scholarly journals Adeno-associated Virus (AAV) versus Immune Response

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 102 ◽  
Author(s):  
Joseph Rabinowitz ◽  
Ying Kai Chan ◽  
Richard Jude Samulski
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Binding Sites ◽  
Adeno Associated Virus ◽  
Host Immune Responses ◽  
Experimental Drugs ◽  
Tissue Targeting ◽  
Targeting Delivery ◽  
Antibody Epitopes ◽  
Made In

Decades ago, Friedmann and Roblin postulated several barriers to gene therapy, including tissue targeting, delivery across the blood–brain barrier (BBB), and host immune responses. These issues remain pertinent till today. Since then, several advances have been made in elucidating structures of adeno-associated virus (AAV) serotypes, antibody epitopes, and ways to modify antibody-binding sites. AAVs capsid has also been engineered to re-direct tissue tropism, reduce ubiquitination, and promote passage across the BBB. Furthermore, the use of high(er) dose recombinant AAV (rAAV) has been accompanied by a better understanding of immune responses in both experimental animals and early clinical trials, and novel work is being performed to modulate the immune response. While the immune responses to rAAV remains a major challenge in translating experimental drugs to approved medicine, and will likely require more than a single solution, we now better understand the hurdles to formulate and test experimental solutions to surmount them.

scholarly journals Microrna-130a Downregulates HCV Replication through an atg5-Dependent Autophagy Pathway

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 338 ◽  
Author(s):  
Xiaoqiong Duan ◽  
Xiao Liu ◽  
Wenting Li ◽  
Jacinta A. Holmes ◽  
Annie J. Kruger ◽  
...  
Keyword(s):  
Immune Responses ◽  
Binding Sites ◽  
Target Gene ◽  
Target Genes ◽  
Pyruvate Metabolism ◽  
Host Immune Responses ◽  
Qrt Pcr ◽  
Antiviral Genes ◽  
Autophagy Pathway ◽  
Host Antiviral Response

We previously identified that miR-130a downregulates HCV replication through two independent pathways: restoration of host immune responses and regulation of pyruvate metabolism. In this study, we further sought to explore host antiviral target genes regulated by miR-130a. We performed a RT² Profiler™ PCR array to identify the host antiviral genes regulated by miR-130a. The putative binding sites between miR-130a and its downregulated genes were predicted by miRanda. miR-130a and predicted target genes were over-expressed or knocked down by siRNA or CRISPR/Cas9 gRNA. Selected gene mRNAs and their proteins, together with HCV replication in JFH1 HCV-infected Huh7.5.1 cells were monitored by qRT-PCR and Western blot. We identified 32 genes that were significantly differentially expressed more than 1.5-fold following miR-130a overexpression, 28 of which were upregulated and 4 downregulated. We found that ATG5, a target gene for miR-130a, significantly upregulated HCV replication and downregulated interferon stimulated gene expression. miR-130a downregulated ATG5 expression and its conjugation complex with ATG12. ATG5 and ATG5-ATG12 complex affected interferon stimulated gene (ISG) such as MX1 and OAS3 expression and subsequently HCV replication. We concluded that miR-130a regulates host antiviral response and HCV replication through targeting ATG5 via the ATG5-dependent autophagy pathway.

scholarly journals Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 629
Author(s):  
Megan M. Dunagan ◽  
Kala Hardy ◽  
Toru Takimoto
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Influenza A Virus ◽  
Influenza A ◽  
Human Populations ◽  
Lymphocyte Migration ◽  
Host Immune Responses ◽  
Mhc Molecules ◽  
The Impact

Influenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and NS1, which antagonize the host innate immune response. By transcriptomic analysis, we previously showed that PA-X is a major contributor for general shutoff, while shutoff active NS1 specifically inhibits the expression of host cytokines, MHC molecules, and genes involved in innate immunity in cultured human cells. So far, the impact of these shutoff proteins in the acquired immune response in vivo has not been determined in detail. In this study, we analyzed the effects of PA-X and NS1 shutoff activities on immune response using recombinant influenza A/California/04/2009 viruses containing mutations affecting the expression of shutoff active PA-X and NS1 in a mouse model. Our data indicate that the virus without shutoff activities induced the strongest T and B cell responses. Both PA-X and NS1 reduced host immune responses, but shutoff active NS1 most effectively suppressed lymphocyte migration to the lungs, antibody production, and the generation of IAV specific CD4+ and CD8+ T cells. NS1 also prevented the generation of protective immunity against a heterologous virus challenge. These data indicate that shutoff active NS1 plays a major role in suppressing host immune responses against IAV infection.

scholarly journals Extracellular Vesicles from Different Pneumococcal Serotypes Are Internalized by Macrophages and Induce Host Immune Responses

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1530
Author(s):  
Alfonso Olaya-Abril ◽  
Rafael Prados-Rosales ◽  
José A. González-Reyes ◽  
Arturo Casadevall ◽  
Liise-anne Pirofski ◽  
...  
Keyword(s):  
Immune Response ◽  
Biological Activity ◽  
Immune Responses ◽  
Extracellular Vesicles ◽  
Host Cells ◽  
Pneumococcal Serotypes ◽  
Human Pathogen ◽  
Host Immune Responses ◽  
Serotype 1 ◽  
Transient Loss

Bacterial extracellular vesicles are membranous ultrastructures released from the cell surface. They play important roles in the interaction between the host and the bacteria. In this work, we show how extracellular vesicles produced by four different serotypes of the important human pathogen, Streptococcus pneumoniae, are internalized by murine J774A.1 macrophages via fusion with the membrane of the host cells. We also evaluated the capacity of pneumococcal extracellular vesicles to elicit an immune response by macrophages. Macrophages treated with the vesicles underwent a serotype-dependent transient loss of viability, which was further reverted. The vesicles induced the production of proinflammatory cytokines, which was higher for serotype 1 and serotype 8-derived vesicles. These results demonstrate the biological activity of extracellular vesicles of clinically important pneumococcal serotypes.

scholarly journals Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis

2021 ◽  
Author(s):  
Elina Panahi ◽  
Danielle I. Stanisic ◽  
Christopher S. Peacock ◽  
Lara J. Herrero
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Cutaneous Leishmaniasis ◽  
Adaptive Immune Response ◽  
Leishmania Parasite ◽  
Host Immune System ◽  
Phagocytic Cells ◽  
Host Immune Responses ◽  
Outcome Severity ◽  
Common Clinical Presentation

Leishmania (Kinetoplastida: Trypanosomatidae) parasites are known to cause a broad spectrum of clinical diseases in humans, collectively known as the leishmaniases. Cutaneous leishmaniasis is the most common clinical presentation with varying degrees of severity largely driven by host immune responses, specifically the interplay between innate and adaptive immune response. The establishment of a T lymphocyte driven cell-mediated immune response, leading to activated phagocytic cells, leading to Leishmania parasite killing and control of infection. Alternatively, the Leishmania parasite manipulates the host immune system, enabling parasite proliferation and clinical disease. Here we review how the cumulative interactions of different aspects of the host immune response determines disease outcome, severity, and immunity to re-infection.

scholarly journals Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories

2020 ◽  
Author(s):  
Yapeng Su ◽  
Daniel Chen ◽  
Christopher Lausted ◽  
Dan Yuan ◽  
Jongchan Choi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Surface Proteins ◽  
Host Immune Responses ◽  
Therapeutic Development ◽  
Clinical Measures ◽  
Whole Transcriptome

SUMMARYHost immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

scholarly journals Host Immune Response and Novel Diagnostic Approach to NTM Infections

2020 ◽  
Vol 21 (12) ◽  
pp. 4351
Author(s):  
Yuko Abe ◽  
Kiyoharu Fukushima ◽  
Yuki Hosono ◽  
Yuki Matsumoto ◽  
Daisuke Motooka ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Humoral Immunity ◽  
Diagnostic Approach ◽  
Post Transplantation ◽  
Diagnosis And Management ◽  
Immunological Responses ◽  
Host Immune Responses ◽  
Diagnostic Approaches ◽  
Proper Diagnosis

The incidence and prevalence of non-tuberculous mycobacteria (NTM) infections are steadily increasing worldwide, partially due to the increased incidence of immunocompromised conditions, such as the post-transplantation state. The importance of proper diagnosis and management of NTM infection has been recently recognized. Host immunological responses play integral roles in vulnerability to NTM infections, and may contribute to the onset of specific types of NTM infection. Furthermore, distinct NTM species are known to affect and attenuate these host immune responses in unique manners. Therefore, host immune responses must be understood with respect to each causative NTM species. Here, we review innate, cellular-mediated, and humoral immunity to NTM and provide perspectives on novel diagnostic approaches regarding each NTM species.

scholarly journals Infection, Inflammation and Immunity in Covid-19 Infection

2021 ◽  
Vol 48 (3) ◽  
pp. 77-82
Author(s):  
R. Cherneva ◽  
Z. Cherneva
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Immune Responses ◽  
Systemic Inflammation ◽  
Multiple Organ ◽  
Host Immunity ◽  
Effective Prevention ◽  
Systemic Complications ◽  
Host Immune Responses ◽  
Prevention And Treatment

Abstract The COVID-19 pandemic caused by the SARS-CoV-2 has increased the burden on healthcare system. Despite some progress in its diagnostics has been made, effective prevention and treatment are still insufficient. Since SARS-CoV-2 infections often cause systemic inflammation and multiple organ failure, the therapeutic options aimed at modulating the host immune responses to prevent subsequent systemic complications are demanding. The review provides a summary of the SARS-CoV-2 virus infection and underlines the current perception of pulmonary host’s immune response and its contributions to disease severity and systemic inflammation. Signaling pathways which have the potential to manipulate host immunity and improve clinical outcomes are also presented.

scholarly journals Established Cotton Stainer Gut Bacterial Mutualists Evade Regulation by Host Antimicrobial Peptides

2019 ◽  
Vol 85 (13) ◽  
Author(s):  
Thomas Ogao Onchuru ◽  
Martin Kaltenpoth
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Target Genes ◽  
Quantitative Composition ◽  
Bacterial Symbionts ◽  
Immune Systems ◽  
Host Fitness ◽  
Host Immune Responses ◽  
Cotton Stainer ◽  
The Impact

ABSTRACT Symbioses with microorganisms are ubiquitous in nature and confer important ecological traits to animal hosts but also require control mechanisms to ensure homeostasis of the symbiotic interactions. In addition to protecting hosts against pathogens, animal immune systems recognize, respond to, and regulate mutualists. The gut bacterial symbionts of the cotton stainer bug, Dysdercus fasciatus, elicit an immune response characterized by the upregulation of c-type lysozyme and the antimicrobial peptide pyrrhocoricin in bugs with their native gut microbiota compared to that in dysbiotic insects. In this study, we investigated the impact of the elicited antimicrobial immune response on the established cotton stainer gut bacterial symbiont populations. To this end, we used RNA interference (RNAi) to knock down immunity-related genes hypothesized to regulate the symbionts, and we subsequently measured the effect of this silencing on host fitness and on the abundance of the major gut bacterial symbionts. Despite successful downregulation of target genes by both ingestion and injection of double-stranded RNA (dsRNA), the silencing of immunity-related genes had no effect on either host fitness or the qualitative and quantitative composition of established gut bacterial symbionts, indicating that the host immune responses are not actively involved in the regulation of the nutritional and defensive gut bacterial mutualists. These results suggest that close associations of bacterial symbionts with their hosts can result in the evolution of mechanisms ensuring that symbionts remain insensitive to host immunological responses, which may be important for the evolutionary stability of animal-microbe symbiotic associations. IMPORTANCE Animal immune systems are central for the protection of hosts against enemies by preventing or eliminating successful infections. However, in the presence of beneficial bacterial mutualists, the immune system must strike a balance of not killing the beneficial symbionts while at the same time preventing enemy attacks. Here, using the cotton stainer bug, we reveal that its long-term associated bacterial symbionts are insensitive to the host’s immune effectors, suggesting adaptation to the host’s defenses, thereby strengthening the stability of the symbiotic relationship. The ability of the symbionts to elicit host immune responses but remain insensitive themselves may be a mechanism by which the symbionts prime hosts to fight future pathogenic infections.

scholarly journals Complement Is an Essential Component of the Immune Response to Adeno-Associated Virus Vectors

2008 ◽  
Vol 82 (6) ◽  
pp. 2727-2740 ◽  
Author(s):  
Anne K. Zaiss ◽  
Matthew J. Cotter ◽  
Lindsay R. White ◽  
Sharon A. Clark ◽  
Norman C. W. Wong ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Human Serum ◽  
Factor H ◽  
Dependent Manner ◽  
Adeno Associated Virus ◽  
Essential Component ◽  
Primary Mouse ◽  
Mouse Macrophages

ABSTRACT Adeno-associated virus (AAV) vectors are associated with relatively mild host immune responses in vivo. Although AAV induces very weak innate immune responses, neutralizing antibodies against the vector capsid and transgene still occur. To understand further the basis of the antiviral immune response to AAV vectors, studies were performed to characterize AAV interactions with macrophages. Primary mouse macrophages and human THP-1 cells transduced in vitro using an AAV serotype 2 (AAV2) vector encoding green fluorescent protein did not result in measurable transgene expression. An assessment of internalized vector genomes showed that AAV2 vector uptake was enhanced in the presence of normal but not heat-inactivated or C3-depleted mouse/human serum. Enhanced uptake in the presence of serum coincided with increased macrophage activation as determined by the expression of NF-κB-dependent genes such as macrophage inflammatory protein 2 (MIP-2), interleukin-1β (IL-1β), IL-8, and MIP-1β. AAV vector serotypes 1 and 8 also activated human and mouse macrophages in a serum-dependent manner. Immunoprecipitation studies demonstrated the binding of iC3b complement protein to the AAV2 capsid in human serum. AAV2 did not activate the alternative pathway of the complement cascade and lacked cofactor activity for factor I-mediated degradation of C3b to iC3b. Instead, our results suggest that the AAV capsid also binds complement regulatory protein factor H. In vivo, complement receptor 1/2- and C3-deficient mice displayed impaired humoral immunity against AAV2 vectors, with a delay in antibody development and significantly lower neutralizing antibody titers. These results show that the complement system is an essential component of the host immune response to AAV.

scholarly journals IL-6 signalling protects zebrafish larvae during Staphylococcus epidermidis infection in a novel bath immersion model

2020 ◽  
Author(s):  
PT Dhanagovind ◽  
Prabeer K. Kujur ◽  
Rajeeb K. Swain ◽  
Sanjita Banerjee
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Staphylococcus Epidermidis ◽  
Signalling Pathway ◽  
Infection Model ◽  
Primary Role ◽  
Signal Transducer ◽  
Host Immune Responses ◽  
Zebrafish Larvae ◽  
Pro Inflammatory Cytokines

AbstractHost immune responses to Staphylococcus epidermidis, a frequent cause of nosocomial infections, are not well understood. We have established a novel bath immersion model of this infection in zebrafish larvae. S.epidermidis infection activates Tlr-2 signalling pathway by upregulation of tlr-2. Macrophages play a primary role in the host immune response and are involved in clearance of infection in the larvae. There is marked inflammation characterised by heightened NF-κB signalling and elevation of several pro-inflammatory cytokines. Infected larvae show rapid upregulation of il-1b and tnf-a transcripts and relatively slower elevation of il-6 transcription. The IL-6 signalling pathway is additionally subject to amplification by elevation of IL-6 signal transducer (il-6st) levels, which negatively correlates with miRNA dre-miR-142-5p expression. Enhanced IL-6 signalling is protective to the host in this model as inhibition of the signalling pathway resulted in increased mortality upon S.epidermidis infection. Our study describes the host immune responses to S.epidermidis infection, identifies a likely role for miR-142-5p – il-6st interaction in modulating this response and establishes the importance of IL-6 signalling in this infection model.

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