Pulmonary Colonization Resistance to Pathogens via Noncanonical Wnt and Interleukin-17A by Intranasal pep27 Mutant Immunization

Kim, Gyu-Lee; Lee, Seung-Yeop; Kim, Se-Jin; Lee, Sion; Pyo, Suhkneung; Rhee, Dong‐Kwon

doi:10.1093/infdis/jiy158

Cited by 12 publications

(13 citation statements)

References 49 publications

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“…pneumoniae has been reported to suppress Wnt5a protein expression (57). Sequencing analyses of lung tissue of mice vaccinated intranasally with S. pneumoniae deficient for the autolysis-inducing factor pep27 revealed enhanced expression of Wnt4, Wnt5b, Wnt7a , and Wnt7b , and impaired Wnt2b, Wnt3, Wnt6, Wnt9a , and Wnt9b mRNA expression (51). Kinase activity profiling in mouse lung tissue of S. pneumoniae -infected mice indicated a reduction in β-catenin-stabilizing signals associated with a decrease in β-catenin protein expression (62).…”

Section: Wnt Responses To Infectionmentioning

confidence: 99%

“…Thus, the cellular mechanisms accelerating the initial bacterial killing might be transient, and could be specific to some pathogens as they did not affect macrophage killing of non-pathogenic E. coli DH5a (98). With Wnt5a expression reported to be suppressed by S. pneumoniae and P. aeruginosa infection of macrophages (57), roles of other WNT ligands responsive to infection (e.g., Wnt4, Wnt5b, Wnt7a, Wnt7b) (51) and the net-outcome of WNT signaling in infected cells will need further exploration. Of note, overexpression of β-catenin in RAW264.7 macrophages has been reported to accelerate killing of engulfed P. aeruginosa , which was associated with suppression of autophagy (63).…”

Section: Wnt Functions In the Host Response To Infectionmentioning

confidence: 99%

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Functions of the WNT Signaling Network in Shaping Host Responses to Infection

et al. 2019

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It is well-established that aberrant WNT expression and signaling is associated with developmental defects, malignant transformation and carcinogenesis. More recently, WNT ligands have emerged as integral components of host responses to infection but their functions in the context of immune responses are incompletely understood. Roles in the modulation of inflammatory cytokine production, host cell intrinsic innate defense mechanisms, as well as the bridging of innate and adaptive immunity have been described. To what degree WNT responses are defined by the nature of the invading pathogen or are specific for subsets of host cells is currently not well-understood. Here we provide an overview of WNT responses during infection with phylogenetically diverse pathogens and highlight functions of WNT ligands in the host defense against infection. Detailed understanding of how the WNT network orchestrates immune cell functions will not only improve our understanding of the fundamental principles underlying complex immune response, but also help identify therapeutic opportunities or potential risks associated with the pharmacological targeting of the WNT network, as currently pursued for novel therapeutics in cancer and bone disorders.

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Section: Wnt Responses To Infectionmentioning

confidence: 99%

Section: Wnt Functions In the Host Response To Infectionmentioning

confidence: 99%

Functions of the WNT Signaling Network in Shaping Host Responses to Infection

et al. 2019

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“…Nevertheless, the mechanism of ER stress-induced NLRP3 activation via Ca 2+ requires further characterization (50). IL-17A not only is essential for the defense against S. pneumoniae but also mediates the early defenses following infection by other gram-positive and gram-negative bacteria (11, 21, 51). In contrast, IL-1β production occurs in a different manner, as the pH of macrophage phagosomes containing gram-positive bacteria is higher than that of gram-negative bacteria.…”

Section: Discussionmentioning

confidence: 99%

ATF3 Stimulates IL-17A by Regulating Intracellular Ca2+/ROS-Dependent IL-1β Activation During Streptococcus pneumoniae Infection

Lee

Kim

et al. 2018

Front. Immunol.

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Activating transcription factor-3 (ATF3) in the ER stress pathway induces cytokine production and promotes survival during gram-positive bacterial infection. IL-17A is a critical cytokine that is essential for clearance of Streptococcus pneumoniae. However, the mechanism by which ATF3 induces IL-17A production remains unknown. Here, we show that ATF3 induces IL-17A production via NLRP3 inflammasome-dependent IL-1β secretion. Survival rates were comparable in IL-17A-depleted and ATF3 KO mice but were lower than in WT mice treated with isotype control, indicating that ATF3 positively regulated IL-17A production. Indeed, ATF3 KO mice showed a marked reduction in IL-17A protein and mRNA expression compared to levels in WT mice. Moreover, mitochondrial IL-1β production by bone marrow-derived macrophages was significantly reduced in ATF3 KO mice as a result of the disruption of cellular ROS and Ca2+ homeostasis. Accordingly, ATF3 KO mice displayed diminished survival and bacterial clearance following S. pneumoniae infection. Taken together, these data suggest a mechanism in which macrophage ATF3 promotes IL-17A production in γδ T cells to rapidly induce host defenses during early S. pneumoniae infection.

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“…Furthermore, different types of T cell responses might be required depending on the body compartment(51,52). For example, Th17 responses are relevant in the skin and mucosal surfaces in defense against S. aureus(53,54), and have also been found to be important for clearance of ESCAPE pathogens such as Klebsiella spp., P. aeruginosa and A. baumanii(55)(56)(57)(58)(59)(60)(61)(62)(63)(64). Thus, vaccine formulations targeting colonizing pathogens might need to be optimized to induce Th17 responses(24,58,65).…”

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confidence: 99%

Challenges for Clinical Development of Vaccines for Prevention of Hospital-Acquired Bacterial Infections

Bekeredjian‐Ding

2020

Front. Immunol.

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Increasing antibiotic resistance in bacteria causing endogenous infections has entailed a need for innovative approaches to therapy and prophylaxis of these infections and raised a new interest in vaccines for prevention of colonization and infection by typically antibiotic resistant pathogens. Nevertheless, there has been a long history of failures in late stage clinical development of this type of vaccines, which remains not fully understood. This article provides an overview on present and past vaccine developments targeting nosocomial bacterial pathogens; it further highlights the specific challenges associated with demonstrating clinical efficacy of these vaccines and the facts to be considered in future study designs. Notably, these vaccines are mainly applied to subjects with preexistent immunity to the target pathogen, transient or chronic immunosuppression and ill-defined microbiome status. Unpredictable attack rates and changing epidemiology as well as highly variable genetic and immunological strain characteristics complicate the development. In views of the clinical need, rethinking of the study designs and expectations seems warranted: first of all, vaccine development needs to be footed on a clear rationale for choosing the immunological mechanism of action and the optimal time point for vaccination, e.g., (1) prevention (or reduction) of colonization vs. prevention of infection and (2) boosting of a preexistent immune response vs. altering the quality of the immune response. Furthermore, there are different, probably redundant, immunological and microbiological defense mechanisms that provide protection from infection. Their interplay is not well-understood but as a consequence their effect might superimpose vaccine-mediated resolution of infection and lead to failure to demonstrate efficacy. This implies that improved characterization of patient subpopulations within the trial population should be obtained by pro-and retrospective analyses of trial data on subject level. Statistical and systems biology approaches could help to define immune and microbiological biomarkers that discern populations that benefit from vaccination from those where vaccines might not be effective.

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Pulmonary Colonization Resistance to Pathogens via Noncanonical Wnt and Interleukin-17A by Intranasal pep27 Mutant Immunization

Abstract: Therefore, Δpep27 immunization can provide nonspecific respiratory colonization resistance via noncanonical Wnt signaling and IL-17A-related pathways.

Cited by 12 publications

References 49 publications

Functions of the WNT Signaling Network in Shaping Host Responses to Infection

Functions of the WNT Signaling Network in Shaping Host Responses to Infection

ATF3 Stimulates IL-17A by Regulating Intracellular Ca2+/ROS-Dependent IL-1β Activation During Streptococcus pneumoniae Infection

Challenges for Clinical Development of Vaccines for Prevention of Hospital-Acquired Bacterial Infections

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