Bispecific antibody targets multiple Pseudomonas aeruginosa evasion mechanisms in the lung vasculature

Thanabalasuriar, Ajitha; Surewaard, Bas G.J.; Willson, Michelle Elizabeth; Neupane, Arpan Sharma; Stover, C. Kendall; Warrener, Paul; Wilson, George; Keller, Ashley; Sellman, Bret R.; DiGiandomenico, Antonio; Kubes, Paul

doi:10.1172/jci89652

Cited by 72 publications

(87 citation statements)

References 30 publications

(44 reference statements)

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“…Mice were anesthetized and livers and lungs were prepared for intravital microscopy as previously described (Surewaard and Kubes, 2017; Thanabalasuriar et al, 2017). Skin was prepared as described recently (Jenne et al, 2011; Yipp et al, 2012).…”

Section: Star Methodsmentioning

confidence: 99%

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

Surewaard

Thanabalasuriar

Zeng

et al. 2018

Cell Host & Microbe

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109

112

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During sepsis, small blood vessels can become occluded by large platelet aggregates of poorly understood etiology. During Staphylococcal aureus infection, sepsis severity is linked to the bacterial α-toxin (α-hemolysin, AT) through unclear mechanisms. In this study, we visualized intravascular events in the microcirculation and found that intravenous AT injection induces rapid platelet aggregation, forming dynamic micro-thrombi in the microcirculation. These aggregates are retained in the liver sinusoids and kidney glomeruli, causing multi-organ dysfunction. Acute staphylococcal infection results in sequestration of most bacteria by liver macrophages. Platelets are initially recruited to these macrophages and help eradicate S. aureus. However, at later time points, AT causes aberrant and damaging thrombosis throughout the liver. Treatment with an AT neutralizing antibody (MEDI4893) prevents platelet aggregation and subsequent liver damage, without affecting the initial and beneficial platelet recruitment. Thus, AT neutralization may represent a promising approach to combat staphylococcal-induced intravascular coagulation and organ dysfunction.

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Section: Star Methodsmentioning

confidence: 99%

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

Surewaard

Thanabalasuriar

Zeng

et al. 2018

Cell Host & Microbe

Self Cite

109

112

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“…The microscope was equipped with a LumPlan 40×/0.8 numerical aperture (NA) 20× water immersion objective and digitally recorded with an Olympus DP71 charge‐coupled device video camera and Olympus FluoView 1000 imaging software. Some experiments were carried out using the imaging system as described in . Images and 3D reconstructions were carried out using Image J and MatLab.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, bacteria harbor versatile mechanisms to reduce phagocyte functionality. For example, P. aeruginosa alters the dynamics of cytoskeletal changes associated with phagocytosis, blocks ROS synthesis, and escapes phagocytic vacuoles via effectors released by the type III secretion system …”

Section: Introductionmentioning

confidence: 99%

Frontline Science: Employing enzymatic treatment options for management of ocular biofilm-based infections

Kugadas

Geddes‐McAlister

Guy

et al. 2019

Journal of Leukocyte Biology

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Pseudomonas aeruginosa ‐induced corneal keratitis is a sight‐threatening disease. The rise of antibiotic resistance among P. aeruginosa keratitis isolates makes treatment of this disease challenging, emphasizing the need for alternative therapeutic modalities. By comparing the responses to P. aeruginosa infection between an outbred mouse strain (Swiss Webster, SW) and a susceptible mouse strain (C57BL6/N), we found that the inherent neutrophil‐killing abilities of these strains correlated with their susceptibility to infection. Namely, SW‐derived neutrophils were significantly more efficient at killing P. aeruginosa in vitro than C57BL6/N‐derived neutrophils. To interrogate whether the distinct neutrophil killing capacities were dependent on endogenous or exogenous factors, neutrophil progenitor cell lines were generated. The in vitro differentiated neutrophils from either SW or C57BL6/N progenitors retained the differential killing abilities, illustrating that endogenous factors conferred resistance. Consistently, quantitative LC‐MS/MS analysis revealed strain‐specific and infection‐induced alterations of neutrophil proteomes. Among the distinctly elevated proteins in the SW‐derived proteomes were α‐mannosidases, potentially associated with protection. Inhibition of α‐mannosidases reduced neutrophil bactericidal functions in vitro. Conversely, topical application of α‐mannosidases reduced bacterial biofilms and burden of infected corneas. Cumulatively, these data suggest novel therapeutic approaches to control bacterial biofilm assembly and improve bacterial clearance via enzymatic treatments.

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“…It was found that a virulence factor, specifically the exopolysaccharide Psl, allowed Pseudomonas aeruginosa to cloak itself from the neutrophils. Targeting this virulence factor with a therapeutic antibody unveiled the bacteria to the neutrophils and allowed phagocytosis . Interestingly, Pseudomonas aeruginosa utilized another virulence factor, the type III secretion system, to secrete effector molecules that hindered intracellular killing by the neutrophils.…”

Section: Systemic Infectionsmentioning

confidence: 99%

“…18 In a more physiologic model of infection with Escherichia coli, Yipp et al showed that these pathways, where effector responses were turned on in minutes, play a crucial role in the rapid capture of Escherichia coli during bloodstream infections. 18 Thanabalasuriar et al 19 used IVM to study another pathogen, Pseudomonas aeruginosa. In this study, Pseudomonas aeruginosa was observed adhering to the lung vasculature during systemic infection and, remarkably, resident patrolling neutrophils were unable to recognize and clear the bacteria.…”

Section: Systemic Infections: Imaging the Lungmentioning

confidence: 99%

Unraveling the host's immune response to infection: Seeing is believing

Scott

Sarkar

Kratofil

et al. 2019

Journal of Leukocyte Biology

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It has long been appreciated that understanding the interactions between the host and the pathogens that make us sick is critical for the prevention and treatment of disease. As antibiotics become increasingly ineffective, targeting the host and specific bacterial evasion mechanisms are becoming novel therapeutic approaches. The technology used to understand host‐pathogen interactions has dramatically advanced over the last century. We have moved away from using simple in vitro assays focused on single‐cell events to technologies that allow us to observe complex multicellular interactions in real time in live animals. Specifically, intravital microscopy (IVM) has improved our understanding of infection, from viral to bacterial to parasitic, and how the host immune system responds to these infections. Yet, at the same time it has allowed us to appreciate just how complex these interactions are and that current experimental models still have a number of limitations. In this review, we will discuss the advances in vivo IVM has brought to the study of host‐pathogen interactions, focusing primarily on bacterial infections and innate immunity.

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Bispecific antibody targets multiple Pseudomonas aeruginosa evasion mechanisms in the lung vasculature

Cited by 72 publications

References 30 publications

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

Frontline Science: Employing enzymatic treatment options for management of ocular biofilm-based infections

Unraveling the host's immune response to infection: Seeing is believing

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