TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury

Hussain, Salik; Johnson, Christina; Sciurba, Joseph; Meng, Xianglin; Stober, Vandy P.; Liu, Caini; Cyphert-Daly, Jaime M.; Bulek, Katarzyna; Wen, Qian; Solis, Alma; Sakamachi, Yosuke; Trempus, Carol S.; Aloor, Jim J.; Gowdy, Kym M; Foster, W. Michael; Hollingsworth, John W.; Tighe, Robert; Li, Xiaoxia; Fessler, Michael B.; Garantziotis, Stavros

doi:10.7554/elife.50458

Cited by 56 publications

(45 citation statements)

References 48 publications

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“…Hussain et al recently demonstrated that the flagella receptor TLR5 is physically associated with the LPS receptor TLR4, diverting TLR4 signalling to the MyD88 pathway. After exposure of primary murine macrophages to ultra-pure LPS, TLR5 was co-immunopreserved with MyD88, TLR4 and LPS, suggesting an updated paradigm for TLR4/TLR5 signalling [64].…”

Section: Host Immune Response Against P Aeruginosamentioning

confidence: 99%

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

Sainz-Mejías

Jurado‐Martín

McClean

2020

Cells

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Pseudomonas aeruginosa is a leading cause of chronic respiratory infections in people with cystic fibrosis (CF), bronchiectasis or chronic obstructive pulmonary disease (COPD), and acute infections in immunocompromised individuals. The adaptability of this opportunistic pathogen has hampered the development of antimicrobial therapies, and consequently, it remains a major threat to public health. Due to its antimicrobial resistance, vaccines represent an alternative strategy to tackle the pathogen, yet despite over 50 years of research on anti-Pseudomonas vaccines, no vaccine has been licensed. Nevertheless, there have been many advances in this field, including a better understanding of the host immune response and the biology of P. aeruginosa. Multiple antigens and adjuvants have been investigated with varying results. Although the most effective protective response remains to be established, it is clear that a polarised Th2 response is sub-optimal, and a mixed Th1/Th2 or Th1/Th17 response appears beneficial. This comprehensive review collates the current understanding of the complexities of P. aeruginosa-host interactions and its implication in vaccine design, with a view to understanding the current state of Pseudomonal vaccine development and the direction of future efforts. It highlights the importance of the incorporation of appropriate adjuvants to the protective antigen to yield optimal protection.

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Section: Host Immune Response Against P Aeruginosamentioning

confidence: 99%

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

Sainz-Mejías

Jurado‐Martín

McClean

2020

Cells

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“…Interestingly, the release of MIP-2 from microglia exposed to LPS was significantly enhanced in the absence of TLR5, while IL-6 and IL-10 responses were reduced compared to wild-type cells. One may speculate that TLR5 cooperates with TLR4 [28], which is the LPS-recognizing receptor, in an unknown manner, resulting in enhancing (IL-6, IL-10) or inhibiting (MIP-2) effects on cytokine production. In addition, as TLR5 can interact with TIR-domain-containing adapter-inducing interferon-β (TRIF), LPS stimulation might modulate the cytokine response through the associated pathway [8].…”

Section: Discussionmentioning

confidence: 99%

Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury

Ifuku

Hinkelmann

Kuhrt

et al. 2020

acta neuropathol commun

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Microglia are the primary immune-competent cells of the central nervous system (CNS) and sense both pathogen- and host-derived factors through several receptor systems including the Toll-like receptor (TLR) family. Although TLR5 has previously been implicated in different CNS disorders including neurodegenerative diseases, its mode of action in the brain remained largely unexplored. We sought to determine the expression and functional consequences of TLR5 activation in the CNS. Quantitative real-time PCR and immunocytochemical analysis revealed that microglia is the major CNS cell type that constitutively expresses TLR5. Using Tlr5−/− mice and inhibitory TLR5 antibody we found that activation of TLR5 in microglial cells by its agonist flagellin, a principal protein component of bacterial flagella, triggers their release of distinct inflammatory molecules, regulates chemotaxis, and increases their phagocytic activity. Furthermore, while TLR5 activation does not affect tumor growth in an ex vivo GL261 glioma mouse model, it triggers microglial accumulation and neuronal apoptosis in the cerebral cortex in vivo. TLR5-mediated microglial function involves the PI3K/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway, as specific inhibitors of this signaling pathway abolish microglial activation. Taken together, our findings establish TLR5 as a modulator of microglial function and indicate its contribution to inflammatory and injurious processes in the CNS.

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“…FlgC is the structural unit of the bacterial agellum, which can interact with TLR5-expressing cells (e.g., monocytes, neutrophils, DCs, lymphocytes, and macrophages) as an agonist of TLR5 51,52 . Some studies reported the synergistic effects of the TLR4 and 5 signaling pathways; therefore, the use of FlgC might modulate initial innate and then the subsequent adaptive immune responses 51,53 . We have validated the interaction of vaccine construct with the TLR4 and TLR5 using molecular docking and then molecular dynamics simulations (Figs.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic domain-based vaccine against SARS-CoV-2, causative agent of COVID-19 pandemic

Pourseif

Parvizpour

Jafari

et al. 2020

Preprint

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Coronavirus disease 2019 (COVID-19) is undoubtedly the most challenging pandemic in the current century with more than 253,381 deaths worldwide since its emergence in late 2019 (updated May 6th, 2020). COVID-19 is caused by a novel emerged coronavirus named as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Today, the world needs crucially to develop a prophylactic vaccine scheme for such emerged and emerging infectious pathogens. In this study, we have targeted spike (S) glycoprotein, as an important surface antigen of SARS-CoV-2, to identify its immunodominant B- and T-cell epitopes. We have conducted a multi-method B-cell epitope (BCE) prediction approach using different predictor algorithms to discover most potential BCEs. Besides, we sought among a pool of MHC class I and II-associated peptide binders provided by the IEDB server through the strict cut-off values. To design a broad-coverage vaccine, we carried out a population coverage analysis for a set of candidate T-cell epitopes and based on the HLA allele frequency in the top most-affected countries by COVID-19 (update 02 April 2020). The final determined B- and T-cell epitopes were mapped on the S glycoprotein sequence, and three potential hub regions covering the largest number of overlapping epitopes were identified for the vaccine designing (I531–N711; T717–C877; and V883–E973). Here, we have designed two domain-based constructs to be produced and delivered through the recombinant protein- and gene-based approaches, including (i) an adjuvanted domain-based protein vaccine construct (DPVC), and (ii) a self-amplifying mRNA vaccine (SAMV) construct. The safety, stability, and immunogenicity of the DPVC were validated using the integrated sequential (i.e. allergenicity, autoimmunity, and physicochemical features) and structural (i.e. molecular docking between the vaccine and human Toll-like receptors (TLRs) 4 and 5) analysis. The stability of the docked complexes was evaluated using the molecular dynamics (MD) simulations. These rigorous in silico validations supported the potential of the DPVC and SAMV to promote both innate and specific immune responses in the animal studies.

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TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury

Cited by 56 publications

References 48 publications

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

Activation of Toll-like receptor 5 in microglia modulates their function and triggers neuronal injury

Prophylactic domain-based vaccine against SARS-CoV-2, causative agent of COVID-19 pandemic

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