Lee-Ann H Allen

Lee-Ann H Allen
University of Iowa | UI · Department of Internal Medicine

PhD

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84
Publications
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Publications

Publications (84)
Article
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Neutrophils are the most abundant and shortest-lived leukocytes in humans and tight regulation of neutrophil turnover via constitutive apoptosis is essential for control of infection and resolution of inflammation. Accordingly, aberrant neutrophil turnover is hallmark of many disease states. We have shown in previous work that the intracellular bac...
Article
Full-text available
Neutrophils (polymorphonuclear leukocytes, PMNs) have a distinctively short lifespan, and tight regulation of cell survival and death is imperative for their normal function. We demonstrated previously that Francisella tularensis extends human neutrophil lifespan, which elicits an impaired immune response characterized by neutrophil dysfunction. He...
Article
T-cell activation and expansion in the tumor microenvironment (TME) are critical for antitumor immunity. Neutrophils in the TME acquire a complement-dependent T-cell suppressor phenotype that is characterized by inhibition of T-cell proliferation and activation through mechanisms distinct from those of myeloid-derived suppressor cells. In this stud...
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Neutrophils (also called polymorphonuclear leukocytes, PMNs) are heterogeneous and can exhibit considerable phenotypic and functional plasticity. In keeping with this, we discovered previously that Helicobacter pylori infection induces N1-like subtype differentiation of human PMNs that is notable for profound nuclear hypersegmentation. Herein, we u...
Article
Neutrophils are recruited rapidly to sites of infection in response to host- and/or microbe-derived proinflammatory molecules. At such sites, neutrophils phagocytose microbes and are activated to produce superoxide and other reactive oxygen species (ROS). In addition, neutrophils contain stores of antimicrobial peptides and enzymes that work in con...
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Fibromyalgia (FM) is characterized by widespread chronic pain, fatigue, and somatic symptoms. The influence of phenotypic changes in monocytes on symptoms associated with FM are not fully understood. The primary aim of this study was to take a comprehensive whole-body to molecular approach in characterizing relationships between monocyte phenotype...
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Activity-induced pain is common in those with chronic musculoskeletal pain and limits participation in daily activities and exercise. Our laboratory developed a model of activity-induced pain and shows that depletion of muscle macrophages prevents development of hyperalgesia. Adenosine triphosphate (ATP) is released from fatiguing muscle and activa...
Article
Neutrophils are a crucial first line of defense against infection, migrating rapidly into tissues where they deploy granule components and toxic oxidants for efficient phagocytosis and microbe killing. Subsequent apoptosis and clearance of dying neutrophils are essential for control of infection and resolution of the inflammatory response. A subset...
Article
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Neutrophil migration across tissue barriers to the site of injury involves integration of complex danger signals and is critical for host survival. Numerous studies demonstrate that these environmental signals fundamentally alter the responses of extravasated or “primed” neutrophils. Triggering receptor expressed on myeloid cells 1 (TREM-1) plays a...
Data
Supplemental Figure 1. A tolC mutant is cytotoxic to human macrophages. Primary human monocyte‐derived macrophages were left untreated or were infected with wild‐type LVS or the ΔtolC mutant for 24 hours and cell death was measured by quantitation of lactate dehydrogenase release. Data are the mean + SEM of five independent experiments. p‐values we...
Article
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F. tularensis infects several cell types including neutrophils, and aberrant neutrophil accumulation contributes to tissue destruction during tularemia. We demonstrated previously that F. tularensis strains Schu S4 and LVS markedly delay human neutrophil apoptosis and thereby prolong cell lifespan, but the bacterial factors that mediate this aspect...
Article
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In this issue of Blood, Prince et al provide fundamental insight into the function of proteins in the NR4A orphan nuclear receptor protein family, identifying NR4A2 and NR4A3 as critical regulators of neutrophil lifespan and homeostasis, and demonstrating that they act via a cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA)-dependent...
Article
Francisella novicida is a Gram-negative bacterium that is closely related to the highly virulent facultative intracellular pathogen, Francisella tularensis Data published by us and others demonstrate that F. tularensis virulence correlates directly with its ability to impair constitutive apoptosis and extend human neutrophil lifespan. In contrast,...
Article
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Helicobacter pylori infects the human stomach and causes a spectrum of disease that includes gastritis, peptic ulcers, and gastric adenocarcinoma. A chronic, neutrophil-rich inflammatory response characterizes this infection. It is established that H. pylori stimulates neutrophil chemotaxis and a robust respiratory burst, but other aspects of this...
Article
Francisella tularensis in an intracellular bacterial pathogen that causes a potentially lethal disease called tularemia. Studies performed nearly 100 years ago revealed that neutrophil accumulation in infected tissues correlates directly with the extent of necrotic damage during F. tularensis infection. However, the dynamics and details of bacteria...
Article
Tularemia is a disease characterized by profound neutrophil accumulation and tissue destruction. The causative organism, Francisella tularensis, is a facultative intracellular bacterium that replicates in neutrophil cytosol, inhibits caspase activation and profoundly prolongs cell lifespan. Here, we identify unique features of this infection and pr...
Article
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Regular physical activity in healthy individuals prevents development of chronic musculoskeletal pain; however, the mechanisms underlying this exercise-induced analgesia are not well understood. Interleukin-10(IL-10), an anti-inflammatory cytokine which can reduce nociceptor sensitization, increases during regular physical activity. Since macrophag...
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The lipopolysaccharide (LPS) and O-antigen polysaccharide capsule structures of Francisella tularensis play significant roles in helping these highly virulent bacteria avoid detection within a host. We previously created pools of F. tularensis mutants that we screened to identify strains that were not reactive to a monoclonal antibody to the O-anti...
Article
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Francisella tularensis is a Gram-negative, facultative intracellular pathogen that replicates in the cytosol of macrophages and is the causative agent of the potentially fatal disease tularemia. A characteristic feature of F. tularensis is its limited proinflammatory capacity, but the mechanisms that underlie the diminished host response to this or...
Article
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Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed to effectively treat some cancers. However, many cancers such as metastatic prostate cancer have yet to be treated with current smart drug technology. Here, we describe the thorough preclinical characte...
Article
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Neutrophils (also called polymorphonuclear leukocytes, PMNs) are the most abundant white blood cells in humans and play a central role in innate host defense. Another distinguishing feature of PMNs is their short lifespan. Specifically, these cells survive for less than 24 hours in the bloodstream and are inherently pre-programed to die by constitu...
Article
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The central role of neutrophils in innate immunity and host defense has long been recognized, and the ability of these cells to efficiently engulf and kill invading bacteria has been extensively studied, as has the role of neutrophil apoptosis in resolution of the inflammatory response. In the past few years additional immunoregulatory properties o...
Article
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The Francisella tularensis pathogenicity island (FPI) encodes many proteins that are required for virulence. Expression of these genes depends upon the FevR (PigR) regulator and its interactions with the MglA/SspA and RNA polymerase transcriptional complex. Experiments to identify how transcription of the FPI genes is activated have led to identifi...
Article
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Francisella tularensis is a facultative intracellular bacterial pathogen and the causative agent of tularemia. After infection of macrophages, this organism escapes from its phagosome and replicates to high density in the cytosol, but the bacterial factors required for these aspects of virulence are incompletely defined. Here we describe the isolat...
Article
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We demonstrated recently that Francisella tularensis profoundly impairs human neutrophil apoptosis, but how this is achieved is largely unknown. Herein we used human oligonucleotide microarrays to test the hypothesis that changes in neutrophil gene expression contribute to this phenotype, and now demonstrate that F. tularensis live vaccine strain (...
Article
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A fundamental step in the life cycle of Francisella tularensis is bacterial entry into host cells. F. tularensis activates complement, and recent data suggest that the classical pathway is required for complement factor C3 deposition on the bacterial surface. Nevertheless, C3 deposition is inefficient and neither the specific serum components neces...
Article
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Flavocytochrome b(558), the catalytic core of the phagocyte NADPH oxidase (NOX2), mediates electron transfer from NADPH to molecular oxygen to generate superoxide, the precursor of highly ROS for host defense. Flavocytochrome b(558) is an integral membrane heterodimer consisting of a large glycosylated subunit, gp91(phox), and a smaller subunit, p2...
Article
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Francisella tularensis is a facultative intracellular bacterium that infects many cell types, including neutrophils. We demonstrated previously that F. tularensis inhibits NADPH oxidase assembly and activity and then escapes the phagosome to the cytosol, but effects on other aspects of neutrophil function are unknown. Neutrophils are short-lived ce...
Article
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A workshop organized by the Society for Leukocyte Biology offered advice to young scientists on how to decipher the grant-submission process of the US National Institutes of Health and compose a clear, compelling and fundable grant.
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The life stages of Leishmania spp. include the infectious promastigote and the replicative intracellular amastigote. Each stage is phagocytosed by macrophages during the parasite life cycle. We previously showed that caveolae, a subset of cholesterol-rich membrane lipid rafts, facilitate uptake and intracellular survival of virulent promastigotes b...
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Francisella tularensis is capable of rampant intracellular growth and causes a potentially fatal disease in humans. Whereas many mutational studies have been performed with avirulent strains of Francisella, relatively little has been done with strains that cause human disease. We generated a near-saturating transposon library in the virulent strain...
Article
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Ft is a facultative intracellular pathogen that infects many cell types, including neutrophils. In previous work, we demonstrated that the type B Ft strain LVS disrupts NADPH oxidase activity throughout human neutrophils, but how this is achieved is incompletely defined. Here, we used several type A and type B strains to demonstrate that Ft-mediate...
Article
The remarkable infectiousness of Francisella tularensis suggests that the bacterium efficiently evades innate immune responses that typically protect the host during its continuous exposure to environmental and commensal microbes. In our studies of the innate immune response to F. tularensis, we have observed that, unlike the live vaccine strain (L...
Article
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Francisella tularensis, the etiological agent of tularemia, is capable of infecting a wide range of animals and causes a severe, lethal disease in humans. The pathogen evades killing by cells of the innate immune system utilizing genes encoding a pathogenicity island, including iglABCD, and instead utilizes these cells as a niche for replication an...
Article
Full-text available
Flavocytochrome b(558), the catalytic core of the phagocytic NADPH oxidase, mediates the transfer of electrons from NADPH to molecular oxygen to generate superoxide for host defense. Flavocytochrome b is a membrane heterodimer consisting of a large subunit gp91(phox) (NOX2) and a smaller subunit, p22(phox). Although in neutrophils flavocytochrome b...
Article
Full-text available
Francisella tularensis is a facultative intracellular pathogen and the causative agent of tularemia. We have shown that F. tularensis subspecies holarctica strain LVS prevents NADPH oxidase assembly and activation in human neutrophils, but how this is achieved is unclear. Herein, we used random transposon mutagenesis to identify LVS genes that affe...
Article
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Helicobacter pylori is a Gram-negative bacterium that colonizes the gastric epithelium and plays a causative role in the development of peptic ulcers and gastric cancer. Phagocytosis is an element of innate defense used by macrophages and neutrophils to engulf microorganisms. We and others have shown that strains of H. pylori that contain the cag p...
Article
Neutrophils accumulate rapidly at sites of infection, and the ability of these cells to phagocytose and kill microorganisms is an essential component of the innate immune response. Relatively few microbial pathogens are able to evade neutrophil killing. Herein, we describe the novel strategies used by Helicobacter pylori and Francisella tularensis...
Article
Helicobacter pylori is a spiral-shaped, flagellated, microaerophilic Gram-negative bacterium that colonizes the gastric epithelium of humans. All persons infected with H. pylori have gastritis, and some will develop severe disease such as peptic ulcers or gastric cancer. A characteristic feature of this infection is the pronounced accumulation of p...
Article
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Otoconia are small biominerals in the inner ear that are indispensable for the normal perception of gravity and motion. Normal otoconia biogenesis requires Nox3, a Nox (NADPH oxidase) highly expressed in the vestibular system. In HEK-293 cells (human embryonic kidney cells) transfected with the Nox regulatory subunits NoxO1 (Nox organizer 1) and No...
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Neutrophils are short-lived granulocytes essential for innate host defense. We describe here methods for analysis of resting and activated cells using immunofluorescence and confocal microscopy. Procedures for stimulation of adherent and suspended cells are provided along with protocols for particle opsonization and synchronized phagocytosis. Most...
Article
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Francisella tularensis is a Gram-negative bacterium and the causative agent of tularemia. Recent data indicate that F. tularensis replicates inside macrophages, but its fate in other cell types, including human neutrophils, is unclear. We now show that F. tularensis live vaccine strain (LVS), opsonized with normal human serum, was rapidly ingested...
Article
Full-text available
Francisella tularensis (Ft) is a Gram-negative bacterium and the causative agent of tularemia. It is well established that this organism replicates inside macrophages, but we are only beginning to understand this interface at the molecular level. Herein, we compared directly the ability of Ft subspecies holarctica live-vaccine strain to infect fres...
Article
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Previous studies have demonstrated that Helicobacter pylori (Hp) delays its entry into macrophages and persists inside megasomes, which are poorly acidified and accumulate early endosome autoantigen 1. Herein, we explored the role of Hp urease in bacterial survival in murine peritoneal macrophages and J774 cells. Plasmid-free mutagenesis was used t...
Article
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Tularemia is a zoonosis of humans caused by infection with the facultative intracellular bacterium Francisella tularensis. Interest in F. tularensis has increased markedly in the past few years because of its potential use as an agent of bioterrorism. Five subspecies of this organism are found in the Northern hemisphere, but only F. tularensis subs...
Article
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We have shown previously that ulcerogenic (type I) strains of Helicobacter pylori (Hp) retard their entry into macrophages. However, the signaling pathways that regulate Hp phagocytosis are largely undefined. We show here that Hp strongly activated class IA phosphoinositide3-kinases (PI3Ks) in macrophages, coincident with phagocytosis, and endogeno...
Article
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Helicobacter pylori (Hp) infection triggers a chronic influx of polymorphonuclear leukocyte neutrophils (PMNs) into the gastric mucosa. Although Hp reside in a neutrophil-rich environment, how these organisms evade phagocytic killing is largely unexplored. We now show that live Hp (strains 11637, 60190, DT61A, and 11916) are readily ingested by PMN...
Article
Few microorganisms evade killing by neutrophils. Summarized here are the mechanisms used by Yersinia, group A streptococci, Helicobacter, Ehrlichia and Francisella to block phagocytosis, disrupt phagosome maturation or perturb the respiratory burst. Also discussed are mechanisms used by neutrophils to control organisms that replicate inside macroph...
Article
Phagocytosis is a rapid actin-dependent endocytic process used by macrophages and neutrophils to ingest and kill microorganisms. Perturbation of phagocytosis is central to the ability of some pathogenic microbes to cause disease, and we demonstrated previously that the ulcerogenic bacterium Helicobacter pylori (Hp) actively retards its uptake by ma...
Article
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During phagocytosis, macrophages rapidly internalize a substantial fraction of plasma membrane without a net loss of surface area, suggesting that membranes are targeted to the cell surface from intracellular sites. Nevertheless, a requirement for mobilization of specific membrane compartments has not been demonstrated. We used bone marrow-derived...
Article
Recent advances in our understanding of Helicobacter pylori-phagocyte interactions indicate that these organisms actively modulate phagocyte function in order to retard phagocytosis, while simultaneously inducing a strong respiratory burst. The central players in this dynamic include H. pylori neutrophil activating protein and factors that are asso...
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Salmonella typhimurium requires a type III secretion system encoded by pathogenicity island (SPI)-2 to survive and proliferate within macrophages. This survival implies that S. typhimurium avoids or withstands bactericidal events targeted to the microbe-containing vacuole, which include intraphagosomal production of reactive oxygen species (ROS), p...
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To investigate the physiological function of the VAMP3 vesicle SNARE (v-SNARE) isoform in the regulation of GLUT4 vesicle trafficking, we generated homozygotic VAMP3 null mice by targeted gene disruption. The VAMP3 null mice had typical growth rate and weight gain, with normal maintenance of fasting serum glucose and insulin levels. Analysis of glu...
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Expression of SH2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), a hematopoietic cell-specific adapter protein, is required to couple Syk family tyrosine kinase activation to downstream mediators such as phospholipase C (PLC)-gamma following TCR, platelet collagen receptor and mast cell Fc epsilon R stimulation. In addition...
Article
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Helicobacter pylori (Hp) is a highly successful human pathogen that has colonized the gastric mucosa of approximately half of the world's population. Infection with this gram-negative bacterium induces a state of chronic inflammation that does not resolve the underlying infection and often leads to