Peptidoglycan sensing by octopaminergic neurons modulates Drosophila oviposition

As infectious diseases pose a threat to host integrity, eukaryotes have evolved mechanisms to eliminate pathogens. In addition to develop strategies reducing infection, animals can engage in behaviors that lower the impact of the infection. The molecular mechanisms by which microbes impact host behavior are not well understood. We demonstrate that bacterial infection of Drosophila females reduces oviposition and that peptidoglycan, the component that activates Drosophila antibacterial response, is also the elicitor of this behavioral change. We show that peptidoglycan regulates egg-laying rate by activating NF-κB signaling pathway in octopaminergic neurons and that, a dedicated peptidoglycan degrading enzyme acts in these neurons to buffer this behavioral response. This study shows that a unique ligand and signaling cascade are used in immune cells to mount an immune response and in neurons to control fly behavior following infection. This may represent a case of behavioral immunity.

Download Full-text

Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties

Journal of Clinical Medicine ◽

10.3390/jcm9041185 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1185 ◽

Cited By ~ 3

Author(s):

Martha Baydoun ◽

Olivier Moralès ◽

Céline Frochot ◽

Colombeau Ludovic ◽

Bertrand Leroux ◽

...

Keyword(s):

Ovarian Cancer ◽

Immune Response ◽

Photodynamic Therapy ◽

Cancer Cells ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Immune Cells ◽

Surgical Techniques ◽

Ovarian Cancer Cells ◽

The Impact

Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable.

Download Full-text

The Drosophila Inhibitor of Apoptosis Protein DIAP2 Functions in Innate Immunity and Is Essential To Resist Gram-Negative Bacterial Infection

Molecular and Cellular Biology ◽

10.1128/mcb.00548-06 ◽

2006 ◽

Vol 26 (21) ◽

pp. 7821-7831 ◽

Cited By ~ 88

Author(s):

François Leulier ◽

Nouara Lhocine ◽

Bruno Lemaitre ◽

Pascal Meier

Keyword(s):

Immune Response ◽

Bacterial Infection ◽

Null Alleles ◽

Signaling Cascade ◽

Inhibitor Of Apoptosis ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein

ABSTRACT The founding member of the inhibitor of apoptosis protein (IAP) family was originally identified as a cell death inhibitor. However, recent evidence suggests that IAPs are multifunctional signaling devices that influence diverse biological processes. To investigate the in vivo function of Drosophila melanogaster IAP2, we have generated diap2 null alleles. diap2 mutant animals develop normally and are fully viable, suggesting that diap2 is dispensable for proper development. However, these animals were acutely sensitive to infection by gram-negative bacteria. In Drosophila, infection by gram-negative bacteria triggers the innate immune response by activating the immune deficiency (imd) signaling cascade, a NF-κB-dependent pathway that shares striking similarities with the pathway of mammalian tumor necrosis factor receptor 1 (TNFR1). diap2 mutant flies failed to activate NF-κB-mediated expression of antibacterial peptide genes and, consequently, rapidly succumbed to bacterial infection. Our genetic epistasis analysis places diap2 downstream of or in parallel to imd, Dredd, Tak1, and Relish. Therefore, DIAP2 functions in the host immune response to gram-negative bacteria. In contrast, we find that the Drosophila TNFR-associated factor (Traf) family member Traf2 is dispensable in resistance to gram-negative bacterial infection. Taken together, our genetic data identify DIAP2 as an essential component of the Imd signaling cascade, protecting the organism from infiltrating microbes.

Download Full-text

Prediction and evolution of the molecular fitness of SARS-CoV-2 variants: Introducing SpikePro

10.1101/2021.04.11.439322 ◽

2021 ◽

Author(s):

Fabrizio Pucci ◽

Marianne Rooman

Keyword(s):

Immune Response ◽

Neutralizing Antibodies ◽

Molecular Mechanisms ◽

Population Level ◽

Critical Issue ◽

Spike Protein ◽

Human Immune Response ◽

Human Immune ◽

The Stability ◽

The Impact

The understanding of the molecular mechanisms driving the fitness of the SARS-CoV-2 virus and its mutational evolution is still a critical issue. We built a simplified computational model, called SpikePro, to predict the SARS-CoV-2 fitness from the amino acid sequence and structure of the spike protein. It contains three contributions: the viral transmissibility predicted from the stability of the spike protein, the infectivity computed in terms of the affinity of the spike protein for the ACE2 receptor, and the ability of the virus to escape from the human immune response based on the binding affinity of the spike protein for a set of neutralizing antibodies. Our model reproduces well the available experimental, epidemiological and clinical data on the impact of variants on the biophysical characteristics of the virus. For example, it is able to identify circulating viral strains that, by increasing their fitness, recently became dominant at the population level. SpikePro is a useful instrument for the genomic surveillance of the SARS-CoV-2 virus, since it predicts in a fast and accurate way the emergence of new viral strains and their dangerousness. It is freely available in the GitHub repository github.com/3BioCompBio/SpikeProSARS-CoV-2.

Download Full-text

Dooming Phagocyte Responses: Inflammatory Effects of Endogenous Oxidized Phospholipids

Frontiers in Endocrinology ◽

10.3389/fendo.2021.626842 ◽

2021 ◽

Vol 12 ◽

Author(s):

Marco Di Gioia ◽

Ivan Zanoni

Keyword(s):

Immune Cells ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Biological Activities ◽

Oxidized Lipids ◽

Oxidized Phospholipids ◽

Clinical Tools ◽

Stress Mediators ◽

The Impact

Endogenous oxidized phospholipids are produced during tissue stress and are responsible for sustaining inflammatory responses in immune as well as non-immune cells. Their local and systemic production and accumulation is associated with the etiology and progression of several inflammatory diseases, but the molecular mechanisms that underlie the biological activities of these oxidized phospholipids remain elusive. Increasing evidence highlights the ability of these stress mediators to modulate cellular metabolism and pro-inflammatory signaling in phagocytes, such as macrophages and dendritic cells, and to alter the activation and polarization of these cells. Because these immune cells serve a key role in maintaining tissue homeostasis and organ function, understanding how endogenous oxidized lipids reshape phagocyte biology and function is vital for designing clinical tools and interventions for preventing, slowing down, or resolving chronic inflammatory disorders that are driven by phagocyte dysfunction. Here, we discuss the metabolic and signaling processes elicited by endogenous oxidized lipids and outline new hypotheses and models to elucidate the impact of these lipids on phagocytes and inflammation.

Download Full-text

Dynamics of Dual Specificity Phosphatases and Their Interplay with Protein Kinases in Immune Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms20092086 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2086 ◽

Cited By ~ 5

Author(s):

Yashwanth Subbannayya ◽

Sneha M. Pinto ◽

Korbinian Bösl ◽

T. S. Keshava Prasad ◽

Richard K. Kandasamy

Keyword(s):

Immune Response ◽

Protein Kinases ◽

Immune Cells ◽

Molecular Mechanisms ◽

Tlr4 Signaling ◽

Cyclin Dependent Kinases ◽

Therapeutic Modalities ◽

Dual Specificity ◽

Mitogen Activated Protein ◽

Dual Specificity Phosphatases

Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen-activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focus on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSP-mediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR, and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study have the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

Download Full-text

Obesity and COVID-19: Molecular Mechanisms Linking Both Pandemics

International Journal of Molecular Sciences ◽

10.3390/ijms21165793 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5793 ◽

Cited By ~ 4

Author(s):

Andreas Ritter ◽

Nina-Naomi Kreis ◽

Frank Louwen ◽

Juping Yuan

Keyword(s):

Stem Cells ◽

Immune Response ◽

Mesenchymal Stem Cells ◽

Systemic Inflammation ◽

Molecular Mechanisms ◽

Airway Epithelial Cells ◽

Metabolic Dysfunction ◽

Health Crisis ◽

Susceptible Population ◽

The Impact

The coronavirus disease 2019 COVID-19 pandemic is rapidly spreading worldwide and is becoming a major public health crisis. Increasing evidence demonstrates a strong correlation between obesity and the COVID-19 disease. We have summarized recent studies and addressed the impact of obesity on COVID-19 in terms of hospitalization, severity, mortality, and patient outcome. We discuss the potential molecular mechanisms whereby obesity contributes to the pathogenesis of COVID-19. In addition to obesity-related deregulated immune response, chronic inflammation, endothelium imbalance, metabolic dysfunction, and its associated comorbidities, dysfunctional mesenchymal stem cells/adipose-derived mesenchymal stem cells may also play crucial roles in fueling systemic inflammation contributing to the cytokine storm and promoting pulmonary fibrosis causing lung functional failure, characteristic of severe COVID-19. Moreover, obesity may also compromise motile cilia on airway epithelial cells and impair functioning of the mucociliary escalators, reducing the clearance of severe acute respiratory syndrome coronavirus (SARS-CoV-2). Obese diseased adipose tissues overexpress the receptors and proteases for the SARS-CoV-2 entry, implicating its possible roles as virus reservoir and accelerator reinforcing violent systemic inflammation and immune response. Finally, anti-inflammatory cytokines like anti-interleukin 6 and administration of mesenchymal stromal/stem cells may serve as potential immune modulatory therapies for supportively combating COVID-19. Obesity is conversely related to the development of COVID-19 through numerous molecular mechanisms and individuals with obesity belong to the COVID-19-susceptible population requiring more protective measures.

Download Full-text

HTLV-1 ORF-I Encoded Proteins and the Regulation of Host Immune Response: Viral Induced Dysregulation of Intracellular Signaling

Journal of Immunology Research ◽

10.1155/2015/498054 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Carolina Rosadas ◽

Marzia Puccioni-Sohler

Keyword(s):

Immune Response ◽

Cell Proliferation ◽

T Cell ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

T Cell Proliferation ◽

Human T Cell ◽

Encoded Proteins ◽

Infected Cells ◽

The Impact

The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus associated with both proliferative and inflammatory disorders. This virus causes a persistent infection, mainly in CD4+ T lymphocyte. The ability to persist in the host is associated with the virus capacity to evade the immune response and to induce infected T-cell proliferation, once the HTLV-1 maintains the infection mainly by clonal expansion of infected cells. There are several evidences that ORF-I encoded proteins, such as p12 and p8, play an important role in this context. The present study will review the molecular mechanisms that HTLV-1 ORF-I encoded proteins have to induce dysregulation of intracellular signaling, in order to escape from immune response and to increase the infected T-cell proliferation rate. The work will also address the impact of ORF-I mutations on the human host and perspectives in this study field.

Download Full-text

Computational Modeling of Microabscess Formation

Computational and Mathematical Methods in Medicine ◽

10.1155/2012/736394 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 11

Author(s):

Alexandre Bittencourt Pigozzo ◽

Gilson Costa Macedo ◽

Rodrigo Weber dos Santos ◽

Marcelo Lobosco

Keyword(s):

Immune Response ◽

Immune System ◽

Computational Modeling ◽

Bacterial Infection ◽

Computational Model ◽

Immune Cells ◽

Bacterial Infections ◽

Distinct Pattern ◽

Human Immune System ◽

Human Immune

Bacterial infections can be of two types: acute or chronic. The chronic bacterial infections are characterized by being a large bacterial infection and/or an infection where the bacteria grows rapidly. In these cases, the immune response is not capable of completely eliminating the infection which may lead to the formation of a pattern known as microabscess (or abscess). The microabscess is characterized by an area comprising fluids, bacteria, immune cells (mainly neutrophils), and many types of dead cells. This distinct pattern of formation can only be numerically reproduced and studied by models that capture the spatiotemporal dynamics of the human immune system (HIS). In this context, our work aims to develop and implement an initial computational model to study the process of microabscess formation during a bacterial infection.

Download Full-text

The hypothalamic-pituitary-gonadal axis: immune function and autoimmunity

Journal of Endocrinology ◽

10.1677/joe.0.1760293 ◽

2003 ◽

Vol 176 (3) ◽

pp. 293-304 ◽

Cited By ~ 195

Author(s):

F Tanriverdi ◽

LF Silveira ◽

GS MacColl ◽

PM Bouloux

Keyword(s):

Immune Response ◽

Immune System ◽

Immune Function ◽

Immune Cells ◽

Sex Steroids ◽

Hormone Replacement ◽

Experimental Studies ◽

Cell Activity ◽

Gnrh Analogues ◽

The Impact

GnRH and sex steroids play an important role in immune system modulation and development. GnRH and the GnRH receptor are produced locally by immune cells, suggesting an autocrine role for GnRH. Experimental studies show a stimulatory action of exogenous GnRH on the immune response. The immune actions of GnRH in vivo are, however, less well established. Oestrogen and androgen receptors are expressed in primary lymphoid organs and peripheral immune cells. Experimental data have established that oestrogens enhance the humoral immune response and may have an activating role in autoimmune disorders. Testosterone enhances suppressor T cell activity. Although there are some clinical studies consistent with these findings, the impact of sex steroids in autoimmune disease pathogenesis and the risk or benefits of their usage in normal and autoimmune-disordered patients remain to be elucidated. There are neither experimental nor clinical data evaluating functional GnRH-sex steroid interactions within the human immune system, and there is a paucity of data relating to GnRH analogues, hormone replacement therapy and oral contraceptive and androgen action in autoimmune diseases. However, a growing body of experimental evidence suggests that an extra-pituitary GnRH immune mechanism plays a role in the programming of the immune system. The implications of these findings in understanding immune function are discussed.

Download Full-text

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Cells ◽

10.3390/cells9010198 ◽

2020 ◽

Vol 9 (1) ◽

pp. 198 ◽

Cited By ~ 20

Author(s):

Ufuk Degirmenci ◽

Mei Wang ◽

Jiancheng Hu

Keyword(s):

Cancer Therapy ◽

Molecular Mechanisms ◽

Mapk Pathway ◽

Mapk Signaling ◽

Erk Signaling ◽

Signaling Cascade ◽

Cellular Functions ◽

Cell Functions ◽

Core Elements ◽

The Impact

The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

Download Full-text