scholarly journals Street RABV Induces the Cholinergic Anti-inflammatory Pathway in Human Monocyte-Derived Macrophages by Binding to nAChr α7

2021 ◽  
Vol 12 ◽  
Author(s):  
Carmen W. E. Embregts ◽  
Lineke Begeman ◽  
Cees J. Voesenek ◽  
Byron E. E. Martina ◽  
Marion P. G. Koopmans ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Macrophage Polarization ◽  
Flow Cytometric Analysis ◽  
Human Monocyte ◽  
Host Immune System ◽  
Inflammatory Pathway ◽  
Anti Inflammatory ◽  
Alpha Bungarotoxin

Rabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection via a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (rRABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr α7) on MDMs, and confirmed the specificity using the nAChr α7 antagonist alpha-bungarotoxin (α-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor α (TNF-α) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs might affect their function as T cell activators as well, as we found a significant decrease in proliferation of CD8+ T cells and an increased production of the anti-inflammatory cytokine IL-10. Lastly, using flow cytometric analysis we observed a significant increase in expression of the M2-c surface marker CD163, hinting that street RABV might be able to affect macrophage polarization. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, possibly affecting T cell functioning.

scholarly journals Street RABV induces the cholinergic anti-inflammatory pathway in human monocyte-derived macrophages by binding to nAChr ɑ7, and upregulates the M2-c marker CD163

2021 ◽  
Author(s):  
C.W.E. Embregts ◽  
L. Begeman ◽  
C.J. Voesenek ◽  
B.E.E. Martina ◽  
M.P.G. Koopmans ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Human Monocyte ◽  
T Cell Proliferation ◽  
Strong Immune Response ◽  
Inflammatory Pathway ◽  
Inflammatory State ◽  
The Central Nervous System ◽  
Anti Inflammatory ◽  
Antigen Presenting

AbstractRabies virus (RABV) is able to reach the central nervous system (CNS) without triggering a strong immune response, using multiple mechanisms to evade and suppress the host immune system. After infection via a bite or scratch from a rabid animal, RABV comes into contact with macrophages, which are the first antigen-presenting cells (APCs) that are recruited to the area and play an essential role in the onset of a specific immune response. It is poorly understood how RABV affects macrophages, and if the interaction contributes to the observed immune suppression. This study was undertaken to characterize the interactions between RABV and human monocyte-derived macrophages (MDMs). We showed that street RABV does not replicate in human MDMs. Using a recombinant trimeric RABV glycoprotein (RABV-tG) we showed binding to the nicotinic acetylcholine receptor alpha 7 (nAChr ɑ7) on MDMs, and confirmed the specificity using the nAChr ɑ7 antagonist alpha-bungarotoxin (ɑ-BTX). We found that this binding induced the cholinergic anti-inflammatory pathway (CAP), characterized by a significant decrease in tumor necrosis factor ɑ (TNF-ɑ) upon LPS challenge. Using confocal microscopy we found that induction of the CAP is associated with significant cytoplasmic retention of nuclear factor κB (NF-κB). Co-cultures of human MDMs exposed to street RABV and autologous T cells further revealed that the observed suppression of MDMs affects their function as T cell activators as well, as we found a significant decrease in proliferation of CD8+ T cells. Lastly, using flow cytometric analysis we observed a significant increase in expression of CD163, hinting that street RABV is able to polarize macrophages towards a M2-c anti-inflammatory phenotype. Taken together, these results show that street RABV is capable of inducing an anti-inflammatory state in human macrophages, which affects T cell proliferation.Author summaryRabies virus (RABV) is transmitted by a bite or a scratch from an infected animal. Infection leads to a lethal encephalitis and once clinical symptoms occur, there is no effective treatment available. The virus is able to travel from the initial site of infection to the central nervous system without triggering a strong immune response, using multiple mechanisms to evade and suppress the immune system. Up to present it is unclear when and where this immunosuppression is initiated, and if local immune cells are involved as well. Understanding the complete mechanisms of immunosuppression by RABV is essential for the development and improvement of effective post-exposure treatments. In this paper we studied if RABV is able to suppress human primary macrophages as these will be the first antigen-presenting cells that are recruited to the site of infection, and are known to be important in initiating an efficient immune response. We show that RABV is able to bind, but not infect, human macrophages. Binding induces an anti-inflammatory pathway, which leads to limited T cell proliferation and directs macrophages towards and anti-inflammatory state. These results show that RABV-macrophage interactions might indeed be one of the early steps in the onset of RABV-induced immunosuppression.

scholarly journals Tuberculosis–Cancer Parallels in Immune Response Regulation

2020 ◽  
Vol 21 (17) ◽  
pp. 6136
Author(s):  
Thomas E. Bickett ◽  
Sana D. Karam
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Research Collaboration ◽  
Macrophage Polarization ◽  
Innate Immune ◽  
Host Immune System ◽  
Cancer Therapies ◽  
Development Of Resistance ◽  
New Cancer Therapies

Mycobacterium tuberculosis and cancer are two diseases with proclivity for the development of resistance to the host immune system. Mechanisms behind resistance can be host derived or disease mediated, but they usually depend on the balance of pro-inflammatory to anti-inflammatory immune signals. Immunotherapies have been the focus of efforts to shift that balance and drive the response required for diseases eradication. The immune response to tuberculosis has widely been thought to be T cell dependent, with the majority of research focused on T cell responses. However, the past decade has seen greater recognition of the importance of the innate immune response, highlighting factors such as trained innate immunity and macrophage polarization to mycobacterial clearance. At the same time, there has been a renaissance of immunotherapy treatments for cancer since the first checkpoint inhibitor passed clinical trials, in addition to work highlighting the importance of innate immune responses to cancer. However, there is still much to learn about host-derived responses and the development of resistance to new cancer therapies. This review examines the similarities between the immune responses to cancer and tuberculosis with the hope that their commonalities will facilitate research collaboration and discovery.

scholarly journals Lipoteichoic Acid Inhibits Interleukin-2 (IL-2) Function by Direct Binding to IL-2

2001 ◽  
Vol 8 (5) ◽  
pp. 972-979 ◽  
Author(s):  
Lisa M. Plitnick ◽  
Robert A. Jordan ◽  
Jeffrey A. Banas ◽  
Dawn M. Jelley-Gibbs ◽  
Mary C. Walsh ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Flow Cytometric Analysis ◽  
Lipoteichoic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Direct Binding

ABSTRACT Lipoteichoic acid (LTA) is associated with the cell envelope of most gram-positive bacteria. Although previously thought to act mainly as a virulence factor by virtue of its adhesive nature, evidence is now provided that LTA can also suppress the function of interleukin-2 (IL-2), an autocrine growth factor for T cells. LTA from four separate bacterial strains lowered the levels of detectable IL-2 during a peripheral blood mononuclear cell response to the antigen tetanus toxoid (TT). T-cell proliferation in response to TT was similarly inhibited by LTA. In contrast, levels of detectable gamma interferon increased. In addition, LTA inhibited IL-2 detection by enzyme-linked immunosorbent assay (ELISA) and blocked the proliferative response of an IL-2-dependent T-cell line to soluble IL-2. Further studies using ELISA demonstrated that LTA blocks IL-2 detection and function by binding directly to IL-2. Flow cytometric analysis revealed that IL-2 binding to T cells is inhibited in the presence of purified LTA but not LTA plus anti-LTA monoclonal antibody. In summary, these studies demonstrate a novel effect of LTA on the immune response through direct binding to IL-2 and inhibition of IL-2 function. Importantly, gram-positive organisms from which LTA is obtained not only play an important role in the pathology of diseases such as bacterial endocarditis, septic shock, acute respiratory distress syndrome, and multiple organ failure but also comprise a significant portion of commensal populations within the human host. Inhibition of IL-2 function by LTA may represent yet another mechanism by which gram-positive bacteria dampen the host immune response and facilitate survival. Thus, LTA provides a potential target for therapeutic intervention when gram-positive organisms are involved.

scholarly journals Pathogen-encoded evasion of CXCL10 and T cell responses

2019 ◽  
Author(s):  
Alejandro L. Antonia ◽  
Monica I. Alvarez ◽  
Esme Trahair ◽  
Kyle D. Gibbs ◽  
Kelly J. Pittman ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Cd8 T Cells ◽  
Salmonella Enterica ◽  
T Cell Response ◽  
Host Immune System ◽  
Intracellular Pathogens ◽  
Lesion Development

AbstractClearance of intracellular pathogens, such asLeishmania (L.) major, depends on a well-regulated adaptive T cell response. Here we describe a pathogen-encoded mechanism to alter T cell recruitment by suppressing CXCL10, a chemokine that recruits CD4+ and CD8+ T cells by signaling through the CXCR3 receptor.L. majorsuppresses CXCL10 through the virulence factor and protease, glycoprotein-63(gp63).GP63 cleaves CXCL10 after amino acid A81, impairing T-cell chemotaxisin vitro.GP63 from either extracellular promastigotes or intracellular amastigotes is capable of cleaving CXCL10. Consistent with CXCL10 cleavage during infection, we observed GP63-mediated impairment of activated CD8+ T-cells in the draining lymph nodes of C57BL/6JWTmice. Correspondingly, in C57BL/6JWTmice,gp63deletion resulted in slower lesion development and a smaller maximum lesion size. However, infection in C57BL/6Jcxcr3−/−mice revealed the delay to lesion development required CXCR3 signaling. Finally,Salmonella entericaandChlamydia trachomatisinfection also suppress CXCL10, demonstrating convergent evolution of this immune evasion strategy in diverse intracellular pathogens. Understanding mechanisms of CXCL10 evasion may facilitate the development of novel therapeutic strategies to treat intracellular pathogens.Author SummaryLeishmaniasis is an infectious disease that affects over one million people annually. It is caused by intracellular parasites that have evolved to evade the host’s attempts to eliminate the parasite. The most common form of disease, cutaneous leishmaniasis, causes disfiguring skin lesions if the host immune system does not appropriately respond to the infection. A family of molecules called chemokines are critical for the recruitment of specific subsets of immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that the parasiteLeishmania (L.) majoremploys to disrupt the immune response by interfering with chemokine signaling. By this strategy,L. majoruses a protease to cleave chemokines known to recruit T-cells required for fighting off infection. We show thatL. majorcleavage of these immune signals changes the recruitment of CD8+ T-cells and alters disease progression in mice. Finally, we observe that multiple common human intracellular pathogens, includingChlamydia trachomatisandSalmonella enterica, interfere with the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival and exacerbate disease outcomes.

scholarly journals LXR nuclear receptors prompt a pro-inflammatory gene and functional profile in human macrophages

2021 ◽  
Author(s):  
Arturo González de la Aleja1 ◽  
Mónica Torres-Torresano ◽  
Juan Vladimir de la Rosa ◽  
Barbara Alonso ◽  
Enrique Capa-Sardón ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
Cholesterol Metabolism ◽  
Macrophage Polarization ◽  
Human Monocyte ◽  
Gene Signature ◽  
Human Macrophage ◽  
Human Macrophages ◽  
Inflammatory Gene ◽  
Anti Inflammatory

Abstract Liver X Receptors (LXR) control cholesterol metabolism and exert anti-inflammatory actions in activated macrophages. However, their contribution to human macrophage polarization in the absence of pathogenic stimuli remains unclear. In fact, the LXR pathway has been reported to be significantly enriched in pro-inflammatory synovial macrophages from rheumatoid arthritis patients as well as in immunosuppressive tumors-associated macrophages from human metastatic colon tumors. To determine the role of LXR on macrophage differentiation and polarization, we have analyzed the contribution of LXR to the acquisition of the inflammatory and T-cell-activating functions of human monocyte-derived macrophages. We now report that LXR activation prompts the acquisition of a pro-inflammatory gene signature in human macrophages, whereas LXR inactivation results in enrichment of an anti-inflammatory gene profile. Accordingly, activation and inhibition of LXR oppositely alter the production of cytokines (e.g., TNF, IL1b, CCL17, CCL19, IFNb1) and T cell stimulation activities associated to human macrophage polarization. Mechanistically, the LXR-stimulated macrophage polarization shift relies on their ability to modulate the expression of MAFB and MAF, which govern the acquisition of the macrophage anti-inflammatory profile. The pathological significance of the LXR-mediated macrophage polarization shift was demonstrated by the ability of LXR agonists to modulate macrophage polarization promoted by either tumor-derived ascitic fluids or by synovial fluid from rheumatoid arthritis patients. As a whole, our results demonstrate that LXR activation prompts the acquisition of a pro-inflammatory transcriptional and functional specialization in human macrophages .

Prediction of Prophylactic Peptide Vaccine Candidates for Human Papillomavirus (HPV): An Immunoinformatics and Reverse Vaccinology Approach

2020 ◽  
Vol 17 ◽  
Author(s):  
Mehreen Ismail ◽  
Zureesha Sajid ◽  
Amjad Ali ◽  
Xiaogang Wu ◽  
Syed Aun Muhammad ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
T Cell ◽  
Binding Affinity ◽  
Cd8 T Cells ◽  
Reverse Vaccinology ◽  
Host Immune System ◽  
T Cell Epitopes ◽  
Multiple Alleles ◽  
Vaccine Candidates

Background: Human Papillomavirus (HPV) is responsible for substantial morbidity and mortality worldwide. We predicted immunogenic promiscuous monovalent and polyvalent T-cell epitopes from the polyprotein of the Human Papillomavirus (HPV) using a range of bioinformatics tools and servers. Methods: We used immunoinformatics and reverse vaccinology-based approaches to design prophylactic peptides by antigenicity analysis, Tcell epitopes prediction, proteasomal and conservancy evaluation, host-pathogen protein interactions, and in silico binding affinity analysis. Results: We found two early proteins (E2 and E6) and two late proteins (L1 and L2) of HPV as potential vaccine candidates. Of these proteins (E2, E6, L1 & L2), 2-epitopes of each candidate protein for multiple alleles of MHC class I and II bearing significant binding affinity (>-6.0 kcal/mole). These potential epitopes for CD4+ and CD8+ T-cells were also linked to design polyvalent construct using GPGPG linkers. Cholera toxin B and mycobacterial heparin-binding hemagglutinin adjuvant with a molecular weight of 12.5 and 18.5 kDa were used for epitopes of CD4+ and CD8+ T-cells respectively. The molecular docking indicated the optimum binding affinity of HPV peptides with MHC molecules. This interaction showed that our predicted vaccine candidates are suitable to trigger the host immune system to prevent HPV infections. Conclusion: The predicted conserved T-cell epitopes would contribute to the imminent design of HPV vaccine candidates, which will be able to induce a broad range of immune-responses in a heterogeneous HLA population.

scholarly journals The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tian-Yu Lei ◽  
Ying-Ze Ye ◽  
Xi-Qun Zhu ◽  
Daniel Smerin ◽  
Li-Juan Gu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Ischaemic Stroke ◽  
Immune Cells ◽  
Tissue Injury ◽  
Recovery Period ◽  
Vital Functions ◽  
Anti Inflammatory

AbstractThrough considerable effort in research and clinical studies, the immune system has been identified as a participant in the onset and progression of brain injury after ischaemic stroke. Due to the involvement of all types of immune cells, the roles of the immune system in stroke pathology and associated effects are complicated. Past research concentrated on the functions of monocytes and neutrophils in the pathogenesis of ischaemic stroke and tried to demonstrate the mechanisms of tissue injury and protection involving these immune cells. Within the past several years, an increasing number of studies have elucidated the vital functions of T cells in the innate and adaptive immune responses in both the acute and chronic phases of ischaemic stroke. Recently, the phenotypes of T cells with proinflammatory or anti-inflammatory function have been demonstrated in detail. T cells with distinctive phenotypes can also influence cerebral inflammation through various pathways, such as regulating the immune response, interacting with brain-resident immune cells and modulating neurogenesis and angiogenesis during different phases following stroke. In view of the limited treatment options available following stroke other than tissue plasminogen activator therapy, understanding the function of immune responses, especially T cell responses, in the post-stroke recovery period can provide a new therapeutic direction. Here, we discuss the different functions and temporal evolution of T cells with different phenotypes during the acute and chronic phases of ischaemic stroke. We suggest that modulating the balance between the proinflammatory and anti-inflammatory functions of T cells with distinct phenotypes may become a potential therapeutic approach that reduces the mortality and improves the functional outcomes and prognosis of patients suffering from ischaemic stroke.

scholarly journals Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rhianna Jones ◽  
Kyle Kroll ◽  
Courtney Broedlow ◽  
Luca Schifanella ◽  
Scott Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Rhesus Macaques ◽  
Oral Microbiome ◽  
Probiotic Supplementation ◽  
Siv Infection ◽  
Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

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