The long-lasting enigma of polycytidine (polyC) tract

Long polycytidine (polyC) tracts varying in length from 50 to 400 nucleotides were first described in the 5′-noncoding region (NCR) of genomes of picornaviruses belonging to the Cardio- and Aphthovirus genera over 50 years ago, but the molecular basis of their function is still unknown. Truncation or complete deletion of the polyC tracts in picornaviruses compromises virulence and pathogenicity but do not affect replicative fitness in vitro, suggesting a role as “viral security” RNA element. The evidence available suggests that the presence of a long polyC tract is required for replication in immune cells, which impacts viral distribution and targeting, and, consequently, pathogenic progression. Viral attenuation achieved by reduction of the polyC tract length has been successfully used for vaccine strategies. Further elucidation of the role of the polyC tract in viral replication cycle and its connection with replication in immune cells has the potential to expand the arsenal of tools in the fight against cancer in oncolytic virotherapy (OV). Here, we review the published data on the biological significance and mechanisms of action of the polyC tract in viral pathogenesis in Cardio- and Aphthoviruses.

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Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

Science Advances ◽

10.1126/sciadv.abc2331 ◽

2021 ◽

Vol 7 (8) ◽

pp. eabc2331 ◽

Cited By ~ 1

Author(s):

Jose M. Ayuso ◽

Shujah Rehman ◽

Maria Virumbrales-Munoz ◽

Patrick H. McMinn ◽

Peter Geiger ◽

...

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Molecular Mechanisms ◽

Nk Cell ◽

Checkpoint Inhibitors ◽

Waste Product ◽

Extended Period ◽

Cell Exhaustion

Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.

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Novel Insights on the Role of Nitric Oxide in the Ovary: A Review of the Literature

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18030980 ◽

2021 ◽

Vol 18 (3) ◽

pp. 980

Author(s):

Maria Cristina Budani ◽

Gian Mario Tiboni

Keyword(s):

Nitric Oxide ◽

In Vivo Studies ◽

Published Data ◽

Vitro Fertilization ◽

Peripheral Neurons ◽

Relevant Role ◽

Oocyte Meiotic Maturation

Nitric oxide (NO) is formed during the oxidation of L-arginine to L-citrulline by the action of multiple isoenzymes of NO synthase (NOS): neuronal NOS (nNOS), endotelial NOS (eNOS), and inducible NOS (iNOS). NO plays a relevant role in the vascular endothelium, in central and peripheral neurons, and in immunity and inflammatory systems. In addition, several authors showed a consistent contribution of NO to different aspects of the reproductive physiology. The aim of the present review is to analyse the published data on the role of NO within the ovary. It has been demonstrated that the multiple isoenzymes of NOS are expressed and localized in the ovary of different species. More to the point, a consistent role was ascribed to NO in the processes of steroidogenesis, folliculogenesis, and oocyte meiotic maturation in in vitro and in vivo studies using animal models. Unfortunately, there are few nitric oxide data for humans; there are preliminary data on the implication of nitric oxide for oocyte/embryo quality and in-vitro fertilization/embryo transfer (IVF/ET) parameters. NO plays a remarkable role in the ovary, but more investigation is needed, in particular in the context of human ovarian physiology.

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Linc00426 accelerates lung adenocarcinoma progression by regulating miR-455-5p as a molecular sponge

Cell Death and Disease ◽

10.1038/s41419-020-03259-2 ◽

2020 ◽

Vol 11 (12) ◽

Author(s):

Hongli Li ◽

Qingjie Mu ◽

Guoxin Zhang ◽

Zhixin Shen ◽

Yuanyuan Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Ectopic Expression ◽

Tumor Development ◽

Biological Significance ◽

Mesenchymal Transition

AbstractIncreasing lines of evidence indicate the role of long non-coding RNAs (LncRNAs) in gene regulation and tumor development. Hence, it is important to elucidate the mechanisms of LncRNAs underlying the proliferation, metastasis, and invasion of lung adenocarcinoma (LUAD). We employed microarrays to screen LncRNAs in LUAD tissues with and without lymph node metastasis and revealed their effects on LUAD. Among them, Linc00426 was selected for further exploration in its expression, the biological significance, and the underlying molecular mechanisms. Linc00426 exhibits ectopic expression in LUAD tissues and cells. The ectopic expression has been clinically linked to tumor size, lymphatic metastasis, and tumor differentiation of patients with LUAD. The deregulation of Linc00426 contributes to a notable impairment in proliferation, invasion, metastasis, and epithelial–mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the deregulation of Linc00426 could reduce cytoskeleton rearrangement and matrix metalloproteinase expression. Meanwhile, decreasing the level of Linc00426 or increasing miR-455-5p could down-regulate the level of UBE2V1. Thus, Linc00426 may act as a competing endogenous RNA (ceRNA) to abate miR-455-5p-dependent UBE2V1 reduction. We conclude that Linc00426 accelerates LUAD progression by acting as a molecular sponge to regulate miR-455-5p, and may be a potential novel tumor marker for LUAD.

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Fluorescence-Reported Allelic Exchange Mutagenesis Reveals a Role for Chlamydia trachomatis TmeA in Invasion That Is Independent of Host AHNAK

Infection and Immunity ◽

10.1128/iai.00640-17 ◽

2017 ◽

Vol 85 (12) ◽

Cited By ~ 8

Author(s):

M. J. McKuen ◽

K. E. Mueller ◽

Y. S. Bae ◽

K. A. Fields

Keyword(s):

Tissue Culture ◽

Host Cells ◽

Coding Sequences ◽

Content Type ◽

Allelic Exchange ◽

Infection Models ◽

Virulence Protein ◽

Complete Deletion

ABSTRACT Development of approaches to genetically manipulate Chlamydia is fostering important advances in understanding pathogenesis. Fluorescence-reported allelic exchange mutagenesis (FRAEM) now enables the complete deletion of specific genes in C. trachomatis L2. We have leveraged this technology to delete the coding sequences for a known type III effector. The evidence provided here indicates that CT694/CTL0063 is a virulence protein involved in chlamydial invasion. Based on our findings, we designate the gene product corresponding to ct694-ctl0063 translocated membrane-associated effector A (TmeA). Deletion of tmeA did not impact development of intracellular chlamydiae. However, the absence of TmeA manifested as a decrease in infectivity in both tissue culture and murine infection models. The in vitro defect was reflected by impaired invasion of host cells. TmeA binds human AHNAK, and we demonstrate here that AHNAK is transiently recruited by invading chlamydiae. TmeA, however, is not required for endogenous AHNAK recruitment. TmeA also impairs AHNAK-dependent actin bundling activity. This TmeA-mediated effect likely does not explain impaired invasion displayed by the tmeA strain of Chlamydia, since AHNAK-deficient cells revealed no invasion phenotype. Overall, our data indicate the efficacy of FRAEM and reveal a role of TmeA during chlamydial invasion that manifests independently of effects on AHNAK.

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Role of Leptin in the Activation of Immune Cells

Mediators of Inflammation ◽

10.1155/2010/568343 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 201

Author(s):

Patricia Fernández-Riejos ◽

Souad Najib ◽

Jose Santos-Alvarez ◽

Consuelo Martín-Romero ◽

Antonio Pérez-Pérez ◽

...

Keyword(s):

Immune Response ◽

Immune Cells ◽

Energy Homeostasis ◽

Humoral Factors ◽

Endocrine Organ ◽

Pathological Conditions ◽

Immune Mediated ◽

Infection Susceptibility

Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response, innate and adaptive response, both in normal and pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory pathogenic cytokines. Thus, leptin is a mediator of the inflammatory response.

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Cell-intrinsic requirement for pRb in erythropoiesis

Blood ◽

10.1182/blood-2004-02-0618 ◽

2004 ◽

Vol 104 (5) ◽

pp. 1324-1326 ◽

Cited By ~ 42

Author(s):

Allison J. Clark ◽

Kathryn M. Doyle ◽

Patrick O. Humbert

Keyword(s):

Erythroid Differentiation ◽

Published Data ◽

Erythroid Cells ◽

Cell Cycle Exit ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

A Cell ◽

Rb Gene

Abstract Retinoblastoma (Rb) and family members have been implicated as key regulators of cell proliferation and differentiation. In particular, accumulated data have suggested that the Rb gene product pRb is an important controller of erythroid differentiation. However, current published data are conflicting as to whether the role of pRb in erythroid cells is cell intrinsic or non–cell intrinsic. Here, we have made use of an in vitro erythroid differentiation culture system to determine the cell-intrinsic requirement for pRb in erythroid differentiation. We demonstrate that the loss of pRb function in primary differentiating erythroid cells results in impaired cell cycle exit and terminal differentiation. Furthermore, we have used coculture experiments to establish that this requirement is cell intrinsic. Together, these data unequivocally demonstrate that pRb is required in a cell-intrinsic manner for erythroid differentiation and provide clarification as to its role in erythropoiesis.

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In vitro immunogenicity prediction: bridging between innate and adaptive immunity

Bioanalysis ◽

10.4155/bio-2021-0077 ◽

2021 ◽

Author(s):

Sivan Cohen ◽

Shan Chung

Keyword(s):

Immune Cells ◽

Immune Cell ◽

In Vitro Assays ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Clinical Consequences ◽

Immune Cell Response ◽

Adaptive Immune Systems

Development of antidrug antibodies (ADAs) is an undesirable potential outcome of administration of biotherapeutics and involves the innate and adaptive immune systems. ADAs can have detrimental clinical consequences: they can reduce biotherapeutic efficacy or produce adverse events. Because animal models are considered poor predictors of immunogenicity in humans, in vitro assays with human innate and adaptive immune cells are commonly used alternatives that can reveal cell-mediated unwanted immune responses. Multiple methods have been developed to assess the immune cell response following exposure to biotherapeutics and estimate the potential immunogenicity of biotherapeutics. This review highlights the role of innate and adaptive immune cells as the drivers of immunogenicity and summarizes the use of these cells in assays to predict clinical ADA.

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Prevention of lipopolysaccharide-induced CD11b+ immune cell infiltration in the kidney: role of AT2 receptors

Bioscience Reports ◽

10.1042/bsr20190429 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 1

Author(s):

Sanket Patel ◽

Isha Dhande ◽

Elizabeth Alana Gray ◽

Quaisar Ali ◽

Tahir Hussain

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Interleukin 10 ◽

Conditioned Media ◽

Cell Infiltration ◽

Low Grade ◽

Immune Cell Infiltration ◽

Anti Inflammatory

AbstractImmune cell infiltration plays a central role in mediating endotoxemic acute kidney injury (AKI). Recently, we have reported the anti-inflammatory and reno-protective role of angiotensin-II type-2 receptor (AT2R) activation under chronic low-grade inflammatory condition in the obese Zucker rat model. However, the role of AT2R activation in preventing lipopolysaccharide (LPS)-induced early infiltration of immune cells, inflammation and AKI is not known. Mice were treated with AT2R agonist C21 (0.3 mg/kg), with and without AT2R antagonist PD123319 (5 mg/kg) prior to or concurrently with LPS (5 mg/kg) challenge. Prior-treatment with C21, but not concurrent treatment, significantly prevented the LPS-induced renal infiltration of CD11b+ immune cells, increase in the levels of circulating and/or renal chemotactic cytokines, particularly interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) and markers of renal dysfunction (blood urea nitrogen and albuminuria), while preserving anti-inflammatory interleukin-10 (IL-10) production. Moreover, C21 treatment in the absence of LPS increased renal and circulating IL-10 levels. To investigate the role of IL-10 in a cross-talk between epithelial cells and monocytes, we performed in vitro conditioned media (CM) studies in human kidney proximal tubular epithelial (HK-2) cells and macrophages (differentiated human monocytes, THP-1 cells). These studies revealed that the conditioned-media derived from the C21-treated HK-2 cells reduced LPS-induced THP-1 tumor necrosis factor-α (TNF-α) production via IL-10 originating from HK-2 cells. Our findings suggest that prior activation of AT2R is prophylactic in preventing LPS-induced renal immune cell infiltration and dysfunction, possibly via IL-10 pathway.

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Impact ofActinobacillus pleuropneumoniaebiofilm mode of growth on the lipid A structures and stimulation of immune cells

Innate Immunity ◽

10.1177/1753425916649676 ◽

2016 ◽

Vol 22 (5) ◽

pp. 353-362 ◽

Cited By ~ 7

Author(s):

Skander Hathroubi ◽

Francis Beaudry ◽

Chantale Provost ◽

Léa Martelet ◽

Mariela Segura ◽

...

Keyword(s):

Immune Cells ◽

Lipid A ◽

Etiologic Agent ◽

Porcine Pleuropneumonia ◽

Abiotic Surfaces ◽

Lipid A Structure ◽

Accurate Mass Spectrometry ◽

Relative Mrna Expression

Actinobacillus pleuropneumoniae (APP), the etiologic agent of porcine pleuropneumonia, forms biofilms on biotic and abiotic surfaces. APP biofilms confers resistance to antibiotics. To our knowledge, no studies have examined the role of APP biofilm in immune evasion and infection persistence. This study was undertaken to (i) investigate biofilm-associated LPS modifications occurring during the switch to biofilm mode of growth; and (ii) characterize pro-inflammatory cytokines expression in porcine pulmonary alveolar macrophages (PAMs) and proliferation in porcine PBMCs challenged with planktonic or biofilm APP cells. Extracted lipid A samples from biofilm and planktonic cultures were analyzed by HPLC high-resolution, accurate mass spectrometry. Biofilm cells displayed significant changes in lipid A profiles when compared with their planktonic counterparts. Furthermore, in vitro experiments were conducted to examine the inflammatory response of PAMs exposed to UV-inactivated APP grown in biofilm or in suspension. Relative mRNA expression of pro-inflammatory genes IL1, IL6, IL8 and MCP1 decreased in PAMs when exposed to biofilm cells compared to planktonic cells. Additionally, the biofilm state reduced PBMCs proliferation. Taken together, APP biofilm cells show a weaker ability to stimulate innate immune cells, which could be due, in part, to lipid A structure modifications.

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What Is in a Cat Scratch? Growth of Bartonella henselae in a Biofilm

Microorganisms ◽

10.3390/microorganisms9040835 ◽

2021 ◽

Vol 9 (4) ◽

pp. 835

Author(s):

Udoka Okaro ◽

Sierra George ◽

Burt Anderson

Keyword(s):

Biofilm Formation ◽

Current Knowledge ◽

Bartonella Henselae ◽

Biological Significance ◽

Mammalian Host ◽

Cat Scratch Disease ◽

Cat Flea ◽

Clinical Presentations

Bartonella henselae (B. henselae) is a gram-negative bacterium that causes cat scratch disease, bacteremia, and endocarditis, as well as other clinical presentations. B. henselae has been shown to form a biofilm in vitro that likely plays a role in the establishment and persistence of the bacterium in the host. Biofilms are also known to form in the cat flea vector; hence, the ability of this bacterium to form a biofilm has broad biological significance. The release of B. henselae from a biofilm niche appears to be important in disease persistence and relapse in the vertebrate host but also in transmission by the cat flea vector. It has been shown that the BadA adhesin of B. henselae is critical for adherence and biofilm formation. Thus, the upregulation of badA is important in initiating biofilm formation, and down-regulation is important in the release of the bacterium from the biofilm. We summarize the current knowledge of biofilm formation in Bartonella species and the role of BadA in biofilm formation. We discuss the evidence that defines possible mechanisms for the regulation of the genes required for biofilm formation. We further describe the regulation of those genes in the conditions that mimic both the arthropod vector and the mammalian host for B. henselae. The treatment for persistent B. henselae infection remains a challenge; hence, a better understanding of the mechanisms by which this bacterium persists in its host is critical to inform future efforts to develop drugs to treat such infections.

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