Sublingual Flagellin Protects against Acute Pneumococcal Pneumonia in a TLR5-Dependent and NLRC4-Independent Fashion

Muñoz‐Wolf, Natalia; Rial, Analía; Fougeron, Delphine; Tabareau, Julien; Sirard, Jean‐Claude; Chabalgoity, José A.

doi:10.2217/fmb-2016-0045

Cited by 7 publications

(5 citation statements)

References 30 publications

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“…It is noteworthy that flagellin was found to be very effective in activating neonatal lung antigen-presenting cells (40). Furthermore, flagellin-TLR5 activation was observed to protect mice from invasive pneumonia through early clearance of Pseudomonas aeruginosa in respiratory epithelial cells (2,32). These studies support the concept that flagellin or pharmacological TLR5 agonists (i.e., entolimod, currently under clinical trials) can be redirected as a potent therapeutic to eliminate SARS-CoV-2.…”

supporting

confidence: 57%

Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease

Golonka

Saha

Yeoh

et al. 2020

Physiological Genomics

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supporting

confidence: 57%

Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease

Golonka

Saha

Yeoh

et al. 2020

Physiological Genomics

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“…Furthermore, the administration of TLR5 agonist (flagellin) enhances the IL-22 production from group 3 ILCs during S. pneumoniae-induced pneumonia ( Figure 2B). Studies have also shown earlier, the protective action of mucosal (including sublingual root) flagellin administration to mice infected with S. pneumoniae-induced pneumonia without the activation of NLRC4 inflammasome (138,139). Also, the TLR5 agonist (flagellin) administration increases the efficacy of antibiotic treatment during pneumonia (140).…”

Section: Pulmonary Innate Lymphoid Cells (Ilcs) During Pneumonia and mentioning

confidence: 91%

Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury

2020

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The lung is a primary organ for gas exchange in mammals that represents the largest epithelial surface in direct contact with the external environment. It also serves as a crucial immune organ, which harbors both innate and adaptive immune cells to induce a potent immune response. Due to its direct contact with the outer environment, the lung serves as a primary target organ for many airborne pathogens, toxicants (aerosols), and allergens causing pneumonia, acute respiratory distress syndrome (ARDS), and acute lung injury or inflammation (ALI). The current review describes the immunological mechanisms responsible for bacterial pneumonia and sepsis-induced ALI. It highlights the immunological differences for the severity of bacterial sepsis-induced ALI as compared to the pneumonia-associated ALI. The immune-based differences between the Gram-positive and Gram-negative bacteria-induced pneumonia show different mechanisms to induce ALI. The role of pulmonary epithelial cells (PECs), alveolar macrophages (AMs), innate lymphoid cells (ILCs), and different pattern-recognition receptors (PRRs, including Toll-like receptors (TLRs) and inflammasome proteins) in neutrophil infiltration and ALI induction have been described during pneumonia and sepsis-induced ALI. Also, the resolution of inflammation is frequently observed during ALI associated with pneumonia, whereas sepsis-associated ALI lacks it. Hence, the review mainly describes the different immune mechanisms responsible for pneumonia and sepsis-induced ALI. The differences in immune response depending on the causal pathogen (Gram-positive or Gram-negative bacteria) associated pneumonia or sepsis-induced ALI should be taken in mind specific immune-based therapeutics.

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“…Mucosal administration of flagellin conferred resistance to S. pneumoniae lung infection whereby flagellin treatment increased bacterial clearance which was associated with increased neutrophil mobilization independent of B- and T-cells ( 120 ). More recently, this research group showed that sublingual administration of flagellin also effectively protects against pneumonia ( 85 ). Demonstrating cross-protection, treatment with bacterial flagellin was able to prevent infection with or cure ongoing infection of rotavirus in mice independent of adaptive immunity ( 84 ).…”

Section: Toll-like Receptor Agonist-mediated Trained Immunity and Promentioning

confidence: 99%

TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection

et al. 2021

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Despite advances in critical care medicine, infection remains a significant problem that continues to be complicated with the challenge of antibiotic resistance. Immunocompromised patients are highly susceptible to development of severe infection which often progresses to the life-threatening condition of sepsis. Thus, immunotherapies aimed at boosting host immune defenses are highly attractive strategies to ward off infection and protect patients. Recently there has been mounting evidence that activation of the innate immune system can confer long-term functional reprogramming whereby innate leukocytes mount more robust responses upon secondary exposure to a pathogen for more efficient clearance and host protection, termed trained immunity. Toll-like receptor (TLR) agonists are a class of agents which have been shown to trigger the phenomenon of trained immunity through metabolic reprogramming and epigenetic modifications which drive profound augmentation of antimicrobial functions. Immunomodulatory TLR agonists are also highly beneficial as vaccine adjuvants. This review provides an overview on TLR signaling and our current understanding of TLR agonists which show promise as immunotherapeutic agents for combating infection. A brief discussion on our current understanding of underlying mechanisms is also provided. Although an evolving field, TLR agonists hold strong therapeutic potential as immunomodulators and merit further investigation for clinical translation.

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Sublingual Flagellin Protects against Acute Pneumococcal Pneumonia in a TLR5-Dependent and NLRC4-Independent Fashion

Abstract: Ligation of TLR5, a pathogen recognition receptor not naturally engaged by pneumococcus, protects mice from invasive pneumonia when administered via sublingual route. This can be a highly cost-effective alternative therapy against pneumonia.

Cited by 7 publications

References 30 publications

Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease

Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease

Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury

TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection

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