scholarly journals Antiviral Functions of Monoclonal Antibodies against Chikungunya Virus

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 305 ◽  
Author(s):  
Jing Jin ◽  
Graham Simmons
Keyword(s):  
Immune Response ◽  
Monoclonal Antibodies ◽  
Chikungunya Virus ◽  
Therapeutic Antibodies ◽  
Mechanistic Studies ◽  
Chikv Infection ◽  
The Past ◽  
New Generation ◽  
Human And Mouse

Chikungunya virus (CHIKV) is the most common alphavirus infecting humans worldwide. Antibodies play pivotal roles in the immune response to infection. Increasingly, therapeutic antibodies are becoming important for protection from pathogen infection for which neither vaccine nor treatment is available, such as CHIKV infection. The new generation of ultra-potent and/or broadly cross-reactive monoclonal antibodies (mAbs) provides new opportunities for intervention. In the past decade, several potent human and mouse anti-CHIKV mAbs were isolated and demonstrated to be protective in vivo. Mechanistic studies of these mAbs suggest that mAbs exert multiple modes of action cooperatively. Better understanding of these antiviral mechanisms for mAbs will help to optimize mAb therapies.

scholarly journals Structural basis of Chikungunya virus inhibition by monoclonal antibodies

2020 ◽  
Vol 117 (44) ◽  
pp. 27637-27645
Author(s):  
Qun Fei Zhou ◽  
Julie M. Fox ◽  
James T. Earnest ◽  
Thiam-Seng Ng ◽  
Arthur S. Kim ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Chikungunya Virus ◽  
Neutralizing Antibody ◽  
Structural Basis ◽  
Chikv Infection ◽  
Receptor Binding Site ◽  
Viral Pathogen ◽  
Virus Attachment

Chikungunya virus (CHIKV) is an emerging viral pathogen that causes both acute and chronic debilitating arthritis. Here, we describe the functional and structural basis as to how two anti-CHIKV monoclonal antibodies, CHK-124 and CHK-263, potently inhibit CHIKV infection in vitro and in vivo. Our in vitro studies show that CHK-124 and CHK-263 block CHIKV at multiple stages of viral infection. CHK-124 aggregates virus particles and blocks attachment. Also, due to antibody-induced virus aggregation, fusion with endosomes and egress are inhibited. CHK-263 neutralizes CHIKV infection mainly by blocking virus attachment and fusion. To determine the structural basis of neutralization, we generated cryogenic electron microscopy reconstructions of Fab:CHIKV complexes at 4- to 5-Å resolution. CHK-124 binds to the E2 domain B and overlaps with the Mxra8 receptor-binding site. CHK-263 blocks fusion by binding an epitope that spans across E1 and E2 and locks the heterodimer together, likely preventing structural rearrangements required for fusion. These results provide structural insight as to how neutralizing antibody engagement of CHIKV inhibits different stages of the viral life cycle, which could inform vaccine and therapeutic design.

scholarly journals Anti–4-1bb Monoclonal Antibodies Abrogate T Cell–Dependent Humoral Immune Responses in Vivo through the Induction of Helper T Cell Anergy

1999 ◽  
Vol 190 (10) ◽  
pp. 1535-1540 ◽  
Author(s):  
Robert S. Mittler ◽  
Tina S. Bailey ◽  
Kerry Klussman ◽  
Mark D. Trailsmith ◽  
Michael K. Hoffmann
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cells ◽  
Humoral Immunity ◽  
Cd8 T Cells ◽  
Immunodeficient Mice ◽  
Humoral Immune

The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti–mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti–4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell–independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti–4-1BB mAb was given within 1 wk after immunization. Anti–4-1BB inhibition was observed in mice lacking functional CD8+ T cells, indicating that CD8+ T cells were not required for the induction of anergy. Analysis of the requirements for the anti–4-1BB–mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti–4-1BB–treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti–4-1BB–treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti–4-1BB–treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti–4-1BB mAbs.

scholarly journals Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1803 ◽  
Author(s):  
Amira Mbarek ◽  
Ghina Moussa ◽  
Jeanne Leblond Chain
Keyword(s):  
Cardiovascular Disease ◽  
Neurodegenerative Disorders ◽  
Therapeutic Agents ◽  
Mechanistic Studies ◽  
Molecular Tweezers ◽  
The Past ◽  
Pharmaceutical Applications ◽  
Controlled Motion

Synthetic acyclic receptors, composed of two arms connected with a spacer enabling molecular recognition, have been intensively explored in host-guest chemistry in the past decades. They fall into the categories of molecular tweezers, clefts and clips, depending on the geometry allowing the recognition of various guests. The advances in synthesis and mechanistic studies have pushed them forward to pharmaceutical applications, such as neurodegenerative disorders, infectious diseases, cancer, cardiovascular disease, diabetes, etc. In this review, we provide a summary of the synthetic molecular tweezers, clefts and clips that have been reported for pharmaceutical applications. Their structures, mechanism of action as well as in vitro and in vivo results are described. Such receptors were found to selectively bind biological guests, namely, nucleic acids, sugars, amino acids and proteins enabling their use as biosensors or therapeutics. Particularly interesting are dynamic molecular tweezers which are capable of controlled motion in response to an external stimulus. They proved their utility as imaging agents or in the design of controlled release systems. Despite some issues, such as stability, cytotoxicity or biocompatibility that still need to be addressed, it is obvious that molecular tweezers, clefts and clips are promising candidates for several incurable diseases as therapeutic agents, diagnostic or delivery tools.

scholarly journals A blueprint for translational regenerative medicine

2020 ◽  
Vol 12 (572) ◽  
pp. eaaz2253
Author(s):  
James P. K. Armstrong ◽  
Timothy J. Keane ◽  
Anne C. Roques ◽  
P. Stephen Patrick ◽  
Claire M. Mooney ◽  
...  
Keyword(s):  
Immune Response ◽  
Regenerative Medicine ◽  
In Vivo Imaging ◽  
Imaging Modalities ◽  
Proof Of Concept ◽  
The Past ◽  
Valley Of Death ◽  
Clinical Adoption ◽  
Selection Of

The past few decades have produced a large number of proof-of-concept studies in regenerative medicine. However, the route to clinical adoption is fraught with technical and translational obstacles that frequently consign promising academic solutions to the so-called “valley of death.” Here, we present a proposed blueprint for translational regenerative medicine. We offer principles to help guide the selection of cells and materials, present key in vivo imaging modalities, and argue that the host immune response should be considered throughout design and development. Last, we suggest a pathway to navigate the often complex regulatory and manufacturing landscape of translational regenerative medicine.

scholarly journals Telmisartan restricts Chikungunya virus infection in vitro and in vivo through the AT1/PPAR-γ/MAPKs pathways

2021 ◽  
Author(s):  
Saikat De ◽  
Prabhudutta Mamidi ◽  
Soumyajit Ghosh ◽  
Supriya Suman Keshry ◽  
Chandan Mahish ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
At1 Receptor ◽  
Host Factors ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Global Public Health ◽  
Chikv Infection ◽  
Ppar Γ

Chikungunya virus (CHIKV) has re-emerged as a global public health threat. The inflammatory pathways of RAS and PPAR-γ are usually involved in viral infections. Thus, Telmisartan (TM) with known capacity to block AT1 receptor and activate PPAR-γ, was investigated against CHIKV. The anti-CHIKV effect of TM was investigated in vitro (Vero, RAW 264.7 cells and hPBMCs) and in vivo (C57BL/6 mice). TM was found to abrogate CHIKV infection efficiently (IC50 of 15.34-20.89μM in the Vero and RAW 264.7 cells respectively). Viral RNA and proteins were reduced remarkably. Additionally, TM interfered in the early and late stages of CHIKV life cycle with efficacy in both pre and post-treatment assay. Moreover, the agonist of AT1 receptor and antagonist of PPAR-γ increased CHIKV infection suggesting TM’s anti-viral potential by modulating host factors. Besides, reduced activation of all major MAPKs, NF-κB (p65) and cytokines by TM through the inflammatory axis supported the fact that the anti-CHIKV efficacy of TM is partly mediated through the AT1/PPAR-γ/MAPKs pathways. Interestingly, at the human equivalent dose, TM abrogated CHIKV infection and inflammation significantly leading to reduced clinical score and complete survival of C57BL/6 mice. Additionally, TM reduced infection in hPBMC derived monocyte-macrophage populations in vitro . Hence, TM was found to reduce CHIKV infection by targeting both viral and host factors. Considering its safety and in vivo efficacy, it can be a suitable candidate in future for repurposing against CHIKV.

scholarly journals Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc-FcγR interaction on monocytes

2019 ◽  
Vol 4 (32) ◽  
pp. eaav5062 ◽  
Author(s):  
Julie M. Fox ◽  
Vicky Roy ◽  
Bronwyn M. Gunn ◽  
Ling Huang ◽  
Melissa A. Edeling ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Chikungunya Virus ◽  
Immune Cell ◽  
Transgenic Animals ◽  
Therapeutic Activity ◽  
Fcγ Receptors ◽  
Chikv Infection ◽  
Effector Functions ◽  
Virus Clearance ◽  
Infected Cells

Chikungunya virus (CHIKV) is an emerging mosquito-borne virus that has caused explosive outbreaks worldwide. Although neutralizing monoclonal antibodies (mAbs) against CHIKV inhibit infection in animals, the contribution of Fc effector functions to protection remains unknown. Here, we evaluated the activity of therapeutic mAbs that had or lacked the ability to engage complement and Fcγ receptors (FcγR). When administered as post-exposure therapy in mice, the Fc effector functions of mAbs promoted virus clearance from infected cells and reduced joint swelling—results that were corroborated in antibody-treated transgenic animals lacking activating FcγR. The control of CHIKV infection by antibody-FcγR engagement was associated with an accelerated influx of monocytes. A series of immune cell depletions revealed that therapeutic mAbs required monocytes for efficient clearance of CHIKV infection. Overall, our study suggests that in mice, FcγR expression on monocytes is required for optimal therapeutic activity of antibodies against CHIKV and likely other related viruses.

scholarly journals Distinct Roles of Interferon Alpha and Beta in Controlling Chikungunya Virus Replication and Modulating Neutrophil-Mediated Inflammation

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Lindsey E. Cook ◽  
Marissa C. Locke ◽  
Alissa R. Young ◽  
Kristen Monte ◽  
Matthew L. Hedberg ◽  
...  
Keyword(s):  
Immune Response ◽  
Chikungunya Virus ◽  
Biological Activities ◽  
Neutrophil Infiltration ◽  
Type I Interferons ◽  
Type I ◽  
Functional Variation ◽  
Chikv Infection ◽  
Blocking Antibody ◽  
Type I Ifns

ABSTRACT Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-β developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-β-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-β had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-β-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-β modulating neutrophil-mediated inflammation. IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-α and IFN-β both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-α limits CHIKV replication and dissemination, whereas IFN-β protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.

scholarly journals Molecular basis of inherited human antithrombin deficiency

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2159-2171 ◽  
Author(s):  
MA Blajchman ◽  
RC Austin ◽  
F Fernandez-Rachubinski ◽  
WP Sheffield
Keyword(s):  
Monoclonal Antibodies ◽  
Molecular Basis ◽  
Genetically Engineered ◽  
Foreseeable Future ◽  
Antithrombin Deficiency ◽  
X Ray ◽  
The Past ◽  
Structural Relationships ◽  
At Deficiency

Abstract Figures 1 and 4 summarize the various AT mutations that have been described. The molecular elucidation, over the past decade, of the various AT deficiency types has provided important new insights into functional-structural relationships of AT. This knowledge, together with data provided by monoclonal antibodies and x-ray crystallographic studies of related molecules, has provided important new insights as to how the AT molecule functions in vivo. Finally, such knowledge might, in the foreseeable future, lead to the production of AT molecules that are specifically genetically engineered to be of use in a variety of clinical situations.

Sign in / Sign up

Export Citation Format

Share Document