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1.
Trained Immunity: An Overview and the Impact on COVID-19.
Brueggeman, JM, Zhao, J, Schank, M, Yao, ZQ, Moorman, JP
Frontiers in immunology. 2022;:837524
Abstract
Effectively treating infectious diseases often requires a multi-step approach to target different components involved in disease pathogenesis. Similarly, the COVID-19 pandemic has become a global health crisis that requires a comprehensive understanding of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection to develop effective therapeutics. One potential strategy to instill greater immune protection against COVID-19 is boosting the innate immune system. This boosting, termed trained immunity, employs immune system modulators to train innate immune cells to produce an enhanced, non-specific immune response upon reactivation following exposure to pathogens, a process that has been studied in the context of in vitro and in vivo clinical studies prior to the COVID-19 pandemic. Evaluation of the underlying pathways that are essential to inducing protective trained immunity will provide insight into identifying potential therapeutic targets that may alleviate the COVID-19 crisis. Here we review multiple immune training agents, including Bacillus Calmette-Guérin (BCG), β-glucan, and lipopolysaccharide (LPS), and the two most popular cell types involved in trained immunity, monocytes and natural killer (NK) cells, and compare the signaling pathways involved in innate immunity. Additionally, we discuss COVID-19 trained immunity clinical trials, emphasizing the potential of trained immunity to fight SARS-CoV-2 infection. Understanding the mechanisms by which training agents activate innate immune cells to reprogram immune responses may prove beneficial in developing preventive and therapeutic targets against COVID-19.
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Role of Fcγ receptors in HER2-targeted breast cancer therapy.
Musolino, A, Gradishar, WJ, Rugo, HS, Nordstrom, JL, Rock, EP, Arnaldez, F, Pegram, MD
Journal for immunotherapy of cancer. 2022;(1)
Abstract
Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)-dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance FcγR-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating FcγRIIIa and decrease binding to inhibitory FcγRIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell-mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms.
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3.
Emerging Roles of Vitamin D-Induced Antimicrobial Peptides in Antiviral Innate Immunity.
White, JH
Nutrients. 2022;(2)
Abstract
Vitamin D deficiency, characterized by low circulating levels of calcifediol (25-hydroxyvitamin D, 25D) has been linked to increased risk of infections of bacterial and viral origin. Innate immune cells produce hormonal calcitriol (1,25-dihydroxyvitamin D, 1,25D) locally from circulating calcifediol in response to pathogen threat and an immune-specific cytokine network. Calcitriol regulates gene expression through its binding to the vitamin D receptor (VDR), a ligand-regulated transcription factor. The hormone-bound VDR induces the transcription of genes integral to innate immunity including pattern recognition receptors, cytokines, and most importantly antimicrobial peptides (AMPs). Transcription of the human AMP genes β-defensin 2/defensin-β4 (HBD2/DEFB4) and cathelicidin antimicrobial peptide (CAMP) is stimulated by the VDR bound to promoter-proximal vitamin D response elements. HDB2/DEFB4 and the active form of CAMP, the peptide LL-37, which form amphipathic secondary structures, were initially characterized for their antibacterial actively. Notably, calcitriol signaling induces secretion of antibacterial activity in vitro and in vivo, and low circulating levels of calcifediol are associated with diverse indications characterized by impaired antibacterial immunity such as dental caries and urinary tract infections. However, recent work has also provided evidence that the same AMPs are components of 1,25D-induced antiviral responses, including those against the etiological agent of the COVID-19 pandemic, the SARS-CoV2 coronavirus. This review surveys the evidence for 1,25D-induced antimicrobial activity in vitro and in vivo in humans and presents our current understanding of the potential mechanisms by which CAMP and HBD2/DEFB4 contribute to antiviral immunity.
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4.
Resolving trained immunity with systems biology.
Koeken, VACM, van Crevel, R, Netea, MG, Li, Y
European journal of immunology. 2021;(4):773-784
Abstract
Trained immunity is characterized by long-term functional reprogramming of innate immune cells following challenge with pathogens or microbial ligands during infection or vaccination. This cellular reprogramming leads to increased responsiveness upon restimulation, and is mediated through epigenetic and metabolic modifications. In this review, we describe how molecular mechanisms underlying trained immunity, for example, induced by β-glucan or Bacille Calmette-Guérin (BCG) vaccination, can be investigated by using and integrating different layers of information including genome, epigenome, transcriptome, proteome, metabolome, microbiome, immune cell phenotyping, and function. We also describe the most commonly used experimental and computational techniques. Finally, we provide a number of examples of how a systems biology approach was applied to study trained immunity to understand interindividual variation or the complex interplay between molecular layers. In conclusion, trained immunity represents an opportunity for regulating innate immune function, and understanding the complex interplay of mechanisms that mediate trained immunity might enable us to employ it as a clinical tool in the future.
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5.
DExD/H-box helicases: multifunctional regulators in antiviral innate immunity.
Su, C, Tang, YD, Zheng, C
Cellular and molecular life sciences : CMLS. 2021;(1):2
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Abstract
DExD/H-box helicases play critical roles in multiple cellular processes, including transcription, cellular RNA metabolism, translation, and infections. Several seminal studies over the past decades have delineated the distinct functions of DExD/H-box helicases in regulating antiviral innate immune signaling pathways, including Toll-like receptors, retinoic acid-inducible gene I-like receptors, cyclic GMP-AMP synthase-the stimulator of interferon gene, and NOD-like receptors signaling pathways. Besides the prominent regulatory roles, there is increasing attention on their functions as nucleic acid sensors involved in antiviral innate immunity. Here we summarize the complex regulatory roles of DExD/H-box helicases in antiviral innate immunity. A better understanding of the underlying molecular mechanisms of DExD/H-box helicases' regulatory roles is vital for developing new therapeutics targeting DExD/H-box helicases and their mediated signaling transduction in viral infectious diseases.
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Advances in understanding immune mechanisms of food protein-induced enterocolitis syndrome.
Berin, MC
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2021;(5):478-481
Abstract
OBJECTIVE This review provides an overview of our current understanding of the mechanisms of food protein-induced enterocolitis syndrome (FPIES). DATA SOURCES To capture recent articles published since our previous comprehensive review on the pathophysiology of FPIES, we performed a literature search through PubMed database, using the search terms FPIES and food protein-induced enterocolitis syndrome from 2016 to the current year. STUDY SELECTIONS Studies in English containing biomarker or immune data were reviewed and summarized. RESULTS Studies of peripheral blood fail to exhibit evidence of antigen-specific humoral or cellular immunity underlying clinical reactivity to foods in FPIES. However, growing evidence suggests a robust systemic innate immune activation occurring during FPIES reactions and the activation of neuroendocrine pathways. CONCLUSION FPIES reactions are associated with marked activation of innate immune and neuroendocrine pathways; however, the mechanism underlying the specific recognition of foods remains elusive.
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Human guanylate binding proteins: nanomachines orchestrating host defense.
Kutsch, M, Coers, J
The FEBS journal. 2021;(20):5826-5849
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Abstract
Disease-causing microorganisms not only breach anatomical barriers and invade tissues but also frequently enter host cells, nutrient-enriched environments amenable to support parasitic microbial growth. Protection from many infectious diseases is therefore reliant on the ability of individual host cells to combat intracellular infections through the execution of cell-autonomous defense programs. Central players in human cell-autonomous immunity are members of the family of dynamin-related guanylate binding proteins (GBPs). The importance of these interferon-inducible GTPases in host defense to viral, bacterial, and protozoan pathogens has been established for some time; only recently, cell biological and biochemical studies that largely focused on the prenylated paralogs GBP1, GBP2, and GBP5 have provided us with robust molecular frameworks for GBP-mediated immunity. Specifically, the recent characterization of GBP1 as a bona fide pattern recognition receptor for bacterial lipopolysaccharide (LPS) disrupting the integrity of bacterial outer membranes through LPS aggregation, the discovery of a link between hydrolysis-induced GMP production by GBP1 and inflammasome activation, and the classification of GBP2 and GBP5 as inhibitors of viral envelope glycoprotein processing via suppression of the host endoprotease furin have paved the way for a vastly improved conceptual understanding of the molecular mechanisms by which GBP nanomachines execute cell-autonomous immunity. The herein discussed models incorporate our current knowledge of the antimicrobial, proinflammatory, and biochemical properties of human GBPs and thereby provide testable hypotheses that will guide future studies into the intricacies of GBP-controlled host defense and their role in human disease.
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Immunomodulatory Effects of Dietary Polyphenols.
Shakoor, H, Feehan, J, Apostolopoulos, V, Platat, C, Al Dhaheri, AS, Ali, HI, Ismail, LC, Bosevski, M, Stojanovska, L
Nutrients. 2021;(3)
Abstract
Functional and nutraceutical foods provide an alternative way to improve immune function to aid in the management of various diseases. Traditionally, many medicinal products have been derived from natural compounds with healing properties. With the development of research into nutraceuticals, it is becoming apparent that many of the beneficial properties of these compounds are at least partly due to the presence of polyphenols. There is evidence that dietary polyphenols can influence dendritic cells, have an immunomodulatory effect on macrophages, increase proliferation of B cells, T cells and suppress Type 1 T helper (Th1), Th2, Th17 and Th9 cells. Polyphenols reduce inflammation by suppressing the pro-inflammatory cytokines in inflammatory bowel disease by inducing Treg cells in the intestine, inhibition of tumor necrosis factor-alpha (TNF-α) and induction of apoptosis, decreasing DNA damage. Polyphenols have a potential role in prevention/treatment of auto-immune diseases like type 1 diabetes, rheumatoid arthritis and multiple sclerosis by regulating signaling pathways, suppressing inflammation and limiting demyelination. In addition, polyphenols cause immunomodulatory effects against allergic reaction and autoimmune disease by inhibition of autoimmune T cell proliferation and downregulation of pro-inflammatory cytokines (interleukin-6 (IL-6), IL-1, interferon-γ (IFN-γ)). Herein, we summarize the immunomodulatory effects of polyphenols and the underlying mechanisms involved in the stimulation of immune responses.
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Emerging concepts in the science of vaccine adjuvants.
Pulendran, B, S Arunachalam, P, O'Hagan, DT
Nature reviews. Drug discovery. 2021;(6):454-475
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Abstract
Adjuvants are vaccine components that enhance the magnitude, breadth and durability of the immune response. Following its introduction in the 1920s, alum remained the only adjuvant licensed for human use for the next 70 years. Since the 1990s, a further five adjuvants have been included in licensed vaccines, but the molecular mechanisms by which these adjuvants work remain only partially understood. However, a revolution in our understanding of the activation of the innate immune system through pattern recognition receptors (PRRs) is improving the mechanistic understanding of adjuvants, and recent conceptual advances highlight the notion that tissue damage, different forms of cell death, and metabolic and nutrient sensors can all modulate the innate immune system to activate adaptive immunity. Furthermore, recent advances in the use of systems biology to probe the molecular networks driving immune response to vaccines ('systems vaccinology') are revealing mechanistic insights and providing a new paradigm for the vaccine discovery and development process. Here, we review the 'known knowns' and 'known unknowns' of adjuvants, discuss these emerging concepts and highlight how our expanding knowledge about innate immunity and systems vaccinology are revitalizing the science and development of novel adjuvants for use in vaccines against COVID-19 and future pandemics.
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Immunology of Fungal Infections.
Fernández-García, OA, Cuellar-Rodríguez, JM
Infectious disease clinics of North America. 2021;(2):373-388
Abstract
Complex processes mediate immunity to fungal infections. Responses vary depending on the organism, morphogenic state, and infection site. Innate immune effectors such as epithelia, phagocytes, and soluble molecules detect pathogens, kill fungi, release cytokines, and prime the adaptive response. Adaptive responses to mucocutaneous or invasive disease are markedly different but intersect at certain pathways (molecules required for IL-23 and IL-12 signaling). Many of these pathways have been elucidated from the study of inborn errors of immunity. This review explores the general aspects of antifungal immunity and delves into the mechanisms that mediate protection from frequently encountered fungi.