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Teresa Krakauer
Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, United States of America

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Research article
Published: 11 February 2021 in PLOS Neglected Tropical Diseases
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Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a major cause of sepsis and mortality in endemic regions of Southeast Asia and Northern Australia. B. pseudomallei is a potential bioterrorism agent due to its high infectivity, especially via inhalation, and its inherent resistance to antimicrobials. There is currently no vaccine for melioidosis and antibiotic treatment can fail due to innate drug resistance, delayed diagnosis and treatment, or insufficient duration of treatment. A well-characterized animal model that mimics human melioidosis is needed for the development of new medical countermeasures. This study first characterized the disease progression of melioidosis in the African green monkey (AGM) and rhesus macaque (RM) for non-human primate model down-selection. All AGMs developed acute lethal disease similar to that described in human acute infection following exposure to aerosolized B. pseudomallei strain HBPUB10134a. Only 20% of RMs succumbed to acute disease. Disease progression, immune response and pathology of two other strains of B. pseudomallei, K96243 and MSHR5855, were also compared using AGMs. These three B. pseudomallei strains represent a highly virulent strain from Thailand (HBPUB101034a), a highly virulent strains from Australia (MSHR5855), and a commonly used laboratory strains originating from Thailand (K96243). Animals were observed for clinical signs of infection and blood samples were analyzed for cytokine responses, blood chemistry and leukocyte changes in order to characterize bacterial infection. AGMs experienced fever after exposure to aerosolized B. pseudomallei at the onset of acute disease. Inflammation, abscesses and/or pyogranulomas were observed in lung with all three strains of B. pseudomallei. Inflammation, abscesses and/or pyogranulomas were observed in lymph nodes, spleen, liver and/or kidney with B. pseudomallei, HBPUB10134a and K96243. Additionally, the Australian strain MSHR5855 induced brain lesions in one AGM similar to clinical cases of melioidosis seen in Australia. Elevated serum levels of IL-1β, IL-1 receptor antagonist, IL-6, MCP-1, G-CSF, HGF, IFNγ, MIG, I-TAC, and MIP-1β at terminal end points can be significantly correlated with non-survivors with B. pseudomallei infection in AGM. The AGM model represents an acute model of B. pseudomallei infection for all three strains from two geographical locations and will be useful for efficacy testing of vaccines and therapeutics against melioidosis. In summary, a dysregulated immune response leading to excessive persistent inflammation and inflammatory cell death is the key driver of acute melioidosis. Early intervention in these pathways will be necessary to counter B. pseudomallei and mitigate the pathological consequences of melioidosis.

ACS Style

Sylvia R. Trevino; Jennifer L. Dankmeyer; David P. Fetterer; Christopher P. Klimko; Jo Lynne W. Raymond; Alicia M. Moreau; Carl Soffler; David M. Waag; Patricia L. Worsham; Kei Amemiya; Sara I. Ruiz; Christopher K. Cote; Teresa Krakauer. Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model. PLOS Neglected Tropical Diseases 2021, 15, e0009125 .

AMA Style

Sylvia R. Trevino, Jennifer L. Dankmeyer, David P. Fetterer, Christopher P. Klimko, Jo Lynne W. Raymond, Alicia M. Moreau, Carl Soffler, David M. Waag, Patricia L. Worsham, Kei Amemiya, Sara I. Ruiz, Christopher K. Cote, Teresa Krakauer. Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model. PLOS Neglected Tropical Diseases. 2021; 15 (2):e0009125.

Chicago/Turabian Style

Sylvia R. Trevino; Jennifer L. Dankmeyer; David P. Fetterer; Christopher P. Klimko; Jo Lynne W. Raymond; Alicia M. Moreau; Carl Soffler; David M. Waag; Patricia L. Worsham; Kei Amemiya; Sara I. Ruiz; Christopher K. Cote; Teresa Krakauer. 2021. "Comparative virulence of three different strains of Burkholderia pseudomallei in an aerosol non-human primate model." PLOS Neglected Tropical Diseases 15, no. 2: e0009125.

Review
Published: 23 March 2019 in Toxins
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Staphylococcal enterotoxin B (SEB) and related superantigenic toxins produced by Staphylococcus aureus are potent activators of the immune system. These protein toxins bind to major histocompatibility complex (MHC) class II molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the activation of both monocytes/macrophages and T lymphocytes. The bridging of TCRs with MHC class II molecules by superantigens triggers an early “cytokine storm” and massive polyclonal T-cell proliferation. Proinflammatory cytokines, tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 elicit fever, inflammation, multiple organ injury, hypotension, and lethal shock. Upon MHC/TCR ligation, superantigens induce signaling pathways, including mitogen-activated protein kinase cascades and cytokine receptor signaling, which results in NFκB activation and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. In addition, gene profiling studies have revealed the essential roles of innate antimicrobial defense genes in the pathogenesis of SEB. The genes expressed in a murine model of SEB-induced shock include intracellular DNA/RNA sensors, apoptosis/DNA damage-related molecules, endoplasmic reticulum/mitochondrial stress responses, immunoproteasome components, and IFN-stimulated genes. This review focuses on the signaling pathways induced by superantigens that lead to the activation of inflammation and damage response genes. The induction of these damage response genes provides evidence that SEB induces danger signals in host cells, resulting in multiorgan injury and toxic shock. Therapeutics targeting both host inflammatory and cell death pathways can potentially mitigate the toxic effects of staphylococcal superantigens.

ACS Style

Teresa Krakauer. Staphylococcal Superantigens: Pyrogenic Toxins Induce Toxic Shock. Toxins 2019, 11, 178 .

AMA Style

Teresa Krakauer. Staphylococcal Superantigens: Pyrogenic Toxins Induce Toxic Shock. Toxins. 2019; 11 (3):178.

Chicago/Turabian Style

Teresa Krakauer. 2019. "Staphylococcal Superantigens: Pyrogenic Toxins Induce Toxic Shock." Toxins 11, no. 3: 178.

Review article
Published: 08 January 2019 in Mediators of Inflammation
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Inflammasome activation is an innate host defense mechanism initiated upon sensing pathogens or danger in the cytosol. Both autophagy and cell death are cell autonomous processes important in development, as well as in host defense against intracellular bacteria. Inflammasome, autophagy, and cell death pathways can be activated by pathogens, pathogen-associated molecular patterns (PAMPs), cell stress, and host-derived damage-associated molecular patterns (DAMPs). Phagocytosis and toll-like receptor (TLR) signaling induce reactive oxygen species (ROS), type I IFN, NFκB activation of proinflammatory cytokines, and the mitogen-activated protein kinase cascade. ROS and IFNγare also prominent inducers of autophagy. Pathogens, PAMPs, and DAMPs activate TLRs and intracellular inflammasomes, inducing apoptotic and inflammatory caspases in a context-dependent manner to promote various forms of cell death to eliminate pathogens. Common downstream signaling molecules of inflammasomes, autophagy, and cell death pathways interact to initiate appropriate measures against pathogens and determine host survival as well as pathological consequences of infection. The integration of inflammasome activation, autophagy, and cell death is central to pathogen clearance. Various pathogens produce virulence factors to control inflammasomes, subvert autophagy, and modulate host cell death in order to evade host defense. This review highlights the interaction of inflammasomes, autophagy, and host cell death pathways in counteractingBurkholderia pseudomallei, the causative agent of melioidosis. Contrasting evasion strategies used byB.pseudomallei,Mycobacterium tuberculosis, andLegionella pneumophilato avoid and dampen these innate immune responses will be discussed.

ACS Style

Teresa Krakauer. Inflammasomes, Autophagy, and Cell Death: The Trinity of Innate Host Defense against Intracellular Bacteria. Mediators of Inflammation 2019, 2019, 1 -10.

AMA Style

Teresa Krakauer. Inflammasomes, Autophagy, and Cell Death: The Trinity of Innate Host Defense against Intracellular Bacteria. Mediators of Inflammation. 2019; 2019 ():1-10.

Chicago/Turabian Style

Teresa Krakauer. 2019. "Inflammasomes, Autophagy, and Cell Death: The Trinity of Innate Host Defense against Intracellular Bacteria." Mediators of Inflammation 2019, no. : 1-10.

Journal article
Published: 14 September 2018 in Medical Hypotheses
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Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is a major cause of sepsis and mortality in endemic regions of Southeast Asia and Northern Australia. As a facultative intracellular pathogen, B. pseudomallei produces virulence factors to evade innate host response and survive within host cells. Neutrophils and macrophages are phagocytes that play critical roles in host defense against pathogens by their ability to detect and eliminate microbes. Host defense processes against B. pseudomallei including phagocytosis, oxidative burst, autophagy, apoptosis, and proinflammatory cytokine release are all initiated by these two phagocytes in the fight against this bacterium. In vitro studies with mouse macrophage cell lines revealed multiple evasion strategies used by B. pseudomallei to counteract these innate processes. B. pseudomallei invades and replicates in neutrophils but little is known regarding its evasion mechanisms. The bidirectional interaction of neutrophils and macrophages in controlling B. pseudomallei infection has also been overlooked. Here the hypothesis that B. pseudomallei hijacks neutrophils and uses them to transport and infect new phagocytes is proposed as an evasion strategy to survive and persist in host phagocytes. This two-pronged approach by B. pseudomallei to replicate in two different types of phagocytes and to modulate their cell death modes is effective in promoting persistence and survival of the bacterium.

ACS Style

Teresa Krakauer. Living dangerously: Burkholderia pseudomallei modulates phagocyte cell death to survive. Medical Hypotheses 2018, 121, 64 -69.

AMA Style

Teresa Krakauer. Living dangerously: Burkholderia pseudomallei modulates phagocyte cell death to survive. Medical Hypotheses. 2018; 121 ():64-69.

Chicago/Turabian Style

Teresa Krakauer. 2018. "Living dangerously: Burkholderia pseudomallei modulates phagocyte cell death to survive." Medical Hypotheses 121, no. : 64-69.

Review
Published: 01 May 2017 in ImmunoTargets and Therapy
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FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights Teresa Krakauer Department of Immunology, Molecular Translational Sciences Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, USA Immunostimulating staphylococcal enterotoxin B (SEB) and related superantigenic toxins cause diseases in human beings and laboratory animals by hyperactivating cells of the immune system. These protein toxins bind to the major histocompatibility complex class II (MHC II) molecules and specific Vβ regions of T-cell receptors (TCRs), resulting in the stimulation of both monocytes/macrophages and T lymphocytes. The bridging of TCR with MHC II molecules by superantigens triggers intracellular signaling cascades, resulting in excessive release of proinflammatory mediators and massive polyclonal T-cell proliferation. The early induction of tumor necrosis factor α, interleukin 1 (IL-1), interleukin 2 (IL-2), interferon gamma (IFNγ), and macrophage chemoattractant protein 1 promotes fever, inflammation, and multiple organ injury. The signal transduction pathways for staphylococcal superantigen-induced toxicity downstream from TCR/major histocompatibility complex (MHC) ligation and interaction of cell surface co-stimulatory molecules include the mitogen-activated protein kinase cascades and cytokine receptor signaling, activating nuclear factor kB (NFkB) and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. Knowledge of host regulation within these activated pathways and molecules initiated by SEB and other superantigens enables the selection of US Food and Drug Administration (FDA)-approved drugs to interrupt and prevent superantigen-induced shock in animal models. This review focuses on the use of FDA-approved immunosuppressants in targeting the signaling pathways induced by staphylococcal superantigens. Keywords: immunosuppressant, superantigen, toxic shock, NFkB, mTORC1

ACS Style

Teresa Krakauer. FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights. ImmunoTargets and Therapy 2017, ume 6, 17 -29.

AMA Style

Teresa Krakauer. FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights. ImmunoTargets and Therapy. 2017; ume 6 ():17-29.

Chicago/Turabian Style

Teresa Krakauer. 2017. "FDA-approved immunosuppressants targeting staphylococcal superantigens: mechanisms and insights." ImmunoTargets and Therapy ume 6, no. : 17-29.

Review article
Published: 02 February 2016 in Frontiers in Immunology
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Staphylococcal enterotoxin B (SEB) of Staphylococcus aureus, and related superantigenic toxins produced by myriad microbes, are potent stimulators of the immune system causing a variety of human diseases from transient food poisoning to lethal toxic shock. These protein toxins bind directly to specific V regions of T-cell receptors (TCR) and major histocompatibility complex (MHC) class II on antigen-presenting cells, resulting in hyperactivation of T lymphocytes and monocytes / macrophages. Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines, especially tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 causing clinical symptoms of fever, hypotension, and shock. Because of superantigen-induced T cells skewed towards TH1 helper cells, and the induction of proinflammatory cytokines, superantigens can exacerbate autoimmune diseases. Upon TCR / MHC ligation, pathways induced by superantigens include the mitogen-activated protein kinase cascades and cytokine receptor signaling, resulting in activation of NFκB and the phosphoinositide 3-kinase / mammalian target of rapamycin pathways. Various mouse models exist to study SEB-induced shock including those with potentiating agents, transgenic mice and an “SEB-only” model. However, therapeutics to treat toxic shock remain elusive as host response genes central to pathogenesis of superantigens have only been identified recently. Gene profiling of a murine model for SEB-induced shock reveals novel molecules upregulated in multiple organs not previously associated with SEB-induced responses. The pivotal genes include intracellular DNA / RNA sensors, apoptosis / DNA damage-related molecules, immunoproteasome components, as well as anti-viral and IFN-stimulated genes. The host-wide induction of these, and other, anti-microbial defense genes provide evidence that SEB elicits danger signals resulting in multi-organ damage and toxic shock. Ultimately, these discoveries might lead to novel therapeutics for various superantigen-based diseases.

ACS Style

Teresa Krakauer; Kisha Epradhan; Bradley G. Stiles. Staphylococcal Superantigens Spark Host-Mediated Danger Signals. Frontiers in Immunology 2016, 7, 23 .

AMA Style

Teresa Krakauer, Kisha Epradhan, Bradley G. Stiles. Staphylococcal Superantigens Spark Host-Mediated Danger Signals. Frontiers in Immunology. 2016; 7 ():23.

Chicago/Turabian Style

Teresa Krakauer; Kisha Epradhan; Bradley G. Stiles. 2016. "Staphylococcal Superantigens Spark Host-Mediated Danger Signals." Frontiers in Immunology 7, no. : 23.

Editorial
Published: 08 January 2016 in Toxins
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Note: In lieu of an abstract, this is an excerpt from the first page. The special issue “Enterotoxins: Microbial Proteins and Host Cell Dysregulation” is comprised of research articles and reviews covering a diverse group of toxins that affect the gut and dysregulate host immune response in mechanistically different ways.

ACS Style

Teresa Krakauer. Enterotoxins: Microbial Proteins and Host Cell Dysregulation. Toxins 2016, 8, 17 .

AMA Style

Teresa Krakauer. Enterotoxins: Microbial Proteins and Host Cell Dysregulation. Toxins. 2016; 8 (1):17.

Chicago/Turabian Style

Teresa Krakauer. 2016. "Enterotoxins: Microbial Proteins and Host Cell Dysregulation." Toxins 8, no. 1: 17.

Journal article
Published: 01 December 2015 in Medical Hypotheses
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The mechanisms leading to higher risks of infection in diabetics remain unknown despite recent advances in the understanding of associated immunological and metabolic aberrations. Hyperglycemia and hyperlipidemia in diabetics not only contribute to altered metabolism but glucose and free fatty acids can directly activate inflammation and the production of the proinflammatory cytokine interleukin 1β (IL-1β). Long-chain saturated fatty acids activate toll-like receptor 4 (TLR4), generating diacylglycerol and activating protein kinase C to upregulate the Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway. High glucose uptake switches cell metabolism from oxidative phosphorylation to glycolysis and deactivates AMP-activated protein kinase (AMPK), a critical sensor of nutrient and cellular energy, leading to mTORC1 activation. A deleterious consequence of mTORC1 activation is the suppression of autophagy which is a catabolic process for the lysosomal degradation of damaged organelles, protein aggregates and intracellular pathogens. In addition, high glucose concentration and fatty acids independently activate inflammasome, an intracellular multi-protein complex that promotes the proteolytic activation of caspase 1, leading to the processing and secretion of IL-1β. Other caspases induced by inflammasome can trigger apoptotic cell death. A common upstream signal for the activation of inflammasome and mTORC1 is oxidative stress, which generates reactive oxygen species (ROS) from dysregulated mitochondria. Increased flux of glucose and lipids activates stress kinases, enhances electron transport, and generates ROS in mitochondria. Mitochondrial stress arising from increased mitochondrial respiration and permeability damages mitochondria, activates caspases, which then induce apoptosis via the intrinsic cell death pathway releasing mitochondrial DNA. Normally apoptosis is down-regulated by autophagy as autophagy removes damaged organelles as a result of danger and stress signals. However, in diabetics, hyperactivation of mTORC1 disrupts the host autophagic degradation of microbes and damaged mitochondria which in turn exacerbates inflammasome activation and alters cell resistance to infection. Recognition of viral lipids and bacterial components by host cell pattern recognition receptors including TLR activates NFκB and stress kinase c-jun N-terminal kinase (JNK) signaling. The transcription factor NFκB and JNK independently induce inflammatory cytokines, chemokines, and further activate inflammasome. The convergence of inflammasome and mTORC1 activation with metabolic stress and vascular dysfunction in diabetics prevents pathogen clearance and contributes to an increased risk of infection.

ACS Style

Teresa Krakauer. Inflammasome, mTORC1 activation, and metabolic derangement contribute to the susceptibility of diabetics to infections. Medical Hypotheses 2015, 85, 997 -1001.

AMA Style

Teresa Krakauer. Inflammasome, mTORC1 activation, and metabolic derangement contribute to the susceptibility of diabetics to infections. Medical Hypotheses. 2015; 85 (6):997-1001.

Chicago/Turabian Style

Teresa Krakauer. 2015. "Inflammasome, mTORC1 activation, and metabolic derangement contribute to the susceptibility of diabetics to infections." Medical Hypotheses 85, no. 6: 997-1001.