scholarly journals Interplay of the Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection

2020 ◽  
Author(s):  
Jyoti Pant ◽  
Marie Samanovic ◽  
Maria T Nelson ◽  
Mert K Keceli ◽  
Joseph Verdi ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Immune Cells ◽  
Density Lipoprotein ◽  
Parasite Burden ◽  
Innate Immune ◽  
Infectious Dose ◽  
Trypanosome Lytic Factor ◽  
Metacyclic Promastigotes ◽  
Early Recruitment

AbstractTrypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein complex that contains APOL1, the lytic component. Human TLF confers sterile immunity to many animal-infective extracellular Trypanosoma Ssp, which have been extensively investigated. Here, we have dissected the underappreciated role of TLF and neutrophils against intracellular Leishmania in intradermal infection. Our data show that mice producing human or baboon TLF have reduced parasite burdens when infected intradermally with metacyclic promastigotes of L. major. This TLF-mediated reduction in parasite burden was lost in neutrophil-depleted TLF mice, suggesting that early recruitment of neutrophils is required for TLF-mediated killing of L. major. Neutrophils and macrophages are the predominant phagocytes recruited to the site of infection. Our data show that acidification of the macrophage phagosome is essential for TLF-mediated lysis of metacyclic promastigotes. In vitro we find that only metacyclic promastigotes co-incubated with TLF in an acidic milieu were lysed. However, amastigotes were not killed by TLF at any pH. These findings correlated with binding experiments, revealing that labeled TLF binds specifically to the surface of metacyclic promastigotes, but not to amastigotes. During differentiation to the amastigote stage, the parasites shed their surface glycoconjugates. Metacyclic promastigotes of L. major deficient in the synthesis of surface glycoconjugates (lpg1- and lpg5A-/lpg5B-) were partially resistant to TLF lysis. We propose that TLF binds to the outer surface glycoconjugates of metacyclic promastigotes, whereupon APOL1 forms a pH-gated ion channel in the plasma membrane, resulting in osmotic lysis. We hypothesize that resistance to TLF requires shedding of the surface glycoconjugates, which occurs upon phagocytosis by immune cells.Author SummaryLeishmaniasis is a common term used for disease caused by parasites of the genus Leishmania. Depending on the parasite species and the clinical outcome of the disease, leishmaniasis can be divided into cutaneous, muco-cutaneous and visceral. Of the three, cutaneous leishmaniasis is the most common form, which is usually characterized by a localized lesion due to the infection of immune cells, primarily macrophages of the dermis and local lymph nodes. Sometimes, infected individuals can remain asymptomatic and do not show visible lesions. Moreover, the time between the infection and appearance of lesions are also variable and range from a few weeks to months and a few years in some cases. This subclinical stage of leishmaniasis depends on a variety of factors: parasite virulence, infectious dose, and host immune response. Therefore, it is important to understand the host-parasite interaction and its role in the clinical outcome of the disease. Here, we analyze the interaction between a cutaneous strain of Leishmania and a host innate immune factor called Trypanosome Lytic Factor (TLF). TLF is a type of High-Density Lipoprotein (HDL) complex that circulates in our plasma. TLF kills extracellular African Trypanosomes by lysing the parasites. The lytic ability of TLF is due to the primate specific protein APOL1 that forms pH gated ion channels. APOL1 inserts into biological membranes at acidic pH and forms a closed ion-channel that opens when the membrane associated APOL1 is exposed to neutral pH.Using transgenic mice producing primate TLF, we show both human and baboon TLFs ameliorate cutaneous Leishmania major infection. The reduction in parasite burden correlated with: 1. infectious dose of metacyclic promastigotes and 2. the concentration of circulating TLF in mouse plasma. The early recruitment of neutrophils at the site of infection was required for the reduction of parasite burden by TLF. Macrophages, another major cell that phagocytoses metacyclic promastigotes at the site of infection require an acidified phagosome for TLF mediated killing of L. major. The acidification step is also essential for TLF mediated lysis of axenic metacyclic promastigotes of Leishmania in vitro. The susceptibility of metacyclic promastigotes to TLF mediated lysis is governed by the surface glycoconjugates of Leishmania. We find that surface glycoconjugate deficient Leishmania are resistant to TLF mediated killing. Based on these data, we conclude that the shedding of surface glycoconjugates while transitioning from metacyclic promastigotes to amastigotes results in parasite resistance to TLF mediated lysis. Whether TLF is effective at killing metacyclic promastigotes of other experimentally tractable Leishmania sp. such as L. infantum, and L. donovani, which have slightly different surface glycoconjugate structures is yet to be tested. Our data raise the possibility that TLF can have lytic activity against a broad range of pathogens such as bacteria, viruses, fungi and parasites with surface glycoconjugates that transit through intracellular acidic compartments.

scholarly journals Interplay of Trypanosome Lytic Factor and innate immune cells in the resolution of cutaneous Leishmania infection

2021 ◽  
Vol 17 (9) ◽  
pp. e1008768
Author(s):  
Jyoti Pant ◽  
Marie Samanovic ◽  
Maria T. Nelson ◽  
Mert K. Keceli ◽  
Joseph Verdi ◽  
...  
Keyword(s):  
Immune Cells ◽  
Leishmania Major ◽  
Density Lipoprotein ◽  
Parasite Burden ◽  
Leishmania Infection ◽  
Phlebotomine Sand Flies ◽  
Trypanosome Lytic Factor ◽  
Metacyclic Promastigotes

Trypanosome Lytic Factor (TLF) is a primate-specific high-density lipoprotein (HDL) complex that, through the cation channel-forming protein apolipoprotein L-1 (APOL1), provides innate immunity to a select kinetoplastid parasites. The immunoprotective effects of TLF have been extensively investigated in the context of its interaction with the extracellular protozoan Trypanosoma brucei brucei, to which it confers sterile immunity. We previously showed that TLF could act against intracellular pathogen Leishmania, and here we dissected the role of TLF and its synergy with host-immune cells. Leishmania major is transmitted by Phlebotomine sand flies, which deposit the parasite intradermally into mammalian hosts, where neutrophils are the predominant phagocytes recruited to the site of infection. Once in the host, the parasites are phagocytosed and shed their surface glycoconjugates during differentiation to the mammalian-resident amastigote stage. Our data show that mice producing TLF have reduced parasite burdens when infected intradermally with metacyclic promastigotes of L. major, the infective, fly-transmitted stage. This TLF-mediated reduction in parasite burden was lost in neutrophil-depleted mice, suggesting that early recruitment of neutrophils is required for TLF-mediated killing of L. major. In vitro we find that only metacyclic promastigotes co-incubated with TLF in an acidic milieu were lysed. However, amastigotes were not killed by TLF at any pH. These findings correlated with binding experiments, revealing that labeled TLF binds specifically to the surface of metacyclic promastigotes, but not to amastigotes. Metacyclic promastigotes of L. major deficient in the synthesis of surface glycoconjugates LPG and/or PPG (lpg1- and lpg5A-/lpg5B- respectively whose absence mimics the amastigote surface, were resistant to TLF-mediated lysis. We propose that TLF binds to the outer surface glycoconjugates of metacyclic promastigotes, whereupon it kills the parasite in acidic phagosome of phagocytes. We hypothesize that resistance to TLF requires shedding of the surface glycoconjugates, which occurs several hours after phagocytosis by immune cells, creating a relatively short-lived but effective window for TLF to act against Leishmania.

scholarly journals Oral Exposure to House Dust Mite Activates Intestinal Innate Immunity

Foods ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 561
Author(s):  
Sara Benedé ◽  
Leticia Pérez-Rodríguez ◽  
Mónica Martínez-Blanco ◽  
Elena Molina ◽  
Rosina López-Fandiño
Keyword(s):  
House Dust ◽  
House Dust Mite ◽  
Immune Cells ◽  
Oral Route ◽  
Innate Immune ◽  
Oral Exposure ◽  
Lymphoid Tissues ◽  
Innate Immune Cells ◽  
Dust Mite

Scope: House dust mite (HDM) induces Th2 responses in lungs and skin, but its effects in the intestine are poorly known. We aimed to study the involvement of HDM in the initial events that would promote sensitization through the oral route and eventually lead to allergy development. Methods and results: BALB/c mice were exposed intragastrically to proteolytically active and inactive HDM, as such, or in combination with egg white (EW), and inflammatory and type 2 responses were evaluated. Oral administration of HDM, by virtue of its proteolytic activity, promoted the expression, in the small intestine, of genes encoding tight junction proteins, proinflammatory and Th2-biasing cytokines, and it caused expansion of group 2 innate immune cells, upregulation of Th2 cytokines, and dendritic cell migration and activation. In lymphoid tissues, its proteolytically inactivated counterpart also exerted an influence on the expression of surface DC molecules involved in interactions with T cells and in Th2 cell differentiation, which was confirmed in in vitro experiments. However, in our experimental setting we did not find evidence for the promotion of sensitization to coadministered EW. Conclusion: Orally administered HDM upregulates tissue damage factors and also acts as an activator of innate immune cells behaving similarly to potent oral Th2 adjuvants.

Abstract 1772: Cardiomyocyte Damage-Released S100A1 Protein Evokes A Proinflammatory Phenotype In Cardiac Fibroblasts

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
David Rohde ◽  
Melanie Boerries ◽  
Herzog Nicole ◽  
Gang Qiu ◽  
Philipp Ehlermann ◽  
...  
Keyword(s):  
Western Blotting ◽  
Immune Cells ◽  
Nuclear Translocation ◽  
Cardiac Fibroblasts ◽  
Innate Immune ◽  
Host Cells ◽  
Boyden Chamber ◽  
Innate Immune Cells ◽  
Danger Signal

Background: S100A1, a cardiomyocyte specific inotropic calcium sensor protein, is released from infarcted human myocardium in the extracellular environment and circulation, reaching peak serum levels (1–2 μM) 8–9 hours after clinical onset. As growing evidence indicates that S100 proteins can act as pre-existing danger signals triggering the innate immune system into action upon release from injured host cells, we hypothesized that damage-released S100A1 can act as a cardiac danger signal alerting innate immune cells. Methods and Results: Here we report for the first time that necrotic cardiomyocytes release S100A1 protein in vitro, which is exclusively internalized by cardiac fibroblasts (CFs) in a clathrin- and caveolin-independent manner as shown by IF. Internalized S100A1 specifically activated MAPKs/SAPKs (p38, ERK1/2 and JNK) resulting in nuclear translocation of p65 (NF-kB) as assessed by Western blotting, EMSA and IF. In turn, S100A1 triggered an inflammatory gene program in CFs including enhanced expression of adhesion molecules, integrins, chemokines and cytokines including I-CAM, V-CAM, CD11b/18, IL1-alpha, MCP-1, TNF-alpha, SDF-1 among others as obtained by RT-PCR, Western blotting and ELISA. This resulted in enhanced chemoattraction and adhesion of monocytotic and stem cells to S100A1-activated CF as shown by Boyden-chamber and adhesion assays. In line with their proinflammatory transition, S100A1-activated CFs exhibited decreased collagen-1/-3 expression and de-novo collagen production, enhanced collagenolytic MMP-9 abundance and activity and increased levels of the antiangiogenic matricellular factor thrombospondin-2 reflecting extracellular matrix net degradation. Importantly, the immun-modulatory and antifibrotic actions of S100A1 protein in vitro were restricted to CFs, RAGE independent and occurred at concentrations (0.1–1 μM) that were found in patients after AMI. Conclusion: Our in vitro results indicate that S100A1 has the properties of a pre-exisiting endogenous cardiomyocyte danger signal transforming cardiac fibroblasts into immunmodulatory cells that might recruit innate immune cells to the site of cardiac injury and link cardiomyocyte damage to post-MI inflammation.

scholarly journals Hyperglycemic Memory of Innate Immune Cells Promotes In Vitro Proinflammatory Responses of Human Monocytes and Murine Macrophages

2021 ◽  
pp. ji1901348
Author(s):  
Kathrin Thiem ◽  
Samuel T. Keating ◽  
Mihai G. Netea ◽  
Niels P. Riksen ◽  
Cees J. Tack ◽  
...  
Keyword(s):  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Human Monocytes ◽  
Murine Macrophages ◽  
Proinflammatory Responses

scholarly journals BATF2 inhibits immunopathological Th17 responses by suppressing Il23a expression during Trypanosoma cruzi infection

2017 ◽  
Vol 214 (5) ◽  
pp. 1313-1331 ◽  
Author(s):  
Shoko Kitada ◽  
Hisako Kayama ◽  
Daisuke Okuzaki ◽  
Ritsuko Koga ◽  
Masao Kobayashi ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Parasite Burden ◽  
Innate Immune ◽  
Negative Regulator ◽  
Innate Immune Cells ◽  
Th17 Response ◽  
Ifn Γ ◽  
Cruzi Infection

Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to Trypanosoma cruzi–specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23–IL-17 axis during T. cruzi infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of Il23a in innate immune cells. IL-17, but not IFN-γ, was more highly produced by CD4+ T cells from spleens and livers of T. cruzi–infected Batf2−/− mice than by those of wild-type mice. In this context, Batf2−/− mice showed severe multiorgan pathology despite reduced parasite burden. T. cruzi–induced IL-23 production was increased in Batf2−/− innate immune cells. The T. cruzi–induced enhanced Th17 response was abrogated in Batf2−/−Il23a−/− mice. The interaction of BATF2 with c-JUN prevented c-JUN–ATF-2 complex formation, inhibiting Il23a expression. These results demonstrate that IFN-γ–inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during T. cruzi infection.

scholarly journals The Life Cycle Stages of Pneumocystis murina Have Opposing Effects on the Immune Response to This Opportunistic Fungal Pathogen

2016 ◽  
Vol 84 (11) ◽  
pp. 3195-3205 ◽  
Author(s):  
Heather M. Evans ◽  
Grady L. Bryant ◽  
Beth A. Garvy
Keyword(s):  
Cell Wall ◽  
Life Cycle ◽  
Immune Responses ◽  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Content Type ◽  
Life Cycle Stages ◽  
Ifn Γ

The cell wall β-glucans of Pneumocystis cysts have been shown to stimulate immune responses in lung epithelial cells, dendritic cells, and alveolar macrophages. Little is known about how the trophic life forms, which do not have a fungal cell wall, interact with these innate immune cells. Here we report differences in the responses of both neonatal and adult mice to the trophic and cystic life cycle stages of Pneumocystis murina . The adult and neonatal immune responses to infection with Pneumocystis murina trophic forms were less robust than the responses to infection with a physiologically normal mixture of cysts and trophic forms. Cysts promoted the recruitment of nonresident innate immune cells and T and B cells into the lungs. Cysts, but not trophic forms, stimulated increased concentrations of the cytokine gamma interferon (IFN-γ) in the alveolar spaces and an increase in the percentage of CD4 + T cells that produce IFN-γ. In vitro , bone marrow-derived dendritic cells (BMDCs) stimulated with cysts produced the proinflammatory cytokines interleukin 1β (IL-1β) and IL-6. In contrast, trophic forms suppressed antigen presentation to CD4 + T cells, as well as the β-glucan-, lipoteichoic acid (LTA)-, and lipopolysaccharide (LPS)-induced production of interleukin 1β (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α) by BMDCs. The negative effects of trophic forms were not due to ligation of mannose receptor. Our results indicate that optimal innate and adaptive immune responses to Pneumocystis species are dependent on stimulation with the cyst life cycle stage. Conversely, trophic forms suppress β-glucan-induced proinflammatory responses in vitro , suggesting that the trophic forms dampen cyst-induced inflammation in vivo .

scholarly journals Keratinocytes contribute intrinsically to psoriasis upon loss of Tnip1 function

2016 ◽  
Vol 113 (41) ◽  
pp. E6162-E6171 ◽  
Author(s):  
Sirish K. Ippagunta ◽  
Ruchika Gangwar ◽  
David Finkelstein ◽  
Peter Vogel ◽  
Stephane Pelletier ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Process ◽  
Immune Cell ◽  
Genetic Alterations ◽  
Innate Immune ◽  
Negative Regulator ◽  
Specific Gene ◽  
Innate Immune Cells ◽  
Chemokine Production

Psoriasis is a chronic inflammatory skin disease with a clear genetic contribution, characterized by keratinocyte proliferation and immune cell infiltration. Various closely interacting cell types, including innate immune cells, T cells, and keratinocytes, are known to contribute to inflammation. Innate immune cells most likely initiate the inflammatory process by secretion of IL-23. IL-23 mediates expansion of T helper 17 (Th17) cells, whose effector functions, including IL-17A, activate keratinocytes. Keratinocyte activation in turn results in cell proliferation and chemokine expression, the latter of which fuels the inflammatory process through further immune cell recruitment. One question that remains largely unanswered is how genetic susceptibility contributes to this process and, specifically, which cell type causes disease due to psoriasis-specific genetic alterations. Here we describe a mouse model based on the human psoriasis susceptibility locus TNIP1, also referred to as ABIN1, whose gene product is a negative regulator of various inflammatory signaling pathways, including the Toll-like receptor pathway in innate immune cells. We find that Tnip1-deficient mice recapitulate major features of psoriasis on pathological, genomic, and therapeutic levels. Different genetic approaches, including tissue-specific gene deletion and the use of various inflammatory triggers, reveal that Tnip1 controls not only immune cells, but also keratinocyte biology. Loss of Tnip1 in keratinocytes leads to deregulation of IL-17–induced gene expression and exaggerated chemokine production in vitro and overt psoriasis-like inflammation in vivo. Together, the data establish Tnip1 as a critical regulator of IL-17 biology and reveal a causal role of keratinocytes in the pathogenesis of psoriasis.

scholarly journals Trained Immunity and Reactivity of Macrophages and Endothelial Cells

2020 ◽  
Author(s):  
Charles Drummer ◽  
Fatma Saaoud ◽  
Ying Shao ◽  
Yu Sun ◽  
Keman Xu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Chronic Inflammation ◽  
Immune Cells ◽  
Metabolic Diseases ◽  
Tricarboxylic Acid Cycle ◽  
Density Lipoprotein ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Vaccine Response ◽  
Trained Immunity

Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, bacillus Calmette-Guerin, and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets.

scholarly journals The fungal ligand chitin directly binds and signals inflammation dependent on oligomer size and TLR2

2018 ◽  
Author(s):  
Katharina Fuchs ◽  
Yamel Cardona Gloria ◽  
Olaf-Oliver Wolz ◽  
Franziska Herster ◽  
Lokesh Sharma ◽  
...  
Keyword(s):  
Immune Cells ◽  
Innate Immune ◽  
Novel Therapies ◽  
Toll Like Receptor ◽  
Antagonistic Effects ◽  
Size Dependent ◽  
Activation System ◽  
Chitin Receptor

AbstractChitin is a highly abundant polysaccharide and linked to fungal infection and asthma. Unfortunately, its polymeric structure has hampered the identification of immune receptors directly binding chitin and signaling immune activation and inflammation, because purity, molecular structure and molarity are not well definable for a polymer typically extracted from biomass. Therefore, by using defined chitin (N-acetyl-glucosamine) oligomers, we identified six subunit long chitin chains as the smallest immunologically active motif and the innate immune receptor Toll-like receptor (TLR) 2 as the primary fungal chitin receptor on human and murine immune cells. Chitin oligomers directly bound TLR2 with nanomolar affinity and showed both overlapping and distinct signaling outcomes compared to known mycobacterial TLR2 ligands. Conversely, chitin oligomers shorter than 6 subunits were inactive or showed antagonistic effects on chitin/TLR2-mediated signaling, hinting to a size-dependent sensing/activation system unexpectedly conserved in plants and humans. Since blocking the chitin-TLR2 interaction effectively prevented chitin-mediated inflammation in vitro and in vivo, our study highlights the chitin TLR2 interaction as a potential target for developing novel therapies in chitin-related pathologies and fungal disease.

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