Comparison of host immune responses to LPS in human using an immune profiling panel, in vivo endotoxemia versus ex vivo stimulation

Neospora caninum and Toxoplasma gondii are one of the main concerns of the livestock sector as they cause important economic losses in ruminants due to the reproductive failure. It is well-known that the interaction of these parasites with the placenta determines the course of infection, leading to fetal death or parasite transmission to the offspring. However, to advance the development of effective vaccines and treatments, there are still important gaps on knowledge on the placental host-parasite interactions that need to be addressed. Ruminant animal models are still an indispensable tool for providing a global view of the pathogenesis, lesions, and immune responses, but their utilization embraces important economic and ethics restrictions. Alternative in vitro systems based on caruncular and trophoblast cells, the key cellular components of placentomes, have emerged in the last years, but their use can only offer a partial view of the processes triggered after infection as they cannot mimic the complex placental architecture and neglect the activity of resident immune cells. These drawbacks could be solved using placental explants, broadly employed in human medicine, and able to preserve its cellular architecture and function. Despite the availability of such materials is constrained by their short shelf-life, the development of adequate cryopreservation protocols could expand their use for research purposes. Herein, we review and discuss existing (and potential) in vivo, in vitro, and ex vivo ruminant placental models that have proven useful to unravel the pathogenic mechanisms and the host immune responses responsible for fetal death (or protection) caused by neosporosis and toxoplasmosis.

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Immune profiling reveals early disease trajectories associated with COVID-19 mortality: a sub-study from the ACTT-1 trial

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab035 ◽

2021 ◽

Author(s):

Joshua M Thiede ◽

Abigail R Gress ◽

Samuel D Libby ◽

Christine E Ronayne ◽

William E Matchett ◽

...

Keyword(s):

Immune Responses ◽

Antiviral Therapy ◽

Symptom Onset ◽

Antibody Responses ◽

Early Disease ◽

Host Immune Responses ◽

Study Enrollment ◽

Cytokine Responses ◽

Study Participants ◽

Immune Profiling

Abstract COVID-19 outcomes are linked to host immune responses and may be impacted by antiviral therapy. We investigated antibody and cytokine responses in ACTT-1 study participants enrolled at our center. We studied serum specimens from 19 hospitalized adults with COVID-19 randomized to treatment with remdesivir or placebo. We assessed SARS-CoV-2 antibody responses and identified cytokine signatures using hierarchical clustering. We identified no clear immunologic trends attributable to remdesivir treatment. Seven subjects were initially seronegative at study enrollment, and all four deaths occurred in this group with more recent symptom onset. We identified three dominant cytokine signatures, demonstrating different disease trajectories.

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Decellularised Human Umbilical Artery as a Vascular Graft Elicits Minimal Pro-Inflammatory Host Response Ex Vivo and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms22157981 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7981

Author(s):

Alexander Høgsted Ahlmann ◽

Shu Fang ◽

Sussi Bagge Mortensen ◽

Line Weis Andersen ◽

Pernille Gejl Pedersen ◽

...

Keyword(s):

Vascular Graft ◽

Umbilical Artery ◽

Ex Vivo ◽

White Blood Cells ◽

Small Diameter ◽

M1 Macrophages ◽

Host Immune Responses ◽

Cytokine Levels ◽

Anti Inflammatory Cytokine

Small diameter (<6 mm) vessel grafts still pose a challenge for scientists worldwide. Decellularised umbilical artery (dUA) remains promising as small diameter tissue engineered vascular graft (TEVG), yet their immunogenicity remains unknown. Herein, we evaluated the host immune responses, with a focus on the innate part, towards human dUA implantation in mice, and confirmed our findings in an ex vivo allogeneic human setup. Overall, we did not observe any differences in the number of circulating white blood cells nor the number of monocytes among three groups of mice (1) dUA patch; (2) Sham; and (3) Mock throughout the study (day −7 to 28). Likewise, we found no difference in systemic inflammatory and anti-inflammatory cytokine levels between groups. However, a massive local remodelling response with M2 macrophages were observed in the dUA at day 28, whereas M1 macrophages were less frequent. Moreover, human monocytes from allogeneic individuals were differentiated into macrophages and exposed to lyophilised dUA to maximize an eventual M1 response. Yet, dUA did not elicit any immediate M1 response as determined by the absence of CCR7 and CXCL10. Together this suggests that human dUA elicits a minimal pro-inflammatory response further supporting its use as a TEVG in an allogeneic setup.

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Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses

Vaccines ◽

10.3390/vaccines9060629 ◽

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.

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The Effects of In Vivo Exposure to Copper Oxide Nanoparticles on the Gut Microbiome, Host Immunity, and Susceptibility to a Bacterial Infection in Earthworms

Nanomaterials ◽

10.3390/nano10071337 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1337 ◽

Cited By ~ 2

Author(s):

Elmer Swart ◽

Jiri Dvorak ◽

Szabolcs Hernádi ◽

Tim Goodall ◽

Peter Kille ◽

...

Keyword(s):

Immune Responses ◽

Gut Microbiome ◽

Methodological Approach ◽

Copper Oxide Nanoparticles ◽

Mrna Levels ◽

Immune Genes ◽

Host Immune Responses ◽

Earthworm Gut ◽

Bacterium Bacillus

Nanomaterials (NMs) can interact with the innate immunity of organisms. It remains, however, unclear whether these interactions can compromise the immune functioning of the host when faced with a disease threat. Co-exposure with pathogens is thus a powerful approach to assess the immuno-safety of NMs. In this paper, we studied the impacts of in vivo exposure to a biocidal NM on the gut microbiome, host immune responses, and susceptibility of the host to a bacterial challenge in an earthworm. Eisenia fetida were exposed to CuO-nanoparticles in soil for 28 days, after which the earthworms were challenged with the soil bacterium Bacillus subtilis. Immune responses were monitored by measuring mRNA levels of known earthworm immune genes. Effects of treatments on the gut microbiome were also assessed to link microbiome changes to immune responses. Treatments caused a shift in the earthworm gut microbiome. Despite these effects, no impacts of treatment on the expression of earthworm immune markers were recorded. The methodological approach applied in this paper provides a useful framework for improved assessment of immuno-safety of NMs. In addition, we highlight the need to investigate time as a factor in earthworm immune responses to NM exposure.

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Efficacy of the antimicrobial peptide TP4 against Helicobacter pylori infection: in vitro membrane perturbation via micellization and in vivo suppression of host immune responses in a mouse model

Oncotarget ◽

10.18632/oncotarget.4101 ◽

2015 ◽

Vol 6 (15) ◽

pp. 12936-12954 ◽

Cited By ~ 22

Author(s):

Jayaram Lakshmaiah Narayana ◽

Han-Ning Huang ◽

Chang-Jer Wu ◽

Jyh-Yih Chen

Keyword(s):

Helicobacter Pylori ◽

Mouse Model ◽

Immune Responses ◽

Antimicrobial Peptide ◽

Helicobacter Pylori Infection ◽

Host Immune Responses ◽

Membrane Perturbation

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Seroprevalence of Antibodies against Pkn1, a Novel Potential Immunogen, inChlamydia trachomatis-InfectedMacaca nemestrinaand Human Patients

BioMed Research International ◽

10.1155/2014/245483 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Achchhe L. Patel ◽

Prashant K. Mishra ◽

Divya Sachdev ◽

Uma Chaudhary ◽

Dorothy L. Patton ◽

...

Keyword(s):

Immune Responses ◽

Genital Tract ◽

Protein A ◽

Macaca Nemestrina ◽

Sexually Transmitted ◽

Host Immune Responses ◽

Bioinformatic Tools ◽

Genital Tract Infections ◽

Tract Infections

Chlamydia trachomatis(CT) is an important cause of sexually transmitted genital tract infections (STIs) and trachoma. Despite major research into chlamydial pathogenesis and host immune responses, immunoprotection has been hampered by the incomplete understanding of protective immunity in the genital tract. Characterized vaccine candidates have shown variable efficacy ranging from no protection to partial protectionin vivo. It is therefore a research priority to identify novel chlamydial antigens that may elicit protective immune responses against CT infection. In the present study we assessed the seroprevalence of antibodies against protein kinase1 (Pkn1), DNA ligaseA (LigA), and major outer membrane protein A (OmpA) following natural CT infection in humans and in experimentally induced CT infection inMacaca nemestrina. Antigenic stretches of Pkn1, LigA, and OmpA were identified using bioinformatic tools.Pkn1,LigA, andOmpAgenes were cloned in bacterial expression vector and purified by affinity chromatography. Our results demonstrate significantly high seroprevalence of antibodies against purified Pkn1 and OmpA in sera obtained from the macaque animal model and human patients infected with CT. In contrast no significant seroreactivity was observed for LigA. The seroprevalence of antibodies against Pkn1 suggest that nonsurface chlamydial proteins could also be important for developing vaccines forC. trachomatis.

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Host immune responses in ex vivo approaches to cutaneous gene therapy targeted to keratinocytes

Experimental Dermatology ◽

10.1111/j.1600-0625.2005.00351.x ◽

2005 ◽

Vol 14 (10) ◽

pp. 727-735 ◽

Cited By ~ 19

Author(s):

Z. Lu ◽

S. Ghazizadeh

Keyword(s):

Gene Therapy ◽

Immune Responses ◽

Ex Vivo ◽

Host Immune Responses

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Exploratory Study on Plasma Immunomodulator and Antibody Profiles in Tuberculosis Patients

Clinical and Vaccine Immunology ◽

10.1128/cvi.00213-13 ◽

2013 ◽

Vol 20 (8) ◽

pp. 1283-1290 ◽

Cited By ~ 13

Author(s):

Resmi Ravindran ◽

Viswanathan V. Krishnan ◽

Azra Khanum ◽

Paul A. Luciw ◽

Imran H. Khan

Keyword(s):

Immune Responses ◽

Ex Vivo ◽

Peripheral Circulation ◽

Computer Assisted ◽

Content Type ◽

Tuberculosis Patients ◽

Active Pulmonary Tuberculosis ◽

Host Immune Responses ◽

Data Points ◽

Apparently Healthy

ABSTRACTHost immune responses toMycobacterium tuberculosisare generally able to contain infection and maintain a delicate balance between protection and immunopathology. A shift in this balance appears to underlie active disease observed in about 10% of infected individuals. Effects of local inflammation, combined with anti-M. tuberculosissystemic immune responses, are directly detectable in peripheral circulation, withoutex vivostimulation of blood cells or biopsy of the affected organs. We studied plasma immunomodulator and antibody biomarkers in patients with active pulmonary tuberculosis (TB) by a combination of multiplex microbead immunoassays and computational tools for data analysis. Plasma profiles of 10 immunomodulators and antibodies against eightM. tuberculosisantigens (previously reported by us) were examined in active pulmonary TB patients in a country where TB is endemic, Pakistan. Multiplex analyses were performed on samples from apparently healthy individuals without active TB from the same community as the TB patients to establish the assay baselines for all analytes. Over 3,000 data points were collected from patients (n= 135) and controls (n= 37). The data were analyzed by multivariate and computer-assisted cluster analyses to reveal patterns of plasma immunomodulators and antibodies. This study shows plasma profiles that in most patients represented either strong antibody or strong immunomodulator biomarkers. Profiling of a combination of both immunomodulators and antibodies described here may be valuable for the analysis of host immune responses in active TB in countries where the disease is endemic.

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Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

10.1101/2020.03.14.991760 ◽

2020 ◽

Author(s):

Yuxun Wang ◽

Heping Yang ◽

Huanping Li ◽

Shuda Zhao ◽

Yikun Zeng ◽

...

Keyword(s):

Immune Responses ◽

Drug Targets ◽

Ex Vivo ◽

Single Agent ◽

Cancer Drug ◽

Phase I Clinical Trials ◽

Tlr Agonists ◽

Favorable Safety

ABSTRACTToll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. The selectivity profile distinguished DN052 from all other TLR agonists currently in clinical development. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase I clinical trials.

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