Cytokine Storms: Understanding COVID-19 Mangalmurti, Nilam; Hunter, Christopher A.
Immunity (Cambridge, Mass.),
07/2020, Volume:
53, Issue:
1
Journal Article
Peer reviewed
Open access
The elevated circulating levels of cytokines associated with a variety of infectious and immune-mediated conditions are frequently termed a cytokine storm. Here, we explain the protective functions ...of cytokines in “ideal” responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical outcomes.
The elevated circulating levels of cytokines associated with a variety of infectious and immune-mediated conditions are frequently termed a cytokine storm. Here, we explain the protective functions of cytokines in “ideal” responses; the multi-factorial origins that can drive these responses to become pathological; and how this ultimately leads to vascular damage, immunopathology, and worsening clinical outcomes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
It has been more than 15 years since the identification of individual interleukin-27 (IL-27) and IL-27 receptor components. The last decade has seen the description of the signaling pathways engaged ...by IL-27, and an appreciation has emerged that this cytokine can modulate the intensity and duration of many classes of T cell responses. Here we provide an overview of the immunobiology of IL-27 and review advances in understanding the functions of individual IL-27 and IL-27 receptor subunits and the role of IL-27 in dictating the balance between protective and pathological immunity. Additionally, this cytokine has been proposed as a therapy to modify inflammatory conditions or to promote antitumor responses, and situations where experimental and clinical data sets implicate IL-27 in the outcome of disease are highlighted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Immunobiology of Interleukin-27 Yoshida, Hiroki; Hunter, Christopher A
Annual review of immunology,
03/2015, Volume:
33, Issue:
1
Journal Article
Peer reviewed
Open access
Interleukin-27 (IL-27) is a cytokine with strikingly diverse influences on the immune response. Although it was initially linked with the development of Th1 responses, it is now recognized as a ...potent antagonist of different classes of inflammation through its ability to directly modify CD4
+
and CD8
+
T cell effector functions, to induce IL-10, and to promote specialized T regulatory cell responses. Although this aspect of IL-27 biology has provided insights into how the immune system prevents hyperactivity in the setting of infectious and autoimmune inflammation, in vaccination and cancer models the stimulatory effects of IL-27 on CD8
+
T cell function appear prominent. Additionally, associations between IL-27 and antibody-mediated disease have led to an interest in defining the impact of IL-27 on innate immunity and humoral responses in different disease states. The maturation of this literature has been accompanied by attempts to translate these findings from experimental models into human diseases and by efforts to define where IL-27 might represent a viable therapeutic target.
Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has ...context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Conspectus We describe here a family of coordination cages with interesting structural, guest-binding, and catalytic properties. Flexible bridging ligands containing two bidentate pyrazolylpyridine ...termini assemble with transition-metal dications to afford coordination cages containing a metal ion at each vertex, a bridging ligand spanning each edge, and a 2:3 metal:ligand ratio. This stoichiometry is expressed in structures ranging from M4L6 tetrahedra to M16L24 tetracapped truncated tetrahedra, which are stabilized by the formation of π-stacked arrays between electron-rich and electron-poor ligand segments that form around the cage periphery. In some cases concentration- and/or temperature-dependent equilibria between multiple cage structures occur, arising from a balance between entropy, which favors the formation of a larger number of smaller assemblies, and enthalpy, which maximizes both interligand aromatic stacking and solvophobic effects in the larger assembles. The cages are hollow and can accommodate guestsoften anions or solvent moleculesin the central cavity. For one cage family, M8L12 species with an approximately cubic structure and a ca. 400 Å3 cavity, the guest binding properties have been studied extensively. This cage can accommodate a wide range of neutral organic guests, with binding in water being driven principally by the hydrophobic effect, which leads to binding constants of up to 108 M–1. The accumulation of a large amount of empirical data on guest binding in the M8L12 cage in water provided the basis for a predictive tool for in silico screening of potential guests using the molecular docking program GOLD; this methodology has allowed the identification of numerous new guests with accurately predicted binding constants and provides a transformative new approach to exploring the host/guest chemistry of cages. Binding of benzisoxazole inside the M8L12 cage results in substantial rate enhancementsby a factor of up to 2 × 105of the Kemp elimination, in which benzisoxazole reacts to give 2-cyanophenolate. Catalysis arises because the 16+ cage cation accumulates anions around the surface by ion pairing, leading to a high effective concentration of hydroxide ions surrounding the guest even when the bulk pH is modest. Thus, the catalysis relies on the operation of two orthogonal interactions that bring the reaction partners together: hydrophobic guest binding in the cavity, which is lined with CH groups from the ligands, and ion pairing around the highly cationic cage surface. A consequence of this is that under some conditions the product of the cage-catalyzed Kemp elimination (the 2-cyanophenolate anion) itself accumulates around the cage surface and deprotonates another benzisoxazole guest, perpetuating the reaction in an autocatalytic manner. Thus, different anions accumulating around the cage can act as partners for reaction with a cavity-bound guest, opening up the possibility that the M8L12 cage can act as a general catalyst for reactions of electrophilic guests with surface-bound anions.
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IJS, KILJ, NUK, PNG, UL, UM
Toxoplasma gondii is a common parasite of animals and humans and can cause serious opportunistic infections. However, the majority of infections are asymptomatic, possibly because the organism has ...co-evolved with its many vertebrate hosts and has developed multiple strategies to persist asymptomatically for the lifetime of the host. Over the past two decades, infection studies in the mouse, combined with forward-genetics approaches aimed at unravelling the molecular basis of infection, have revealed that T. gondii virulence is mediated, in part, by secretion of effector proteins into the host cell during invasion. Here, we review recent advances that illustrate how these virulence factors disarm innate immunity and promote survival of the parasite.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize ...shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.
The IL-12 family of cytokines influences the outcome of cancer, infection, and inflammatory diseases. Stumhofer, Hunter, and Tait review the combinatorial biology inherent to this family and the recent clinical insights that underscore the critical role of these pathways in human disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted that innate ...pathways limit pathogen invasion of the CNS and adaptive immunity mediates control of many neural infections. As protective responses can result in bystander damage, there are regulatory mechanisms that balance protective and pathological inflammation, but these mechanisms might also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in our understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege.
The CNS utilizes multiple mechanisms to restrict microbial entry but there are also innate and adaptive mechanisms that control pathogens that access this immune privileged site. Klein and Hunter review the pathogen interactions with the blood brain barrier and resident glial populations that govern the outcome of CNS infection, as well as the immune mechanisms that dictate protective and pathological responses in the brain.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The functional properties of molecular systems are generally determined by the sum of many weak non-covalent interactions, and therefore methods for predicting the relative magnitudes of these ...interactions is fundamental to understanding the relationship between function and structure in chemistry, biology and materials science. This review focuses on the Surface Site Interaction Point (SSIP) approach which describes molecules as a set of points that capture the properties of all possible non-covalent interactions that the molecule might make with another molecule. The first half of the review focuses on the empirical non-covalent interaction parameters,
α
and
β
, and provides simple rules of thumb to estimate free energy changes for interactions between different types of functional group. These parameters have been used to have been used to establish a quantitative understanding of the role of solvent in solution phase equilibria, and to describe non-covalent interactions at the interface between macroscopic surfaces as well as in the solid state. The second half of the review focuses on a computational approach for obtaining SSIPs and applications in multi-component systems where many different interactions compete.
Ab initio
calculation of the Molecular Electrostatic Potential (MEP) surface is used to derive an SSIP description of a molecule, where each SSIP is assigned a value equivalent to the corresponding empirical parameter,
α
or
β
. By considering the free energies of all possible pairing interactions between all SSIPs in a molecular ensemble, it is possible to calculate the speciation of all intermolecular interactions and hence predict thermodynamic properties using the SSIMPLE algorithm. SSIPs have been used to describe both the solution phase and the solid state and provide accurate predictions of partition coefficients, solvent effects on association constants for formation of intermolecular complexes, and the probability of cocrystal formation. SSIPs represent a simple and intuitive tool for describing the relationship between chemical structure and non-covalent interactions with sufficient accuracy to understand and predict the properties of complex molecular ensembles without the need for computationally expensive simulations.
Non-covalent interactions are described using the SSIPs. Simple rules of thumb for predicting binding constants for any functional group interaction in any solvent are described, as well as general treatments of molecular properties like partition.
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