The coagulopathy and vasculopathy of sepsis remain common disabling and life-threatening complications of infection that are increasing in incidence as human populations escalate with the prevalence and virulence of infectious organisms. Lack of sufficient knowledge of the pathophysiology of sepsis is represented by the paucity and ineffectiveness of current treatments. We have recently made discoveries that reveal a novel interaction between the host and pathogen in pneumococcal sepsis during which host glycoproteins in the blood and vasculature undergo a post-translational remodeling that alters their homeostasis and function. This remodeling results in asialoglycoproteins deficient in sialic acid linkages that are then selectively recognized by the endocytic Ashwell-Morell receptor (AMR). Asialoglycoproteins are formed by neuraminidases that hydrolyze sialic acid linkages or by a deficiency of one or more sialyltransferases. Asialoglycoprotein modulation by the AMR results in a profound mitigation of coagulopathy, vasculopathy, and mortality in pneumococcal sepsis. The present application represents an expanded investigation of the role of glycoprotein remodeling in the pathogenesis of coagulopathy and endothelial dysfunction during sepsis. The project takes continued advantage of a unique synergistic and productive interdisciplinary integration of glycobiology, molecular and cell biology with microbiology, immunology and infectious disease modeling that has to date produced unexpected and paradigm changing observations -- ones that carry strong translational implications for novel therapeutics. Glycoprotein remodeling will be modulated genetically in the mouse by targeting the biochemical pathways responsible for biologically important modifications involving terminal sialylation (host sialyltransferases ST3Gal-I and ST3Gal-IV) and by modulating the rapid and powerful asialoglycoprotein clearance function of the hepatic AMR - as we have recently published. From the microbiology perspective, we will expand our studies beyond our published work on Streptococcus pneumoniae (SPN) to include two other major human pathogens associated with invasive bloodstream infections and sepsis, Staphylococcus aureus (SA) and group A Streptococcus (GAS). Additional mechanistic insight will be provided through analysis of virulence factors express by these bacteria that provoke pathogenic coagulation and microvascular dysfunction (coagulases, M protein), including the use of isogenic bacterial mutants. Human tissue culture studies will explore the effects of glycoprotein remodeling on interactions between bacterial sepsis pathogens, coagulation proteins, neutrophils and endothelium. In vivo live infection models with wild-type and genetically engineered mice will guide therapeutic manipulation of glycoprotein remodeling, to identify tools to improve coagulation parameters, endothelial function, bacterial clearance and clinical outcomes in sepsis.
Sepsis is a major cause of human suffering and death, afflicting a million or more people in the U.S. each year. Death as an outcome averages 30%, underscoring our incomplete knowledge of pathogen-host interactions and the absence of more effective therapeutics. This proposal seeks to transform our understanding and treatment of sepsis by research focused on a newly discovered mechanism of pathogen-host interaction and a related possible new treatment that targets the coagulopathy and vasculopathy of this deadly syndrome.
|Askarian, Fatemeh; Wagner, Theresa; Johannessen, Mona et al. (2018) Staphylococcus aureus modulation of innate immune responses through Toll-like (TLR), (NOD)-like (NLR) and C-type lectin (CLR) receptors. FEMS Microbiol Rev 42:656-671|
|Yang, Won Ho; Heithoff, Douglas M; Aziz, Peter V et al. (2018) Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis. Cell Host Microbe 24:500-513.e5|
|Askarian, Fatemeh; Lapek Jr, John D; Dongre, Mitesh et al. (2018) Staphylococcus aureus Membrane-Derived Vesicles Promote Bacterial Virulence and Confer Protective Immunity in Murine Infection Models. Front Microbiol 9:262|
|Gupta, Naveen; Liu, Roland; Shin, Stephanie et al. (2018) SCH79797 improves outcomes in experimental bacterial pneumonia by boosting neutrophil killing and direct antibiotic activity. J Antimicrob Chemother 73:1586-1594|
|Gupta, Naveen; Sinha, Ranjeet; Krasnodembskaya, Anna et al. (2018) The TLR4-PAR1 Axis Regulates Bone Marrow Mesenchymal Stromal Cell Survival and Therapeutic Capacity in Experimental Bacterial Pneumonia. Stem Cells 36:796-806|
|Yamasaki, Tokiwa; Deki-Arima, Norie; Kaneko, Asahito et al. (2017) Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7. Sci Rep 7:7348|
|Escajadillo, Tamara; Olson, Joshua; Luk, Brian T et al. (2017) A Red Blood Cell Membrane-Camouflaged Nanoparticle Counteracts Streptolysin O-Mediated Virulence Phenotypes of Invasive Group A Streptococcus. Front Pharmacol 8:477|
|Ersoy, Selvi C; Heithoff, Douglas M; Barnes 5th, Lucien et al. (2017) Correcting a Fundamental Flaw in the Paradigm for Antimicrobial Susceptibility Testing. EBioMedicine 20:173-181|
|Yang, Won Ho; Heithoff, Douglas M; Aziz, Peter V et al. (2017) Recurrent infection progressively disables host protection against intestinal inflammation. Science 358:|
|Thamphiwatana, Soracha; Angsantikul, Pavimol; Escajadillo, Tamara et al. (2017) Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management. Proc Natl Acad Sci U S A 114:11488-11493|
Showing the most recent 10 out of 22 publications