tlr4 agonist
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Author(s):  
Yongxiang Zhao ◽  
Xinjing Lv ◽  
Jie Huang ◽  
Huiting Zhou ◽  
Hairong Wang ◽  
...  

AbstractSepsis, a life-threatening organ dysfunction induced by severe infection and uncontrolled host immune response, threatens the health of people all over the world. Herein, a type of nanoparticle formulation with simple components is synthesized by encapsulating monophosphoryl lipid A (MPLA), a TLR4 agonist, with poly(lactic-co-glycolic acid) (PLGA) nanoparticle. The obtained nanoparticles (MPLA@PLGA) could provide Escherichia coli (E. coli)-induced sepsis protection by regulating the immune system after sepsis challenge, including promoting the levels of various cytokines, boosting the percentage of natural killer cells and accelerating bacterial clearance. Notably, the survival mice pre-treated with these nanoparticles could resist repeated E. coli-induced sepsis. Our work therefore provides the great promise of MPLA@PLGA nanoparticles as a simple yet effective nano-drug for prevention and protection against E. coli-induced sepsis.


Author(s):  
Nancy M Walker ◽  
Jinghua Liu ◽  
Sarah M Young ◽  
Rowena A Woode ◽  
Lane L. Clarke

Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore we hypothesized that small intestinal enteroids from Cftr knockout (KO) mice would not exhibit goblet cell hyperplasia. Toll-like receptors 2 and 4 (Tlr2, Tlr4) were investigated as markers of inflammation and influence on goblet cell differentiation. Ex vivo studies found goblet cell hyperplasia in Cftr KO jejunum as compared to wild-type (WT). IL-13, SAM pointed domain-containing ETS transcription factor (Spdef), Tlr2 and Tlr4 protein expression was increased in Cftr KO intestine relative to WT. In contrast, WT and Cftr KO enteroids did not exhibit differences in basal or IL-13-stimulated goblet cell numbers, or differences in expression of Tlr2, Tlr4 and Spdef. Ileal goblet cell numbers in Cftr KO/Tlr4 KO and Cftr KO/Tlr2 KO mice were not different from Cftr KO mice, but enumeration was confounded by altered mucosal morphology. Treatment with Tlr4 agonist LPS did not affect goblet cell numbers in WT or Cftr KO enteroids, whereas the Tlr2 agonist Pam3Csk4 stimulated goblet cell hyperplasia in both genotypes. Pam3Csk4 stimulation of goblet cell numbers was associated with suppression of Notch1 and Neurog3 expression and upregulated determinants of goblet cell differentiation. We conclude that goblet cell hyperplasia and inflammation of the Cftr KO small intestine are not exhibited by enteroids, indicating that this manifestation of CF intestinal disease is not epithelial-automatous but secondary to the altered CF intestinal environment.


2021 ◽  
pp. 1-13
Author(s):  
Ahmad S. Halwani ◽  
Carlos Panizo ◽  
Iris Isufi ◽  
Alex F. Herrera ◽  
Craig Y. Okada ◽  
...  

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0259301
Author(s):  
Jardin A. Leleux ◽  
Tina C. Albershardt ◽  
Rebecca Reeves ◽  
Reice James ◽  
Jordan Krull ◽  
...  

Systemic interleukin-12 (IL12) anti-tumor therapy is highly potent but has had limited utility in the clinic due to severe toxicity. Here, we present two IL12-expressing vector platforms, both of which can overcome the deficiencies of previous systemic IL12 therapies: 1) an integrating lentiviral vector, and 2) a self-replicating messenger RNA formulated with polyethyleneimine. Intratumoral administration of either IL12 vector platform resulted in recruitment of immune cells, including effector T cells and dendritic cells, and the complete remission of established tumors in multiple murine models. Furthermore, concurrent intratumoral administration of the synthetic TLR4 agonist glucopyranosyl lipid A formulated in a stable emulsion (GLA-SE) induced systemic memory T cell responses that mediated complete protection against tumor rechallenge in all survivor mice (8/8 rechallenged mice), whereas only 2/6 total rechallenged mice treated with intratrumoral IL12 monotherapy rejected the rechallenge. Taken together, expression of vectorized IL12 in combination with a TLR4 agonist represents a varied approach to broaden the applicability of intratumoral immune therapies of solid tumors.


npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Puthupparampil V. Scaria ◽  
Charles Anderson ◽  
Olga Muratova ◽  
Nada Alani ◽  
Hung V. Trinh ◽  
...  

AbstractMalaria transmission-blocking vaccines candidates based on Pfs25 and Pfs230 have advanced to clinical studies. Exoprotein A (EPA) conjugate of Pfs25 in Alhydrogel® developed functional immunity in humans, with limited durability. Pfs230 conjugated to EPA (Pfs230D1-EPA) with liposomal adjuvant AS01 is currently in clinical trials in Mali. Studies with these conjugates revealed that non-human primates are better than mice to recapitulate the human immunogenicity and functional activity. Here, we evaluated the effect of ALFQ, a liposomal adjuvant consisting of TLR4 agonist and QS21, on the immunogenicity of Pfs25-EPA and Pfs230D1-EPA in Rhesus macaques. Both conjugates generated strong antibody responses and functional activity after two vaccinations though activity declined rapidly. A third vaccination of Pfs230D1-EPA induced functional activity lasting at least 9 months. Antibody avidity increased with each vaccination and correlated strongly with functional activity. IgG subclass analysis showed induction of Th1 and Th2 subclass antibody levels that correlated with activity.


2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A26.1-A26
Author(s):  
E Ushakova ◽  
E Lebedeva ◽  
A Pichugin ◽  
R Ataullakhanov

BackgroundA study of the anti-tumor T-cell response and immunological memory following successful 4T1 breast cancer immunotherapy with the combination of surgical resection of the primary tumor and subsequent macrophage/dendritic cell reprogramming using injections of the pharmaceutical TLR4-agonist.Materials and Methods15,000 cells of the 4T1 mouse breast carcinoma inoculated subcutaneously into BALB/c mice generated solid tumors and metastatic disease ended by the death of all the tumor-bearing animals during 30-40 days. Surgical resection of the primary tumor was performed on day 11. Pharmaceutical TLR4-agonist (Immunomax®) administered intraperitoneally in dose of 14 µg every 2-3 days, in total seven injections per course. Sorted macrophage/dendritic cells reprogramming was examined by RT-PCR. Tumor-reactive IFNγ-secretory T cells were counted using ELISPOT in ex vivo co-cultures of sorted CD4 T cells or CD8 T cells with the tumor lysate-loaded syngeneic dendritic cells or alive 4T1 tumor cells. Sorted CD8 effector T cell cytotoxicity was measured in their co-culture with different numbers of 4T1 target cells.ResultsUsing a combination of surgical resection of the primary 4T1 tumor and immunotherapy with the pharmaceutical TLR4-agonist for the treatment of metastatic disease in BALB/c mice a complete recovery of 20-30% mice was achieved. The complete responder mice effectively generated CD4 T cells and CD8 T cells, which specifically respond to 4T1 tumor antigens by IFN-production and kill 4T1 tumor cells in ex vivo co-cultures. The T-cell response is systemic, as tumor-specific T cells accumulate in the spleen. The second or third inoculation of the 4T1 tumor is accompanied by a complete absence of tumor growth in 50% and inhibition of tumor growth in the rest of the immune mice. An accumulation of significant numbers of T cells that respond to 4T1 tumor antigens by IFNγ-secretion, as well as of CD8 T cells that kill 4T1 tumor cells in a cytotoxic test was found in the secondary (tertiary) tumors, as well as in the draining lymph nodes. Immunological memory in complete responder mice that recovered due to the treatment with resection of the primary tumor and immunotherapy with a 4T1-agonist persisted for a long time (maximum observation period of 260 days).ConclusionsMacrophage/dendritic cell reprogramming with the TLR4-agonist for the post-resectional immunotherapy of 4T1 breast cancer metastatic disease induce tumor-specific CD4 and CD8 T cell responses and T-cell mediated long-living immune memory.FundingThis study was supported by the Russian Science Foundation (project no. 20-15-00391).Disclosure InformationE. Ushakova: None. E. Lebedeva: None. A. Pichugin: None. R. Ataullakhanov: None.


Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 908
Author(s):  
So Yeon Ahn ◽  
Chau Thuy Tien Le ◽  
Eun-Ju Ko

Induction of antigen-specific cell-mediated immunity (CMI), as well as humoral immunity, is critical for successful vaccination against various type of pathogens. Toll-like receptor (TLR) agonists have been developed as adjuvants to promote vaccine efficacy and induce appropriate immune responses. Monophosphoryl lipid A (MPL); a TLR4 agonist, and Poly I:C; a TLR3 agonist, are known as a strong immuno-stimulator which induce Th1 response. Many studies proved and compared the efficacy of each adjuvant, but no study has investigated the combination of them. Using ovalbumin protein antigen, MPL+Poly I:C combination induced more effective antigen-specific CMI response than single adjuvants. Production of inflammatory cytokines, recruitment of innate immune cells and antigen-specific CD4/CD8 memory T cell at the immunized site had been significantly enhanced by MPL+Poly I:C combination. Moreover, MPL+Poly I:C combination enhanced ovalbumin-specific serum IgG, IgG1, and IgG2c production and proliferative function of CD4 and CD8 T cells after in vitro ovalbumin peptide stimulation. Taken together, these data suggest that the combination of MPL and Poly I:C has a potency as a CMI-inducing vaccine adjuvant with synergistically increased effects.


2021 ◽  
Vol 11 (9) ◽  
pp. 1832-1837
Author(s):  
Zhongkui Li ◽  
Wenbo Liu ◽  
Lufang Gao ◽  
Daokang Xiang

MI could affect myocardial function seriously. The action and mechanism of BSMC modified by the transplantation of Toll-like receptor on myocardial function of rats with MI was studied. The sixty SD rats were divided into sham-operation group and model group randomly. The isolated and cultivated BMSC was divided into three groups such as group with added by TLR4 agonist, group with added by TLR-4 antagonist as TAK-242, group with only BMSC. The model of rats with MT was established in model group. BMSC in different group was transplanted into rats respectively. The cardiac function of rats in sham-operation group and model group was observed. The distribution condition of surface molecule in BMSC was detected by FCM. There was expression CD44 (+), CD54 (+), CD90 (+), no expression CD34 (−) from results. It could indicated that BMSCs with high purity was cultivated successfully. The high MT expression was affected by TLR-4 generally which could also illustrate the degree of deformation and necrosis of cardiac muscle cell, could be enhanced in established rat model because of negative regulatory action. The zone of MI in rats could be amplified by TLR-4. The cytobiological function of BMSC could be adjusted by TLR-4 through the transplantation of TLR-4 after there was MI in rats. The cytobiological function of BMSC could be adjusted by TLR-4 through modification of the transplantation of TLT-4 in rats after there was MI in rats. The BMSCs modified by high TLR-4 expression had negative regulatory action on the treatment on MI.


2021 ◽  
Vol 12 ◽  
Author(s):  
Debaki R. Howlader ◽  
Sayan Das ◽  
Ti Lu ◽  
Gang Hu ◽  
David J. Varisco ◽  
...  

Pseudomonas aeruginosa is an opportunistic pathogen responsible for a wide range of infections in humans. In addition to its innate antibiotic resistance, P. aeruginosa is very effective in acquiring resistance resulting in the emergence of multi-drug resistance strains and a licensed vaccine is not yet available. We have previously demonstrated the protective efficacy of a novel antigen PaF (Pa Fusion), a fusion of the type III secretion system (T3SS) needle tip protein, PcrV, and the first of two translocator proteins, PopB. PaF was modified to provide a self-adjuvanting activity by fusing the A1 subunit of the heat-labile enterotoxin from Enterotoxigenic E. coli to its N-terminus to give L-PaF. In addition to providing protection against 04 and 06 serotypes of P. aeruginosa, L-PaF elicited opsonophagocytic killing and stimulated IL-17A secretion, which have been predicted to be required for a successful vaccine. While monomeric recombinant subunit vaccines can be protective in mice, this protection often does not transfer to humans where multimeric formulations perform better. Here, we use two unique formulations, an oil-in-water (o/w) emulsion and a chitosan particle, as well as the addition of a unique TLR4 agonist, BECC438 (a detoxified lipid A analogue designated Bacterial Enzymatic Combinatorial Chemistry 438), as an initial step in optimizing L-PaF for use in humans. The o/w emulsion together with BECC438 provided the best protective efficacy, which correlated with high levels of opsonophagocytic killing and IL-17A secretion, thereby reducing the lung burden among all the vaccinated groups tested.


2021 ◽  
Author(s):  
Mohamed M Aboudounya ◽  
Mark R Holt ◽  
Richard J Heads

Background and aims: TLR4 is an important innate immune receptor that recognizes bacterial LPS, viral proteins and other pathogen associated molecular patterns (PAMPs). It is expressed on tissue-resident and immune cells. We previously proposed a model whereby SARS-CoV-2 activation of TLR4 via its spike glycoprotein S1 domain increases ACE2 expression, viral loads and hyperinflammation with COVID-19 disease [1]. Here we test this hypothesis in vitro and demonstrate that the SARS-CoV-2 spike S1 domain is a TLR4 agonist in rat and human cells and induces a pro-inflammatory M1 macrophage phenotype in human THP-1 monocyte-derived macrophages. Methods: Adult rat cardiac tissue resident macrophage-derived fibrocytes (rcTMFs) were treated with either bacterial LPS or recombinant SARS-CoV-2 spike S1 glycoprotein. The expression of ACE2 and other inflammatory and fibrosis markers were assessed by immunoblotting. S1/TLR4 co-localisation/binding was assessed by immunocytochemistry and proximity ligation assays on rcTMFs and human HEK-293 HA-TLR4-expressing cells. THP-1 monocytes were differentiated into M1 or M2 macrophages with LPS/IFN-γ, S1/IFN-γ or IL-4 and RNA was extracted for RT-qPCR of M1/M2 markers and ACE2. Results: TLR4 activation by spike S1 or LPS resulted in the upregulation of ACE2 in rcTMFs as shown by immunoblotting. Likewise, spike S1 caused TLR4-mediated induction of the inflammatory/wound healing marker COX-2 and concomitant downregulation of the fibrosis markers CTGF and Col3a1, similar to LPS. The specific TLR4 TIR domain signalling inhibitor CLI-095 (Resatorvid), blocked the effects of spike S1 and LPS, confirming that spike S1 is a TLR4 agonist and viral PAMP (VAMP). ACE2 expression was also inhibited by the dynamin inhibitor Dynasore, suggesting ACE2 expression is mediated by the alternative endosomal/β-interferon pathway. Confocal immunofluorescence microscopy confirmed 1:1 stoichiometric spike S1 co-localisation with TLR4 in rat and human cells. Furthermore, proximity ligation assays confirmed spike S1 and TLR4 binding in human and rat cells. Spike S1/IFN-γ treatment of THP-1-derived macrophages induced pro-inflammatory M1 polarisation as shown by an increase in IL-1-β and IL-6 mRNA. Conclusions: These results confirm that TLR4 is activated by the SARS-CoV-2 spike protein S1 domain and therefore TLR4 may be a receptor/accessory factor for the virus. By binding to and activating TLR4, spike S1 caused upregulation of ACE2, which may facilitate viral entry into cells. In addition, pro-inflammatory M1 macrophage polarisation via TLR4 activation, links TLR4 activation by spike S1 to inflammation. The clinical trial testing of CLI-095 (Resatorvid) and other TLR4 antagonists in severe COVID-19, to reduce both viral entry into cells and hyperinflammation, is warranted. Our findings likely represent an important development in COVID-19 pathophysiology and treatment, particularly regarding cardiac complications and the role of macrophages.


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