses and evade phagocytosis by phagocytes to survive in the host [116]. ...
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