The Role of Semaphorins and Their Receptors in Innate Immune Responses and Clinical Diseases of Acute Inflammation

Semaphorins are a group of proteins that have been studied extensively for their critical function in neuronal development. They have been shown to regulate airway development, tumorigenesis, autoimmune diseases, and the adaptive immune response. Notably, emerging literature describes the role of immunoregulatory semaphorins and their receptors, plexins and neuropilins, as modulators of innate immunity and diseases defined by acute injury to the kidneys, abdomen, heart and lungs. In this review we discuss the pathogenic functions of semaphorins in clinical conditions of acute inflammation, including sepsis and acute lung injury, with a focus on regulation of the innate immune response as well as potential future therapeutic targeting.

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Innate Immune Responses of Bat and Human Cells to Filoviruses: Commonalities and Distinctions

Journal of Virology ◽

10.1128/jvi.02471-16 ◽

2017 ◽

Vol 91 (8) ◽

Cited By ~ 22

Author(s):

Ivan V. Kuzmin ◽

Toni M. Schwarz ◽

Philipp A. Ilinykh ◽

Ingo Jordan ◽

Thomas G. Ksiazek ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Antiviral Effect ◽

Human Cells ◽

Innate Immune ◽

Innate Immune Responses ◽

Symptomatic Disease ◽

Ifn Γ

ABSTRACT Marburg (MARV) and Ebola (EBOV) viruses are zoonotic pathogens that cause severe hemorrhagic fever in humans. The natural reservoir of MARV is the Egyptian rousette bat (Rousettus aegyptiacus); that of EBOV is unknown but believed to be another bat species. The Egyptian rousette develops subclinical productive infection with MARV but is refractory to EBOV. Interaction of filoviruses with hosts is greatly affected by the viral interferon (IFN)-inhibiting domains (IID). Our study was aimed at characterization of innate immune responses to filoviruses and the role of filovirus IID in bat and human cells. The study demonstrated that EBOV and MARV replicate to similar levels in all tested cell lines, indicating that permissiveness for EBOV at cell and organism levels do not necessarily correlate. Filoviruses, particularly MARV, induced a potent innate immune response in rousette cells, which was generally stronger than that in human cells. Both EBOV VP35 and VP24 IID were found to suppress the innate immune response in rousette cells, but only VP35 IID appeared to promote virus replication. Along with IFN-α and IFN-β, IFN-γ was demonstrated to control filovirus infection in bat cells but not in human cells, suggesting host species specificity of the antiviral effect. The antiviral effects of bat IFNs appeared not to correlate with induction of IFN-stimulated genes 54 and 56, which were detected in human cells ectopically expressing bat IFN-α and IFN-β. As bat IFN-γ induced the type I IFN pathway, its antiviral effect is likely to be partially induced via cross talk. IMPORTANCE Bats serve as reservoirs for multiple emerging viruses, including filoviruses, henipaviruses, lyssaviruses, and zoonotic coronaviruses. Although there is no evidence for symptomatic disease caused by either Marburg or Ebola viruses in bats, spillover of these viruses into human populations causes deadly outbreaks. The reason for the lack of symptomatic disease in bats infected with filoviruses remains unknown. The outcome of a virus-host interaction depends on the ability of the host immune system to suppress viral replication and the ability of a virus to counteract the host defenses. Our study is a comparative analysis of the host innate immune response to either MARV or EBOV infection in bat and human cells and the role of viral interferon-inhibiting domains in the host innate immune responses. The data are useful for understanding the interactions of filoviruses with natural and accidental hosts and for identification of factors that influence filovirus evolution.

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Induction of the Type I IFN Response by Human Metapneumovirus Lacking SH, G, or M2.2 Expression

Proceedings ◽

10.3390/proceedings2020050143 ◽

2020 ◽

Vol 50 (1) ◽

pp. 143

Author(s):

Kevin Groen ◽

Stefan van Nieuwkoop ◽

Ron Fouchier ◽

Bernadette van den Hoogen

Keyword(s):

Immune Response ◽

Next Generation Sequencing ◽

Immune Responses ◽

A549 Cells ◽

Innate Immune ◽

Innate Immune Responses ◽

Phenotypic Analysis ◽

Hmpv Infection ◽

Generation Sequencing

The human metapneumovirus (HMPV), a member of the Pneumoviridae family, is a major cause of respiratory illness, primarily in young children, the elderly, and immunocompromised individuals. Having a fundamental understanding of the viral evasion of innate immune responses is crucial for the rational design of antiviral therapies. Several studies have reported on how HMPV subverts innate immune responses, with roles for SH, G, and M2.2 proteins. However, these studies often conflict. It has also been reported that eliminating the M2.2 ORF results in insertions and deletions around the M2.2 ORF, which could result in an M2.2-independent interaction with the immune system. We aimed to investigate how HMPV interacts with the innate immune response. Therefore, recombinant viruses lacking M2.2, SH, or G protein expression were generated either by deletion or by ablation of protein expression through mutations. Phenotypic analysis revealed that viruses lacking M2.2 expression are attenuated on interferon-competent A549 cells, but not on interferon-deficient cells. Deletion of ORFs compared to ablation of expression through mutations did not result in differences in replication kinetics. Viruses lacking M2.2 expression induced interferon-ẞ protein production, indicating interferon-antagonistic functions of the M2.2 protein, as previously reported. Phenotypic analysis of A549 cells knocked out for RIG-I, MAVS, and PKR revealed the role of RIG-I in the immune response towards HMPV. Next-generation sequencing analysis of viruses lacking M2.2 expression but not G or SH expression showed hypermutation throughout the virus genome. The hypermutation patterns suggest a role for adenosine deaminase acting on RNA (ADAR) editing. We addressed the question of whether RIG-I activation by viruses lacking M2.2 expression is due to hypermutated genomes or the absence of M2.2 as an interferon antagonist. Additionally, we investigated the role of ADAR in HMPV infection. We present our data on the possible influence of ADAR in HMPV infection by next-generation sequencing of viral stocks in cell knockdowns of ADAR generated by CRISPR-interference.

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The Neutrophil’s Role During Health and Disease

Physiological Reviews ◽

10.1152/physrev.00012.2018 ◽

2019 ◽

Vol 99 (2) ◽

pp. 1223-1248 ◽

Cited By ~ 62

Author(s):

Pei Xiong Liew ◽

Paul Kubes

Keyword(s):

Immune Response ◽

Immune Responses ◽

Adaptive Immune Response ◽

Innate Immune ◽

Acute Injury ◽

Complex Cells ◽

Adaptive Immune ◽

Inflammatory Processes ◽

Health And Disease ◽

Injury And Repair

Neutrophils have always been considered as uncomplicated front-line troopers of the innate immune system equipped with limited proinflammatory duties. Yet recently, the role of the neutrophil has been undergoing a rejuvenation of sorts. Neutrophils are now considered complex cells capable of a significant array of specialized functions, and as an effector of the innate immune response, they are able to regulate many processes such as acute injury and repair, cancer, autoimmunity, and chronic inflammatory processes. Furthermore, evidence exists to indicate that neutrophils also contribute to adaptive immunity by aiding the development of specific adaptive immune responses or guiding the subsequent adaptive immune response. With this revived interest in neutrophils and their many novel functions, it is prudent to review what is currently known about neutrophils and, even more importantly, understand what information is lacking. We discuss the essential features of the neutrophil, from its origins, lifespan, subsets, margination and sequestration of the neutrophil to the death of the neutrophil. We highlight neutrophil recruitment to both infected and injured tissues and outline differences in recruitment of neutrophils between different tissues. Finally, we examine how neutrophils use different mechanisms to either bolster protective immune responses or negatively cause pathological outcomes at different locations.

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Polymorphisms in STING affect human innate immune responses to poxviruses

10.1101/2020.05.28.121657 ◽

2020 ◽

Cited By ~ 1

Author(s):

Richard B. Kennedy ◽

Iana H. Haralambieva ◽

Inna G. Ovsyannikova ◽

Emily A. Voigt ◽

Beth R. Larrabee ◽

...

Keyword(s):

Immune Response ◽

Molecular Modeling ◽

Immune Responses ◽

Genetic Variants ◽

Innate Immune ◽

Smallpox Vaccination ◽

Type I ◽

Innate Immune Responses ◽

Dna Viruses

AbstractWe conducted a large genome-wide association study (GWAS) of the immune responses to primary smallpox vaccination in a combined cohort of > 1,600 subjects. We identified a cluster of SNPs on chromosome 5 (5q31.2) that were significantly associated (p-value: 1.3 × 10−12 – 1.5×10−36) with IFNα response to in vitro poxvirus stimulation. Examination of these SNPs led to the functional testing of rs1131769, a non-synonymous SNP in TMEM173 causing an Arg-to-His change at position 232 in the STING protein—a major regulator of innate immune responses to viral infections. Our findings demonstrate important functional differences between the two alleles, where the major allele (R232) more effectively induces IFNα secretion. Molecular modeling of both alleles identified altered ligand binding characteristics between the two variants, providing a potential mechanism underlying differences in inter-individual responses to poxvirus vaccination. Our data demonstrate that possession of the H232 variant impairs STING-mediated innate immunity to poxviruses. These results clarify prior studies evaluating functional effects of genetic variants in TMEM173 and provide novel data regarding genetic control of poxvirus immunity.Contribution to the FieldHere we report that a single nucleotide non-synonymous polymorphism in the TMEM173 gene encodes for a STING variant conferring a reduced IFN stimulated response compared to wild type. Our results suggest that, upon binding of the STING H232 variant to its ligand, activation of downstream signaling proteins is impaired, resulting in decreased production of IFNα and a weaker interferon-stimulated gene response. Molecular modeling indicates that the diminished functional activity of this variant is likely due to an altered physical structure of the STING protein. STING controls the innate, type I IFN response to double-stranded DNA and cyclic dinucleotides. Individuals with the H232 variant of STING have a much weaker innate immune response to vaccinia virus. Our data help resolve ongoing controversies regarding the role of genetic variants in STING function. Because STING plays an important role in our immune response to DNA viruses and bacteria, our results can be used to predict who will and will not respond to vaccines and treatments, and to design more effective vaccine candidates. Given the role of the STING protein in innate responses to DNA viruses and bacterial pathogens, these data may also be useful in developing novel treatment options for multiple infectious diseases.

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Therapeutic Potentials of Scavenger Receptor CD36 Mediated Innate Immune Responses Against Infectious and Non-Infectious Diseases

Current Drug Discovery Technologies ◽

10.2174/1570163816666190802153319 ◽

2020 ◽

Vol 17 (3) ◽

pp. 299-317

Author(s):

Sooram Banesh ◽

Vishal Trivedi

Keyword(s):

Immune Response ◽

Infectious Diseases ◽

Innate Immune Response ◽

Scavenger Receptor ◽

Innate Immune ◽

Innate Immune Responses ◽

Different Types ◽

Cytosolic Domains ◽

Exogenous Ligands

CD36 is a multifunctional glycoprotein, expressed in different types of cells and known to play a significant role in the pathophysiology of the host. The structural studies revealed that the scavenger receptor consists of short cytosolic domains, two transmembrane domains, and a large ectodomain. The ectodomain serves as a receptor for a diverse number of endogenous and exogenous ligands. The CD36-specific ligands are involved in regulating the immune response during infectious and non-infectious diseases in the host. The role of CD36 in regulating the innate immune response during Pneumonia, Tuberculosis, Malaria, Leishmaniasis, HIV, and Sepsis in a ligand- mediated fashion. Apart from infectious diseases, it is also considered to be involved in metabolic disorders such as Atherosclerosis, Alzheimer’s, cancer, and Diabetes. The ligand binding to scavenger receptor modulates the CD36 down-stream innate immune response, and it can be exploited to design suitable immuno-modulators. Hence, the current review focused on the role of the CD36 in innate immune response and therapeutic potentials of novel heterocyclic compounds as CD36 ligands during infectious and non-infectious diseases.

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Local sympathetic innervations modulate the lung innate immune responses

Science Advances ◽

10.1126/sciadv.aay1497 ◽

2020 ◽

Vol 6 (20) ◽

pp. eaay1497

Author(s):

Tingting Liu ◽

Lu Yang ◽

Xiangli Han ◽

Xiaofan Ding ◽

Jiali Li ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Adrenergic Receptor ◽

Innate Immune ◽

Surgical Removal ◽

Innate Immune Responses ◽

Neural Signals ◽

Critical Function ◽

Local Immunity ◽

Β2 Adrenergic Receptor

Local immunity of the lung needs to be under tight control. However, how efferent neural signals influence lung immunity remains incompletely understood. Here, we report the development of a modified iDISCO-based protocol, iDISCO(ace), for whole-tissue 3D assessment of neural innervations and immune reactions in intact, unsectioned lung tissues. We observed that genetic, pharmacologic, or surgical removal of local sympathetic innervations promoted LPS-elicited innate immune response in the lung. Also, sympathetic ablation enhanced IL-33–elicited type 2 innate immunity. We further show that the sympathetic neurotransmitter norepinephrine, or specific agonists of the β2-adrenergic receptor, can inhibit the LPS- or IL-33–elicited immune response in a cell-intrinsic manner. Moreover, genetic deletion of the β2-adrenergic receptor produced immunomodulatory effects similar to those observed with sympathetic ablation. Together, this study elucidates the critical function of local sympathetic innervations in negatively modulating the lung innate immune responses.

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The Mucosal Innate Immune Response to Cryptosporidium parvum, a Global One Health Issue

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.689401 ◽

2021 ◽

Vol 11 ◽

Author(s):

Charles K. Crawford ◽

Amir Kol

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Cryptosporidium Parvum ◽

Disease Ecology ◽

One Health ◽

Adaptive Immune Response ◽

Parasite Clearance ◽

Economic Loss ◽

Innate Immune ◽

Innate Immune Responses

Cryptosporidium parvum is an apicomplexan parasite that infects the intestinal epithelium of humans and livestock animals worldwide. Cryptosporidiosis is a leading cause of diarrheal-related deaths in young children and a major cause of economic loss in cattle operations. The disease is especially dangerous to infants and immunocompromised individuals, for which there is no effective treatment or vaccination. As human-to-human, animal-to-animal and animal-to-human transmission play a role in cryptosporidiosis disease ecology, a holistic ‘One Health’ approach is required for disease control. Upon infection, the host’s innate immune response restricts parasite growth and initiates the adaptive immune response, which is necessary for parasite clearance and recovery. The innate immune response involves a complex communicative interplay between epithelial and specialized innate immune cells. Traditional models have been used to study innate immune responses to C. parvum but cannot fully recapitulate natural host-pathogen interactions. Recent shifts to human and bovine organoid cultures are enabling deeper understanding of host-specific innate immunity response to infection. This review examines recent advances and highlights research gaps in our understanding of the host-specific innate immune response to C. parvum. Furthermore, we discuss evolving research models used in the field and potential developments on the horizon.

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Deciphering the Role of Leptospira Surface Protein LigA in Modulating the Host Innate Immune Response

Frontiers in Immunology ◽

10.3389/fimmu.2021.807775 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ajay Kumar ◽

Vivek P. Varma ◽

Kavela Sridhar ◽

Mohd Abdullah ◽

Pallavi Vyas ◽

...

Keyword(s):

Immune Response ◽

Immune Modulation ◽

Protein A ◽

Adaptive Immune Response ◽

Surface Protein ◽

Variable Region ◽

Nuclease Activity ◽

Innate Immune ◽

Surface Proteins

Leptospira, a zoonotic pathogen, is known to infect various hosts and can establish persistent infection. This remarkable ability of bacteria is attributed to its potential to modulate (activate or evade) the host immune response by exploiting its surface proteins. We have identified and characterized the domain of the variable region of Leptospira immunoglobulin-like protein A (LAV) involved in immune modulation. The 11th domain (A11) of the variable region of LigA (LAV) induces a strong TLR4 dependent innate response leading to subsequent induction of humoral and cellular immune responses in mice. A11 is also involved in acquiring complement regulator FH and binds to host protease Plasminogen (PLG), there by mediating functional activity to escape from complement-mediated killing. The deletion of A11 domain significantly impaired TLR4 signaling and subsequent reduction in the innate and adaptive immune response. It also inhibited the binding of FH and PLG thereby mediating killing of bacteria. Our study discovered an unprecedented role of LAV as a nuclease capable of degrading Neutrophil Extracellular Traps (NETs). This nuclease activity was primarily mediated by A11. These results highlighted the moonlighting function of LigA and demonstrated that a single domain of a surface protein is involved in modulating the host innate immune defenses, which might allow the persistence of Leptospira in different hosts for a long term without clearance.

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Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies

International Journal of Molecular Sciences ◽

10.3390/ijms21176009 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6009

Author(s):

Valerio Gelfo ◽

Donatella Romaniello ◽

Martina Mazzeschi ◽

Michela Sgarzi ◽

Giada Grilli ◽

...

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Immune Cells ◽

Feedback Loop ◽

Innate Immune ◽

Critical Function ◽

Positive Feedback Loop ◽

Pathological Conditions ◽

Cancer Initiation

IL-1 belongs to a family of 11 members and is one of the seven receptor-agonists with pro-inflammatory activity. Beyond its biological role as a regulator of the innate immune response, IL-1 is involved in stress and chronic inflammation, therefore it is responsible for several pathological conditions. In particular, IL-1 is known to exert a critical function in malignancies, influencing the tumor microenvironment and promoting cancer initiation and progression. Thus, it orchestrates immunosuppression recruiting pro-tumor immune cells of myeloid origin. Furthermore, new recent findings showed that this cytokine can be directly produced by tumor cells in a positive feedback loop and contributes to the failure of targeted therapy. Activation of anti-apoptotic signaling pathways and senescence are some of the mechanisms recently proposed, but the role of IL-1 in tumor cells refractory to standard therapies needs to be further investigated.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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