Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A

Luan, Liming; Patil, Naeem K.; Guo, Yin; Hernandez, Antonio; Bohannon, Julia K.; Fensterheim, Benjamin A.; Wang, Jingbin; Xu, Yaomin; Enkhbaatar, Perenlei; Stark, Ryan J.; Sherwood, Edward R.

doi:10.1038/srep40050

Cited by 31 publications

(28 citation statements)

References 33 publications

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“…Many of the trials targeting immunosuppression are still in progress. More recently, immunoprophylaxis with Toll‐like receptor (TLR) ligands and immunomodulation with Fms‐like tyrosine kinase‐3 ligand (FLT‐3 ligand) have shown efficacy against infection and sepsis in animal studies, bringing hope to clinical prevention and treatment of sepsis …”

Section: Need For New Therapy For Human Sepsismentioning

confidence: 99%

“…More recently, immunoprophylaxis with Toll-like receptor (TLR) ligands and immunomodulation with Fms-like tyrosine kinase-3 ligand (FLT-3 ligand) have shown efficacy against infection and sepsis in animal studies, bringing hope to clinical prevention and treatment of sepsis. [47][48][49][50][51] The failure of targeted interventions in patients with sepsis could be due to the complex and interdependent network of pro-inflammatory responses during sepsis. 52 Also, patients with sepsis that were recruited to trials exhibited considerable heterogeneity in genetic background, nature of the infecting microorganisms, site of infections, magnitude of pro-inflammatory responses and co-morbidities.…”

Section: Need For New Therapy For Human Sepsismentioning

confidence: 99%

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The biology of natural killer cells during sepsis

et al. 2017

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SummaryNatural killer (NK) cells are large granular lymphocytes largely recognized for their importance in tumour surveillance and the host response to viral infections. However, as the major innate lymphocyte population, NK cells also coordinate early responses to bacterial infections by amplifying the antimicrobial functions of myeloid cells, especially macrophages, by production of interferon-c (IFN-c). Alternatively, excessive NK cell activation and IFN-c production can amplify the systemic inflammatory response during sepsis resulting in increased physiological dysfunction and organ injury. Our understanding of NK cell biology during bacterial infections and sepsis is mostly derived from studies performed in mice. Human studies have demonstrated a correlation between altered NK cell functions and outcomes during sepsis. However, mechanistic understanding of NK cell function during human sepsis is limited. In this review, we will review the current understanding of NK cell biology during sepsis and discuss the challenges associated with modulating NK cell function during sepsis for therapeutic benefit.

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Section: Need For New Therapy For Human Sepsismentioning

confidence: 99%

Section: Need For New Therapy For Human Sepsismentioning

confidence: 99%

The biology of natural killer cells during sepsis

et al. 2017

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“…These data not only confirm the previously reported role of DC in AS01 adjuvant effect but also extend this finding by suggesting a requirement for a direct TLR4 engagement for full activation of DC. MPL can directly activate DCs and other human hematopoietic cells as reported using ex vivo stimulated PBMC . In addition, MPL in AS01 is likely to be rapidly drained to the LN to target resident DC.…”

Section: Discussionmentioning

confidence: 87%

Toll‐like receptor 4 signaling in hematopoietic‐lineage cells contributes to the enhanced activity of the human vaccine adjuvant AS01

et al. 2019

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The 3-O-desacyl-4'-monophosphoryl lipid A (MPL) activates immunity through Toll-like receptor 4 (TLR4) signaling. The Adjuvant System AS01 contains MPL and is used in the candidate malaria vaccine and the licensed zoster vaccine. Recent studies reported that AS01 adjuvant activity depends on a transient inflammation at the site of vaccination, but the role of stromal or structural cells in the adjuvant effect is unknown. We investigated this question in mouse models by assessing the role of TLR4 on hematopoietic versus resident structural cells during immunization with AS01-adjuvanted vaccines.We first established that TLR4-deficient animals had a reduced immune response to an AS01-adjuvanted vaccine. Using bone marrow chimera, we consistently found that Tlr4 expression in radio-sensitive cells, i.e., hematopoietic cells, was required for an optimal adjuvant effect on antibody and T-cell responses. At day 1 after injection, the proinflammatory reaction at the site of injection was strongly dependent on TLR4 signaling in hematopoietic cells. Similarly, activation of dendritic cells in muscle-draining lymph nodes was strictly associated with the radio-sensitive cells expressing Tlr4. Altogether, these data suggest that MPL-mediated TLR4-signaling in hematopoietic cells is critical in the mode of action of AS01.Keywords: adjuvant r dendritic cells r hematopoietic cells r TLR4 r vaccine Additional supporting information may be found online in the Supporting Information section at the end of the article. innate immune system conditions the level and/or quality of the immune response specific to the co-administered antigens, which usually translates into improved efficacy [1,2]. A recent study demonstrated that the ability of different adjuvants to trigger an early innate response in humans was associated with higher T-cell and antibody response [3]. The innate response after intramuscular vaccination with adjuvanted vaccines is generally characterized by local cytokine production and cell recruitment in muscle and draining lymph nodes (dLN), as well as by an increase in the

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“…Using in vitro transcriptome analysis, Luan et al . expanded on the idea that LPS structural changes alter immunological outcome 39 . They investigated human leukocyte responses to stimulation with pro-inflammatory canonical LPS and compared them with those from stimulation with less-inflammatory mono-phosphorylated lipid A.…”

Section: Lipopolysaccharide the Major Immune Mediator Of Gram-negatimentioning

confidence: 99%

Bacterial lipids: powerful modifiers of the innate immune response

Chandler

Ernst

2017

F1000Res

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The innate immune system serves as a first line of defense against microbial pathogens. The host innate immune response can be triggered by recognition of conserved non-self-microbial signature molecules by specific host receptor proteins called Toll-like receptors. For bacteria, many of these molecular triggers reside on or are embedded in the bacterial membrane, the interface exposed to the host environment. Lipids are the most abundant component of membranes, and bacteria possess a unique set of lipids that can initiate or modify the host innate immune response. Bacterial lipoproteins, peptidoglycan, and outer membrane molecules lipoteichoic acid and lipopolysaccharide are key modulators of the host immune system. This review article will highlight some of the research emerging at the crossroads of bacterial membranes and innate immunity.

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Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A

Cited by 31 publications

References 33 publications

The biology of natural killer cells during sepsis

The biology of natural killer cells during sepsis

Toll‐like receptor 4 signaling in hematopoietic‐lineage cells contributes to the enhanced activity of the human vaccine adjuvant AS01

Bacterial lipids: powerful modifiers of the innate immune response

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