28 results on '"Thanabalasuriar, Ajitha"'
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2. Visualizing the function and fate of neutrophils in sterile injury and repair
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Wang, Jing, Hossain, Mokarram, Thanabalasuriar, Ajitha, Gunzer, Matthias, Meininger, Cynthia, and Kubes, Paul
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- 2017
3. Bispecific antibody targets multiple pseudomonas aeruginosa evasion mechanisms in the lung vasculature
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Thanabalasuriar, Ajitha, Surewaard, Bas G.J., Willson, Michelle E., Neupane, Arpan S., Stover, Charles K., Warrener, Paul, Wilson, George, Keller, Ashley E., Sellman, Bret R., DiGiandomenico, Antonio, and Kubes, Paul
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Antibodies -- Health aspects -- Analysis ,Lung diseases -- Prevention ,Pseudomonas aeruginosa -- Health aspects -- Analysis ,Health care industry - Abstract
Pseudomonas aeruginosa is a major cause of severe infections that lead to bacteremia and high patient mortality. P. aeruginosa has evolved numerous evasion and subversion mechanisms that work in concert to overcome immune recognition and effector functions in hospitalized and immunosuppressed individuals. Here, we have used multilaser spinning-disk intravital microscopy to monitor the blood-borne stage in a murine bacteremic model of P. aeruginosa infection. P. aeruginosa adhered avidly to lung vasculature, where patrolling neutrophils and other immune cells were virtually blind to the pathogen's presence. This cloaking phenomenon was attributed to expression of Psl exopolysaccharide. Although an antiPsl mAb activated complement and enhanced neutrophil recognition of P. aeruginosa, neutrophil-mediated clearance of the pathogen was suboptimal owing to a second subversion mechanism, namely the type 3 secretion (T3S) injectisome. Indeed, T3S prevented phagosome acidification and resisted killing inside these compartments. Antibody-mediated inhibition of the T3S protein PcrV did not enhance bacterial phagocytosis but did enhance killing of the few bacteria ingested by neutrophils. A bispecific mAb targeting both Psl and PcrV enhanced neutrophil uptake of P. aeruginosa and also greatly increased inhibition of T3S function, allowing for phagosome acidification and bacterial killing. These data highlight the need to block multiple evasion and subversion mechanisms in tandem to kill P. aeruginosa., Introduction Pseudomonas aeruginosa is an important opportunistic bacterial pathogen that causes life-threatening infections in critically ill and immunocompromised individuals. It is one of the most common causes of Gram-negative pneumonia [...]
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- 2017
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4. The inhibition of COPII trafficking is important for intestinal epithelial tight junction disruption during enteropathogenic Escherichia coli and Citrobacter rodentium infection
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Thanabalasuriar, Ajitha, Kim, Jinoh, and Gruenheid, Samantha
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- 2013
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5. Resident macrophages of the lung and liver: The guardians of our tissues.
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Kulle, Amelia, Thanabalasuriar, Ajitha, Cohen, Taylor S., and Szydlowska, Marta
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Resident macrophages play a unique role in the maintenance of tissue function. As phagocytes, they are an essential first line defenders against pathogens and much of the initial characterization of these cells was focused on their interaction with viral and bacterial pathogens. However, these cells are increasingly recognized as contributing to more than just host defense. Through cytokine production, receptor engagement and gap junction communication resident macrophages tune tissue inflammatory tone, influence adaptive immune cell phenotype and regulate tissue structure and function. This review highlights resident macrophages in the liver and lung as they hold unique roles in the maintenance of the interface between the circulatory system and the external environment. As such, we detail the developmental origin of these cells, their contribution to host defense and the array of tools these cells use to regulate tissue homeostasis. [ABSTRACT FROM AUTHOR]
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- 2022
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6. From infection to repair: Understanding the workings of our innate immune cells.
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Mawhinney, Martin, Kulle, Amelia, and Thanabalasuriar, Ajitha
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- 2022
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7. The bacterial virulence factor NleAʼs involvement in intestinal tight junction disruption during enteropathogenic E. coli infection is independent of its putative PDZ binding domain
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Thanabalasuriar, Ajitha, Koutsouris, Athanasia, Hecht, Gail, and Gruenheid, Samantha
- Published
- 2010
8. PD-L1+ neutrophils contribute to injury-induced infection susceptibility.
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Thanabalasuriar, Ajitha, Chiang, Abby J., Morehouse, Christopher, Camara, Margarita, Hawkins, Shonda, Keller, Ashley E., Koksal, Adem C., Caceres, Carolina S., Berlin, Aaron A., Holoweckyj, Nicholas, Takahashi, Virginia N., Cheng, Lily, de los Reyes, Melissa, Pelletier, Mark, Patera, Andriani C., Sellman, Bret, Hess, Sonja, Marelli, Marcello, Boo, Chelsea C., and Cohen, Taylor S.
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NEUTROPHILS , *PSEUDOMONAS aeruginosa infections , *HAIR growth - Abstract
The article presents a study that explores the programmed death ligand 1 (PD-L1) neutrophils contribute to injury-induced infection susceptibility. It describes a rapid increase in neutrophil cell numbers in the lungs following induction of thermal injury. It provides evidence that injury promotes changes to neutrophils that are important for wound healing but contribute to infection susceptibility.
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- 2021
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9. Unraveling the host's immune response to infection: Seeing is believing.
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Scott, Brittney N.V., Sarkar, Tina, Kratofil, Rachel M., Kubes, Paul, and Thanabalasuriar, Ajitha
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IMMUNE response ,BACTERIAL diseases ,NATURAL immunity ,THERAPEUTICS ,INFECTION - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2019
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10. Neonates, antibiotics and the microbiome
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Thanabalasuriar, Ajitha and Kubes, Paul
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Microbiota (Symbiotic organisms) -- Health aspects -- Research ,Antibiotics -- Health aspects -- Usage -- Research ,Infants (Newborn) -- Health aspects -- Research ,Biological sciences ,Health - Abstract
As babies leave their mothers' wombs, they are colonized by commensal bacteria. A new study shows that these microbes in a newborn's gut can promote an increase in circulating neutrophils that can guard the body from infections. Altering a neonate's gut microbiota with perinatal antibiotic treatment can impair neutrophils, leaving the newborn vulnerable to attack by harmful bacteria (pages 524-530)., Globally, around 4 million newborn babies die yearly due to sepsis (1). Prolonged use of antibiotics is currently under clinical practice in the interest of preventing early-onset sepsis in newborns [...]
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- 2014
11. Visualizing the function and fate of neutrophils in sterile injury and repair.
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Jing Wang, Hossain, Mokarram, Thanabalasuriar, Ajitha, Gunzer, Matthias, Meininger, Cynthia, and Kubes, Paul
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- 2017
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12. iNKT Cell Emigration out of the Lung Vasculature Requires Neutrophils and Monocyte-Derived Dendritic Cells in Inflammation.
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Thanabalasuriar, Ajitha, Neupane, Arpan S., Wang, Jing, Krummel, Matthew F., and Kubes, Paul
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Summary iNKT cells are a subset of innate T cells that recognize glycolipids presented on CD1d molecules and protect against bacterial infections, including S. pneumoniae . Using lung intravital imaging, we examined the behavior and mechanism of pulmonary iNKT cell activation in response to the specific iNKT cell ligand α-galactosylceramide or S. pneumoniae infection. In untreated mice, the major fraction of iNKT cells resided in the vasculature, but a small critical population resided in the extravascular space in proximity to monocyte-derived DCs. Administration of either α-GalCer or S. pneumoniae induced CD1d-dependent rapid recruitment of neutrophils out of the vasculature. The neutrophils guided iNKT cells from the lung vasculature via CCL17. Depletion of monocyte-derived DCs abrogated both the neutrophil and subsequent iNKT cell extravasation. Moreover, impairing iNKT cell recruitment by blocking CCL17 increased susceptibility to S. pneumoniae infection, suggesting a critical role for the influx of iNKT cells in host defense. [ABSTRACT FROM AUTHOR]
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- 2016
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13. Identification of Potentially Diarrheagenic Atypical Enteropathogenic Escherichia coli Strains Present in Canadian Food Animals at Slaughter and in Retail Meats.
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Comery, Raven, Thanabalasuriar, Ajitha, Garneau, Philippe, Portt, Andrea, Boerlin, Patrick, Reid-Smith, Richard J., Harel, Josée, Manges, Amee R., and Gruenheid, Samantha
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ESCHERICHIA coli , *BACTERIAL genetics , *FOOD animals , *MICROBIAL virulence -- Molecular aspects , *PATHOGENIC microorganisms , *VIRULENCE of bacteria , *DISEASES - Abstract
This study identified and characterized enteropathogenic Escherichia coli (EPEC) in the Canadian food supply. Eighteen of 450 E. coli isolates from food animal sources were identified as atypical EPEC (aEPEC). Several of the aEPEC isolates identified in this study possessed multiple virulence genes, exhibited adherence and attaching and effacing (ME) lesion formation, disrupted tight junctions, and were coclassified with the extraintestinal pathogenic E. coli (EXPEC) and enterotoxigenic E. coli (ETEC) pathotypes. [ABSTRACT FROM AUTHOR]
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- 2013
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14. Sec24 interaction is essential for localization and virulence-associated function of the bacterial effector protein NleA.
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Thanabalasuriar, Ajitha, Bergeron, Julien, Gillingham, Akira, Mimee, Mark, Thomassin, Jenny-Lee, Strynadka, Nathalie, Kim, Jinoh, and Gruenheid, Samantha
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MICROBIAL virulence , *BACTERIAL proteins , *ESCHERICHIA coli O157:H7 , *GUT microbiome , *FOOD pathogens , *DIARRHEA - Abstract
Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC) are food-borne pathogens that cause severe diarrhoeal disease in humans. Citrobacter rodentium is a related mouse pathogen that serves as a small animal model for EPEC and EHEC infections. EPEC, EHEC and C. rodentium translocate bacterial virulence proteins directly into host cells via a type III secretion system (T3SS). Non-LEE-encoded effector A (NleA) is a T3SS effector that is common to EPEC, EHEC and C. rodentium and is required for bacterial virulence. NleA localizes to the host cell secretory pathway and inhibits vesicle trafficking by interacting with the Sec24 subunit of mammalian coatamer protein II complex (COPII). Mammalian cells express four paralogues of Sec24 (Sec24A-D), which mediate selection of cargo proteins for transport and possess distinct, but overlapping cargo specificities. Here, we show that NleA binds Sec24A-D with two distinct mechanisms. An NleA protein variant with greatly diminished interaction with all Sec24 paralogues does not properly localize, does not inhibit COPII-mediated vesicle budding, and does not confer virulence in the mouse infection model. Together, this work provides strong evidence that the interaction and inhibition of COPII by NleA is an important aspect of EPEC- and EHEC-mediated disease. [ABSTRACT FROM AUTHOR]
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- 2012
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15. The bacterial virulence factor NleA is required for the disruption of intestinal tight junctions by enteropathogenic Escherichia coli.
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Thanabalasuriar, Ajitha, Koutsouris, Athanasia, Weflen, Andrew, Mimee, Mark, Hecht, Gail, and Gruenheid, Samantha
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ESCHERICHIA coli , *EPITHELIAL cells , *SMALL intestine , *PROTEINS , *INTESTINES , *CELLS - Abstract
Enteropathogenic Escherichia coli (EPEC) is a diarrhoeal pathogen that adheres to epithelial cells of the small intestine and uses a type III secretion system to inject effector proteins into host cells. EPEC infection leads to disruption of host intestinal tight junctions that are important for maintaining intestinal barrier function. This disruption is dependent on the bacterial type III secretion system, as well as the translocated effectors EspF and Map. Here we show that a third type III translocated bacterial effector protein, NleA, is also involved in tight junction disruption during EPEC infection. Using the drug Brefeldin A, we demonstrate that the effect of NleA on tight junction integrity is related to its inhibition of host cell protein trafficking through COPII-dependent pathways. These results suggest that NleA's striking effect on virulence is mediated, at least in part, via its role in disruption of intestinal barrier function. [ABSTRACT FROM AUTHOR]
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- 2010
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16. Characterization of the NleF effector protein from attaching and effacing bacterial pathogens.
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Echtenkamp, Frank, Deng, Wanyin, Wickham, Mark E., Vazquez, Alejandra, Puente, Jose L., Thanabalasuriar, Ajitha, Gruenheid, Samantha, Finlay, B. Brett, and Hardwidge, Philip R.
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SCIENTIFIC experimentation ,ESCHERICHIA coli O157:H7 ,PATHOGENIC microorganisms ,HEMORRHAGIC diseases ,SECRETION ,CELL physiology ,GERMFREE animals ,PIGLETS ,ESCHERICHIA coli - Abstract
Enterohemorrhagic Escherichia coli (EHEC) is a water- and food-borne pathogen that causes hemorrhagic colitis. EHEC uses a type III secretion system (T3SS) to translocate effector proteins that subvert host cell function. T3SS-substrates encoded outside of the locus of enterocyte effacement are important to E. coli pathogenesis. We discovered an EHEC secreted protein, NleF, encoded by z6020 in O-island 71 of E. coli EDL933 that we hypothesized to be a T3SS substrate. Experiments are presented that probe the function of NleF and its role in virulence. Immunoblotting of secreted and translocated proteins suggest that NleF is secreted by the T3SS and is translocated into host cells in vitro where it localizes to the host cytoplasm. Infection of HeLa cells with E. coli possessing or lacking nleF and transient expression of NleF-GFP via transfection did not reveal a significant role for NleF in several assays of bacterial adherence, host cytoskeletal remodeling, or host protein secretion. However, competitive coinfection of mice with Citrobacter rodentium strains possessing or lacking nleF suggested a contribution of NleF to bacterial colonization. Challenge of gnotobiotic piglets also revealed a role for NleF in colonization of the piglet colon and rectoanal junction. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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17. The Bacterial Virulence Factor NleA Inhibits Cellular Protein Secretion by Disrupting Mammalian COPII Function.
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Kim, Jinoh, Thanabalasuriar, Ajitha, Chaworth-Musters, Tessa, Fromme, J. Chris, Frey, Elizabeth A., Lario, Paula I., Metalnikov, Pavel, Rizg, Keyrillos, Thomas, Nikhil A., Lee, Sau Fung, Hartland, Elizabeth L., Hardwidge, Philip R., Pawson, Tony, Strynadka, Natalie C., Finlay, B. Brett, Schekman, Randy, and Gruenheid, Samantha
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ESCHERICHIA coli ,MICROBIAL virulence ,PATHOGENIC microorganisms ,MICROBIAL invasiveness - Abstract
Summary: Enterohemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC) maintain an extracellular lifestyle and use a type III secretion system to translocate effector proteins into the host cytosol. These effectors manipulate host pathways to favor bacterial replication and survival. NleA is an EHEC/EPEC- and related species-specific translocated effector protein that is essential for bacterial virulence. However, the mechanism by which NleA impacts virulence remains undetermined. Here we demonstrate that NleA compromises the Sec23/24 complex, a component of the mammalian COPII protein coat that shapes intracellular protein transport vesicles, by directly binding Sec24. Expression of an NleA-GFP fusion protein reduces the efficiency of cellular secretion by 50%, and secretion is inhibited in EPEC-infected cells. Direct biochemical experiments show that NleA inhibits COPII-dependent protein export from the endoplasmic reticulum. Collectively, these findings indicate that disruption of COPII function in host cells contributes to the virulence of EPEC and EHEC. [Copyright &y& Elsevier]
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- 2007
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18. Proteomics: An advanced tool to unravel the role of alveolar macrophages in respiratory diseases.
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Chiang, Abby J., Thanabalasuriar, Ajitha, and Boo, Chelsea C.
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ALVEOLAR macrophages , *RESPIRATORY diseases , *LUNG diseases - Abstract
• Alveolar macrophages are the first line of defense against external insults and maintain lung homeostasis. • Proteomics applications have been used to study the multifaceted roles of AMs in different respiratory diseases. • Advanced proteomics technologies help identify potential candidates in AMs that can be targeted for diagnosis and therapy. As we learn more about chronic lung diseases, we are seeing that an unbalanced immune system plays a key role in disease pathogenesis. Innate immune cells, particularly tissue-resident macrophages, are important navigators of immunity, both during infection and in non-communicable lung disease. In the lung, alveolar macrophages are considered some of the most critical and diverse immune cells, yet despite an array of studies over the years, alveolar macrophages remain poorly understood. In this review, we highlight the importance of alveolar macrophages in health and disease, and discuss how proteomics can be used to elucidate mechanistic information and identify potential targets for therapy development. [ABSTRACT FROM AUTHOR]
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- 2021
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19. Rise and shine: Open your eyes to produce anti‐inflammatory NETs.
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Thanabalasuriar, Ajitha and Kubes, Paul
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LACTOFERRIN ,BIMATOPROST ,DRY eye syndromes ,PERIPHERAL circulation - Abstract
An editorial is presented on the immune privileged eye with recruitment of neutrophils via neutrophil extracellular trap (NET) formation. It discusses the importance of microbiota to the eye health, activation of IL-8, presence of commensals on ocular surface related to the production of immunoglobulin A (IgA).
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- 2019
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20. Neutrophil Extracellular Traps Confine Pseudomonas aeruginosa Ocular Biofilms and Restrict Brain Invasion.
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Thanabalasuriar, Ajitha, Scott, Brittney Noelle Vivian, Peiseler, Moritz, Willson, Michelle Elizabeth, Zeng, Zhutian, Warrener, Paul, Keller, Ashley Elaine, Surewaard, Bas Gerardus Johannes, Dozier, Elizabeth Ashley, Korhonen, Juha Tapio, Cheng, Lily I-ting, Gadjeva, Mihaela, Stover, C. Kendall, DiGiandomenico, Antonio, and Kubes, Paul
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Summary Bacterial biofilm infections are difficult to eradicate because of antibiotic insusceptibility and high recurrence rates. Biofilm formation by Pseudomonas aeruginosa , a leading cause of bacterial keratitis, is facilitated by the bacterial Psl exopolysaccharide and associated with heightened virulence. Using intravital microscopy, we observed that neutrophilic recruitment to corneal infections limits P. aeruginosa biofilms to the outer eye surface, preventing bacterial dissemination. Neutrophils moved to the base of forming biofilms, where they underwent neutrophil extracellular trap formation (NETosis) in response to high expression of the bacterial type-3 secretion system (T3SS). NETs formed a barrier "dead zone," confining bacteria to the external corneal environment and inhibiting bacterial dissemination into the brain. Once formed, ocular biofilms were resistant to antibiotics and neutrophil killing, advancing eye pathology. However, blocking both Psl and T3SS together with antibiotic treatment broke down the biofilm and reversed keratitis, suggesting future therapeutic strategies for this intractable infection. Graphical Abstract Highlights • P. aeruginosa keratitis infections result in biofilm formation on the cornea • NETs form at the base of the biofilm, triggered by the type-3 secretion system (T3SS) • NETs stop bacterial dissemination into the brain but promote antibiotic resistance • Blocking exopolysaccharide Psl and the T3SS allowed neutrophils to break down the biofilm Thanabalasuriar et al. characterize the interplay between neutrophils and Pseudomonas biofilms on the cornea. At the base of the biofilm, neutrophils encountered expression of the type-3 secretion system, leading to an expansive deposition of neutrophil extracellular traps (NETs). NET formation impeded bacterial dissemination into the brain yet promoted antibiotic resistance. [ABSTRACT FROM AUTHOR]
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- 2019
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21. α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis.
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Surewaard, Bas G.J., Thanabalasuriar, Ajitha, Zeng, Zhutian, Tkaczyk, Christine, Cohen, Taylor S., Bardoel, Bart W., Jorch, Selina K., Deppermann, Carsten, Bubeck Wardenburg, Juliane, Davis, Rachelle P., Jenne, Craig N., Stover, Kendall C., Sellman, Bret R., and Kubes, Paul
- Abstract
Summary 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. [ABSTRACT FROM AUTHOR]
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- 2018
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22. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature.
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Kolaczkowska, Elzbieta, Jenne, Craig N., Surewaard, Bas G. J., Thanabalasuriar, Ajitha, Lee, Woo-Yong, Sanz, Maria-Jesus, Mowen, Kerri, Opdenakker, Ghislain, and Kubes, Paul
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- 2015
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23. R-Spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea.
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Papapietro, Olivier, Teatero, Sarah, Thanabalasuriar, Ajitha, Yuki, Kyoko E., Diez, Eduardo, Zhu, Lei, Kang, Eugene, Dhillon, Sandeep, Muise, Aleixo M., Durocher, Yves, Marcinkiewicz, Martin M., Malo, Danielle, and Gruenheid, Samantha
- Abstract
Citrobacter rodentium is a natural mouse pathogen widely used as a model for enteropathogenic and enterohemorrhagic Escherichia coli infections in humans. While C. rodentium causes self-limiting colitis in most inbred mouse strains, it induces fatal diarrhoea in susceptible strains. The physiological pathways as well as the genetic determinants leading to susceptibility have remained largely uncharacterized. Here we use a forward genetic approach to identify the R-spondin2 gene as a major determinant of susceptibility to C. rodentium infection. Robust induction of R-spondin2 expression during infection in susceptible mouse strains causes a potent Wnt-mediated proliferative response of colonic crypt cells, leading to the generation of an immature and poorly differentiated colonic epithelium with deficiencies in ion-transport components. Our data demonstrate a previously unknown role of R-spondins and Wnt signalling in susceptibility to infectious diarrhoea and identify R-spondin2 as a key molecular link between infection and intestinal homoeostasis. [ABSTRACT FROM AUTHOR]
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- 2013
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24. Phosphorylated YDXV Motifs and Nck SH2/SH3 Adaptors Act Cooperatively To Induce Actin Reorganization.
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Blasutig, Ivan M., New, Laura A., Thanabalasuriar, Ajitha, Dayarathna, Thamara K., Goudreault, Marilyn, Quaggin, Susan E., Li, Shawn S.-C., Gruenheid, Samantha, Jones, Nina, and Pawson, Tony
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ACTIN ,PROTEINS ,PHOSPHORYLATION ,POLYMERIZATION ,ESCHERICHIA coli - Abstract
We have analyzed the means by which the Nck family of adaptor proteins couples adhesion proteins to actin reorganization. The nephrin adhesion protein is essential for the formation of actin-based foot processes in glomerular podocytes. The clustering of nephrin induces its tyrosine phosphorylation, Nck recruitment, and sustained localized actin polymerization. Any one of three phosphorylated (p)YDXV motifs on nephrin is sufficient to recruit Nck through its Src homology 2 (SH2) domain and induce localized actin polymerization at these clusters. Similarly, Nck SH3 mutants in which only the second or third SH3 domain is functional can mediate nephrin-induced actin polymerization. However, combining such nephrin and Nck mutants attenuates actin polymerization at nephrin-Nck clusters. We propose that the multiple Nck SH2-binding motifs on nephrin and the multiple SH3 domains of Nck act cooperatively to recruit the high local concentration of effectors at sites of nephrin activation that is required to initiate and maintain actin polymerization in vivo. We also find that YDXV motifs in the Tir protein of enteropathogenic Escherichia coli and nephrin are functionally interchangeable, indicating that Tir reorganizes the actin cytoskeleton by molecular mimicry of nephrin-like signaling. Together, these data identify pYDXV/Nck signaling as a potent and portable mechanism for physiological and pathological actin regulation. [ABSTRACT FROM AUTHOR]
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- 2008
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25. Patrolling Alveolar Macrophages Conceal Bacteria from the Immune System to Maintain Homeostasis.
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Neupane, Arpan Sharma, Willson, Michelle, Chojnacki, Andrew Krzysztof, Vargas E Silva Castanheira, Fernanda, Morehouse, Christopher, Carestia, Agostina, Keller, Ashley Elaine, Peiseler, Moritz, DiGiandomenico, Antonio, Kelly, Margaret Mary, Amrein, Matthias, Jenne, Craig, Thanabalasuriar, Ajitha, and Kubes, Paul
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ALVEOLAR macrophages , *INTERFERON gamma , *IMMUNE system , *NEUTROPHILS , *HOMEOSTASIS , *MUCOCILIARY system , *INTERFERON receptors , *VIRUS diseases - Abstract
During respiration, humans breathe in more than 10,000 liters of non-sterile air daily, allowing some pathogens access to alveoli. Interestingly, alveoli outnumber alveolar macrophages (AMs), which favors alveoli devoid of AMs. If AMs, like most tissue macrophages, are sessile, then this numerical advantage would be exploited by pathogens unless neutrophils from the blood stream intervened. However, this would translate to omnipresent persistent inflammation. Developing in vivo real-time intravital imaging of alveoli revealed AMs crawling in and between alveoli using the pores of Kohn. Importantly, these macrophages sensed, chemotaxed, and, with high efficiency, phagocytosed inhaled bacterial pathogens such as P. aeruginosa and S. aureus , cloaking the bacteria from neutrophils. Impairing AM chemotaxis toward bacteria induced superfluous neutrophil recruitment, leading to inappropriate inflammation and injury. In a disease context, influenza A virus infection impaired AM crawling via the type II interferon signaling pathway, and this greatly increased secondary bacterial co-infection. • AMs patrol and clean the alveolar spaces • AMs have directed movement toward inhaled bacteria • AM migration is crucial for bacterial clearance • AM migration is impaired during viral infection Neupane et al. develop an intravital method to image alveolar macrophages in the lung in real time, overcoming the challenge presented by the air-liquid-air barrier of the alveoli. They use this in vivo approach to show that alveolar macrophages move between alveoli to provide efficient immune surveillance of the airway and phagocytosis of inhaled bacteria before they can induce harmful lung inflammation. Furthermore, they show that respiratory virus infections can interfere with alveolar macrophage surveillance, leading to bacterial superinfection. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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26. Intravital Microscopy for Imaging and Live Cell Tracking of Alveolar Macrophages in Real Time.
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Kwak A and Thanabalasuriar A
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- Animals, Mice, Lung cytology, Host-Pathogen Interactions, Macrophages, Alveolar cytology, Intravital Microscopy methods, Cell Tracking methods
- Abstract
Classic in vitro coculture assays of pathogens with host cells have contributed significantly to our understanding of the intracellular lifestyle of several pathogens. Coculture assays with pathogens and eukaryotic cells can be analyzed through various techniques including plating for colony-forming units (CFU), confocal microscopy, and flow cytometry. However, findings from in vitro assays require validation in an in vivo model. Several physiological conditions can influence host-pathogen interactions, which cannot easily be mimicked in vitro. Intravital microscopy (IVM) is emerging as a powerful tool for studying host-pathogen interactions by enabling in vivo imaging of living organisms. As a result, IVM has significantly enhanced the understanding of infection mediated by diverse pathogens. The versatility of IVM has also allowed for the imaging of various organs as sites of local infection. This chapter specifically focuses on IVM conducted on the lung for elucidating pulmonary immune response, primarily involving alveolar macrophages, to pathogens. Additionally, in this chapter we outline the protocol for lung IVM that utilizes a thoracic suction window to stabilize the lung for acquiring stable images., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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27. PD-L1 + neutrophils contribute to injury-induced infection susceptibility.
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Thanabalasuriar A, Chiang AJ, Morehouse C, Camara M, Hawkins S, Keller AE, Koksal AC, Caceres CS, Berlin AA, Holoweckyj N, Takahashi VN, Cheng L, de Los Reyes M, Pelletier M, Patera AC, Sellman B, Hess S, Marelli M, Boo CC, Cohen TS, and DiGiandomenico A
- Abstract
The underlying mechanisms contributing to injury-induced infection susceptibility remain poorly understood. Here, we describe a rapid increase in neutrophil cell numbers in the lungs following induction of thermal injury. These neutrophils expressed elevated levels of programmed death ligand 1 (PD-L1) and exhibited altered gene expression profiles indicative of a reparative population. Upon injury, neutrophils migrate from the bone marrow to the skin but transiently arrest in the lung vasculature. Arrested neutrophils interact with programmed cell death protein 1 (PD-1) on lung endothelial cells. A period of susceptibility to infection is linked to PD-L1
+ neutrophil accumulation in the lung. Systemic treatment of injured animals with an anti-PD-L1 antibody prevented neutrophil accumulation in the lung and reduced susceptibility to infection but augmented skin healing, resulting in increased epidermal growth. This work provides evidence that injury promotes changes to neutrophils that are important for wound healing but contribute to infection susceptibility., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)- Published
- 2021
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28. Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver.
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Choudhury SR, Babes L, Rahn JJ, Ahn BY, Goring KR, King JC, Lau A, Petri B, Hao X, Chojnacki AK, Thanabalasuriar A, McAvoy EF, Tabariès S, Schraeder C, Patel KD, Siegel PM, Kopciuk KA, Schriemer DC, Muruve DA, Kelly MM, Yipp BG, Kubes P, Robbins SM, and Senger DL
- Subjects
- Animals, Cilastatin pharmacology, Cilastatin therapeutic use, Dipeptidases antagonists & inhibitors, Dipeptidases genetics, Disease Models, Animal, Endotoxemia mortality, Endotoxemia pathology, Endotoxemia prevention & control, GPI-Linked Proteins antagonists & inhibitors, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, Humans, Lipopolysaccharides pharmacology, Liver drug effects, Liver immunology, Liver metabolism, Lung drug effects, Lung immunology, Lung metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Neutrophil Infiltration drug effects, Peptides chemical synthesis, Peptides chemistry, Peptides pharmacology, Survival Rate, Dipeptidases metabolism, Neutrophils physiology, Platelet Glycoprotein GPIb-IX Complex metabolism
- Abstract
A hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these organs. Using biochemical, genetic, and confocal intravital imaging approaches, we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival in models of endotoxemia. Our data establish DPEP1 as a major adhesion receptor on the lung and liver endothelium and identify a therapeutic target for neutrophil-driven inflammatory diseases of the lungs., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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