Summary
We investigated Toll‐like receptor (TLR)‐3/‐7/‐8/‐9 and interferon (IFN)‐α/β/γ mRNA expression in whole blood and serum IFN‐α/β/γ levels in patients with mixed connective tissue disease ...(MCTD), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) and in healthy subjects to assess the association between the TLR–IFN expression and severity of and susceptibility to diseases, and identify potential biomarkers. Expression of the IFN‐γ, TLR‐3 and TLR‐8 was detected only in SLE patients. TLR‐7, IFN‐α and IFN‐β expression was highest in SLE, while TLR‐9 expression was highest in SSc patients. In SLE and MCTD patients a strong correlation was observed between TLR‐7 and IFN‐α expression and IFN‐β and IFN‐α expression. In MCTD patients, negative correlation between IFN‐α and TLR‐9 and TLR‐7 and TLR‐9 was revealed. TLR‐9 expression in anti‐U1‐70k‐negative, anti‐C negative and anti‐SmB‐negative MCTD patients was higher than in MCTD‐positive patients. We observed negative correlations between serum IFN‐α levels and TLR‐7 expression and C3 and C4 levels in SLE patients. In SLE patients we observed that with increased IFN‐γ, TLR‐3 and TLR‐8 expression increased the value of C3 and C4. Our results confirmed that the endosomal TLR–IFN pathway seems to be more important in SLE than in MCTD or SSc, and that IFN‐α and IFN‐β may be possible biomarkers for SLE.
The summary of the article is: “We investigated TLR3/7/8/9 and IFN‐α/β/γ mRNA expression in whole blood and serum IFN‐α/β/γ levels in patients with mixed connective tissue disease (MCTD), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), and in healthy subjects to assess the association between the TLRs‐IFNs expression and severity of and susceptibility to diseases, and identify potential biomarkers. Expression of the IFN‐γ, TLR3, and TLR8 was detected only in SLE patients. Our study indicated that TLRs‐IFNs signaling pathway may be implicated in the pathogenesis of these diseases, but the underlying mechanism is distinct; probably, in each ACTDs, endosomal TLRs are activated on the different cell types and in different immune pathways.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Toll‐like receptors (TLRs) orchestrate immune responses to a wide variety of danger‐ and pathogen‐associated molecular patterns. Compared to the central nervous system (CNS), expression profile and ...function of TLRs in the human peripheral nervous system (PNS) are ill‐defined. We analyzed TLR expression of satellite glial cells (SGCs) and microglia, glial cells predominantly involved in local immune responses in ganglia of the human PNS and normal‐appearing white matter (NAWM) of the CNS, respectively. Ex vivo flow cytometry analysis of cell suspensions obtained from human cadaveric trigeminal ganglia (TG) and NAWM showed that both SGCs and microglia expressed TLR1–5, TLR7, and TLR9, although expression levels varied between these cell types. Immunohistochemistry confirmed expression of TLR1–TLR4 and TLR9 by SGCs in situ. Stimulation of TG‐ and NAWM‐derived cell suspensions with ligands of TLR1–TLR6, but not TLR7 and TLR9, induced interleukin 6 (IL‐6) secretion. We identified CD45LOWCD14POS SGCs and microglia, but not CD45HIGH leukocytes and CD45NEG cells as the main source of IL‐6 and TNF‐α upon stimulation with TLR3 and TLR5 ligands. In conclusion, human TG‐resident SGCs express a broad panel of functional TLRs, suggesting their role in initiating and orchestrating inflammation to pathogens in human sensory ganglia.
Toll‐like receptors (TLRs) orchestrate immune responses to a wide variety of danger and pathogen‐associated molecular patterns, yet expression in peripheral nerve tissues was ill‐defined. In this issue, Mitterreiter et al. phenotypically and functionally characterized expressed TLRs in human trigeminal ganglia‐derived satellite glial cells and white matter‐derived microglia ex vivo. The authors show broad expression of functional TLRs on satellite glia cells in human trigeminal ganglia, suggesting their role in initiating and coordinating immune responses in human sensory ganglia.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The COVID-19 pandemic highlighted healthcare disparities in multiple countries. As such morbidity and mortality vary significantly around the globe between populations and ethnic groups. Underlying ...medical conditions and environmental factors contribute higher incidence in some populations and a genetic predisposition may play a role for severe cases with respiratory failure. Here we investigated whether genetic variation in the key genes for viral entry to host cells—ACE2 and TMPRSS2—and sensing of viral genomic RNAs (i.e., TLR3/7/8) could explain the variation in incidence across diverse ethnic groups. Overall, these genes are under strong selection pressure and have very few nonsynonymous variants in all populations. Genetic determinant for the binding affinity between SARS-CoV-2 and ACE2 does not show significant difference between populations. Non-genetic factors are likely to contribute differential population characteristics affected by COVID-19. Nonetheless, a systematic mutagenesis study on the receptor binding domain of ACE2 is required to understand the difference in host-viral interaction across populations.
•Protein residues in active domains of the essential genes related viral susceptibility are highly conserved among population.•No evidence was found for ethnic group difference in ACE2, TMPRSS2, and genes associated with viral binding and endocytosis.•Disproportionately high incidence and mortality rates in African Americans in the US could be due to non-genetic factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We examine the impact of changes in microbiota induced by antibiotics on intestinal motility, gut inflammatory response, and the function and expression of toll-like receptors (TLRs). Alterations in ...mice intestinal microbiota were induced by antibiotics and evaluated by q-PCR and DGGE analysis. Macroscopic and microscopic assessments of the intestine were performed in control and antibiotic-treated mice. TLR expression was determined in the intestine by q-RT-PCR. Fecal parameter measurements, intestinal transit, and muscle contractility studies were performed to evaluate alterations in intestinal motility. Antibiotics reduced the total bacterial quantity 1000-fold, and diversity was highly affected by treatment. Mice with microbiota depletion had less Peyer’s patches, enlarged ceca, and mild gut inflammation. Treatment with antibiotics increased the expression of TLR4, TLR5, and TLR9 in the ileum and TLR3, TLR4, TLR6, TLR7, and TLR8 in the colon, and it reduced the expression of TLR2, TLR3, and TLR6 in the ileum and TLR2 and TLR9 in the colon. Antibiotics decreased fecal output, delayed the whole gut and colonic transit, and reduced the spontaneous contractions and the response to acetylcholine (ACh) in the ileum and colon. Activation of TLR4 by lipopolysaccharide (LPS) reverted the reduction of the spontaneous contractions induced by antibiotics in the ileum. Activation of TLR4 by LPS and TLR5 by flagellin reduced the response to ACh in the ileum in control mice. Our results confirm the role of the microbiota in the regulation of TLRs expression and shed light on the microbiota connection to motor intestinal alterations.
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BFBNIB, EMUNI, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
The mammalian homolog B1 of Unc-93 Caenorhabditis elegans known as UNC93B1 is a chaperone protein that mediates translocation of the nucleic acid-sensing Toll-like receptors (TLRs) from the ...endoplasmic reticulum to the endolysosomes. The triple deficient (UNC93B1 mutant) mice have a functional single point mutation in the UNC93B1 that results in non-functional TLR3, TLR7, and TLR9. Herein, we demonstrate that UNC93B1 mutant mice, in the C57BL/6 (resistant) genetic background, are highly susceptible to Leishmania major infection. Enhanced swelling of the footpad was associated with high levels of interleukin 10, decreased levels of interferon γ, and increased parasitism. None of the single TLR3, TLR7, and TLR9 knock-out (KO) mice resemble the UNC93B1 mutant phenotype upon infection with L. major. Whereas the double TLR7/TLR9 KO showed a partial phenotype, the triple TLR3/TLR7/TLR9 KO mice were as susceptible as the UNC93B1 mutant mice, when infected with Leishmania parasites. Finally, we demonstrate that treatment with either anti-interleukin 10 receptor monoclonal antibody or recombinant interleukin 12 restored a robust anti-parasite TH1 response and reverted the susceptible phenotype of UNC93B1 mutant mice. Altogether, our results indicate the redundant and essential role of nucleic acid-sensing TLR3, TLR7 and TLR9 in inducing interleukin 12, development of a TH1 response, and resistance to L. major infection in resistant C57BL/6 mice.
Background: MyD88 is a critical element for host resistance to L. major.
Results: UNC93B1 mutant and triple TLR3/7/9 knock-out mice are highly susceptible to infection with L. major.
Conclusion: Nucleic acid-sensing TLRs are key sensors for Leishmania parasites.
Significance: We disclose the mechanism by which L. major initiates IL-12 production and mediates development of Th1 lymphocytes and host resistance to infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bacterial lipoproteins/lipopeptides inducing host innate immune responses are sensed by mammalian Toll-like receptor 2 (TLR2). These bacterial lipoproteins are structurally divided into two groups, ...diacylated or triacylated lipoproteins, by the absence or presence of an amide-linked fatty acid. The presence of diacylated lipoproteins has been predicted in low-GC content Gram-positive bacteria and mycoplasmas based on the absence of one modification enzyme in their genomes; however, we recently determined triacylated structures in low-GC Gram-positive Staphylococcus aureus, raising questions about the actual lipoprotein structure in other low-GC content Gram-positive bacteria. Here, through intensive MS analyses, we identified a novel and unique bacterial lipoprotein structure containing an N-acyl-S-monoacyl-glyceryl-cysteine (named the lyso structure) from low-GC Gram-positive Enterococcus faecalis, Bacillus cereus, Streptococcus sanguinis, and Lactobacillus bulgaricus. Two of the purified native lyso-form lipoproteins induced proinflammatory cytokine production from mice macrophages in a TLR2-dependent and TLR1-independent manner but with a different dependence on TLR6. Additionally, two other new lipoprotein structures were identified. One is the “N-acetyl” lipoprotein structure containing N-acetyl-S-diacyl-glyceryl-cysteine, which was found in five Gram-positive bacteria, including Bacillus subtilis. The N-acetyl lipoproteins induced the proinflammatory cytokines through the TLR2/6 heterodimer. The other was identified in a mycoplasma strain and is an unusual diacyl lipoprotein structure containing two amino acids before the lipid-modified cysteine residue. Taken together, our results suggest the existence of novel TLR2-stimulating lyso and N-acetyl forms of lipoproteins that are conserved in low-GC content Gram-positive bacteria and provide clear evidence for the presence of yet to be identified key enzymes involved in the bacterial lipoprotein biosynthesis.
Background: The lipid-modified structures of bacterial lipoproteins in low-GC Gram-positive bacteria remains elusive.
Results: Three novel structures of bacterial lipoproteins were determined and functioned as TLR2 ligands.
Conclusion: Identified novel TLR2-stimulating lipoprotein structures are conserved in low-GC Gram-positive bacteria.
Significance: Results open further fields of research concerning functions and biosynthesis of bacterial lipoproteins.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
γδ T cells respond to stimulation via toll‐like receptors (TLR). Bovine γδ T cells express TLR3 and TLR7, receptors that are key for the recognition of viruses such as bovine respiratory ...syncytial virus (BRSV); however, responses of γδ T cells to stimulation via these receptors, and their role during viral infections, remains unclear. Here, we demonstrate that neonatal bovine γδ T cells exhibit robust chemokine and cytokine production in response to the TLR3 agonist, Poly(I:C), and the TLR7 agonist, Imiquimod. Importantly, we observe a similar phenotype in γδ T‐cell subsets purified from calves infected with BRSV. Bovine γδ T cells are divided into subsets based upon their expression of WC1, and the response to TLR stimulation and viral infection differs between these subsets, with WC1.1+ and WC1neg γδ T cells producing macrophage inflammatory protein‐1α and granulocyte–macrophage colony‐stimulating factor, and WC1.2+ γδ T cells preferentially producing the regulatory cytokines interleukin‐10 and transforming growth factor‐β. We further report that the active vitamin D metabolite 1,25‐dihydroxyvitamin D3 does not alter γδ T‐cell responses to TLR agonists or BRSV. To our knowledge, this is the first characterization of the γδ T‐cell response during in vivo BRSV infection and the first suggestion that WC1.1+ and WC1neg γδ T cells contribute to the recruitment of inflammatory populations during viral infection. Based on our results, we propose that circulating γδ T cells are poised to rapidly respond to viral infection and suggest an important role for γδ T cells in the innate immune response of the bovine neonate.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Toll-like receptors (TLRs) have a central role in innate immunity as they detect conserved pathogen-associated molecular patterns (PAMPs) on a range of microbes, including viruses, leading to innate ...immune activation and orchestration of the adaptive immune response. To date, a large number of viruses have been shown to trigger innate immunity via TLRs, suggesting that these receptors are likely to be important in the outcome to viral infection. This suggestion is supported by the observation that many viruses have evolved mechanisms not only to evade the innate immune system, but also to subvert it for the benefit of the virus. In this review we will discuss earlier evidence, mainly from knock-out mice studies, implicating TLRs in the innate immune response to viruses, in light of more recent clinical data demonstrating that TLRs are important for anti-viral immunity in humans.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor ...(TLR)7, TLR8, and TLR9 sense microbial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8- or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9 ⁻/⁻) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8 ⁻/⁻ or TLR9 ⁻/⁻ mice. On the cellular level, TLR8 ⁻/⁻ and TLR8/9 ⁻/⁻ dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9 ⁻/⁻ cells responded normally. Moreover, B cells from TLR9 ⁻/⁻ and TLR8/9 ⁻/⁻ mice were hyperesponsive to R848, but TLR8 ⁻/⁻ B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Coronavirus disease‐2019 (COVID‐19) outbreak due to novel coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has come out as a major threat for mankind in recent ...times. It is continually taking an enormous toll on mankind by means of increasing number of deaths, associated comorbidities, and socioeconomic loss around the globe. Unavailability of chemotherapeutics/vaccine has posed tremendous challenges to scientists and doctors for developing an urgent therapeutic strategy. In this connection, the present in silico study aims to understand the sequence divergence of spike protein (the major infective protein of SARS‐CoV‐2), its mode of interaction with the angiotensin‐converting enzyme‐2 receptor (ACE2) receptor of human and related animal hosts/reservoir. Moreover, the involvement of the human Toll‐like receptors (TLRs) against the spike protein has also been demonstrated. Our data indicated that the spike glycoprotein of SARS‐CoV‐2 is phylogenetically close to bat coronavirus and strongly binds with ACE2 receptor protein from both human and bat origin. We have also found that cell surface TLRs, especially TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 to induce inflammatory responses. The present study supported the zoonotic origin of SARS‐CoV‐2 from a bat and also revealed that TLR4 may have a crucial role in the virus‐induced inflammatory consequences associated with COVID‐19. Therefore, selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19. Finally, this study is expected to improve our understanding on the immunobiology of SARS‐CoV‐2 and could be useful in adopting spike protein, ACE2, or TLR‐guided intervention strategy against COVID‐19 shortly.
Highlights
Spike glycoprotein of SARS‐CoV‐2 is phylogenetically close to bat coronavirus.
SARS‐CoV‐2 spike glycoprotein strongly binds with ACE2 receptor protein from both human and bat origin.
Cell surface TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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