SEARCH · Search bioRxiv

Results for “Immunology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 811 records · Page 45Linked to original sources

bioRxiv2021

ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modelling revealed how Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFN{gamma} and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. Key pointsO_LIThe mouse-adapted SARS-CoV-2 strain maVie16 causes fatal disease in BALB/c mice and substantial inflammation, pneumonia and immunity in C57BL/6 mice C_LIO_LITNF/IFN{gamma} blockade ameliorates maVie16-induced immunopathology C_LIO_LIMaVie16 infection depends on ACE2 and soluble ACE2 inhalation can prevent disease C_LI

immunology↗

bioRxiv2021

Durability of SARS-CoV-2-specific T cell responses at 12-months post-infection

BackgroundCharacterizing the longevity and quality of cellular immune responses to SARS-CoV-2 is critical to understanding immunologic approaches to protection against COVID-19. Prior studies suggest SARS-CoV-2-specific T cells are present in peripheral blood 10 months after infection. Further analysis of the function, durability, and diversity of the cellular response long after natural infection, over a wider range of ages and disease phenotypes, is needed to further identify preventative and therapeutic interventions. MethodsWe identified participants in our multi-site longitudinal, prospective cohort study 12-months post SARS-CoV-2 infection representing a range of disease severity. We investigated the function, phenotypes, and frequency of T cells specific for SARS-CoV-2 using intracellular cytokine staining and spectral flow cytometry. In parallel, the magnitude of SARS-CoV-2-specific antibodies was compared. ResultsSARS-CoV-2-specific antibodies and T cells were detected at 12-months post-infection. Severity of acute illness was associated with higher frequencies of SARS-CoV-2-specific CD4 T cells and antibodies at 12-months. In contrast, polyfunctional and cytotoxic T cells responsive to SARS-CoV-2 were identified in participants over a wide spectrum of disease severity. ConclusionsOur data show that SARS-CoV-2 infection induces polyfunctional memory T cells detectable at 12-months post-infection, with higher frequency noted in those who originally experienced severe disease.

immunology↗

bioRxiv2021

Pre-vaccination Frequency of Circulatory Tfh is associated with Robust Immune Response to TV003 Dengue Vaccine

It has been estimated that more than 390 million people are infected with Dengue virus every year; around 96 millions of these infections result in clinical pathologies. To date, there is only one licensed viral vector-based Dengue virus vaccine CYD-TDV approved for use in dengue endemic areas. While initially approved for administration independent of serostatus, the current guidance only recommends the use of this vaccine for seropositive individuals. Therefore, there is a critical need for investigating the influence of Dengue virus serostatus and immunological mechanisms that influence vaccine outcome. Here, we provide comprehensive evaluation of sero-status and host immune factors that correlate with robust immune responses to a Dengue virus vector based tetravalent vaccine (TV003) in a Phase II clinical cohort of human participants. We observed that sero-positive individuals demonstrate a much stronger immune response to the TV003 vaccine. Our multi-layered immune profiling revealed that sero-positive subjects have increased baseline/pre-vaccination frequencies of circulating T follicular helper (cTfh) cells and the Tfh related chemokine CXCL13/BLC. Importantly, this baseline/pre-vaccination cTfh profile correlated with the vaccinees ability to launch neutralizing antibody response against all four sero-types of Dengue virus, an important endpoint for Dengue vaccine clinical trials. Overall, we provide novel insights into the favorable cTfh related immune status that persists in Dengue virus sero-positive individuals that correlate with their ability to mount robust vaccine specific immune responses. Such detailed interrogation of cTfh cell biology in the context of clinical vaccinology will help uncover mechanisms and targets for favorable immuno-modulatory agents. Author summaryDengue virus (DENV) is a worldwide threat that causes significant health and economic burden. Currently, there are several challenges in the development of a DENV vaccine including the existence of four different serotypes all; capable of causing disease and antibody dependent enhancement (ADE). For complete protection, a vaccine must be able to generate neutralizing antibodies against all 4 serotypes to avoid ADE. Currently, there is one licensed DENV vaccine, CYD-TDV (DENGVAXIATM). However, this vaccine is only efficacious in protecting against severe disease in DENV seropositive individuals therefore serostatus effect must be further studied for optimal vaccine design. A subset of CD4+ T cells called T-follicular helper (Tfh) cells have been well known to play a major role in aiding high affinity antibody production. Therefore, we chose to look at subsets of Tfh and the cytokines they produce in human blood that can serve as biomarkers for effective vaccine design. We found that DENV sero-positive participants had increased pre-vaccination frequencies of Tfh cells and higher levels of the Tfh related chemokine CXCL13/BLC that plays a role in directing antigen-specific responses. This pre-vaccination Tfh profile and CXCL13/BLC are then correlated positively with the vaccinees ability to produce neutralizing antibody against all four sero-types (breadth of the Response) of DENV, an important goal for all DENV vaccine trials.

immunology↗

bioRxiv2021

Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and subsequent weight regain.

Most individuals do not maintain weight loss, and weight regain increases cardio-metabolic risk beyond that of obesity. Adipose inflammation directly contributes to insulin resistance; however, immune-related changes that occur with weight loss and weight regain are not well understood. Single cell RNA-sequencing was completed with CITE-sequencing and biological replicates to profile changes in murine immune subpopulations following obesity, weight loss, and weight cycling. Weight loss normalized glucose tolerance, however, type 2 immune cells did not repopulate adipose following weight loss. Many inflammatory populations persisted with weight loss and increased further following weight regain. Obesity drove T cell exhaustion and broad increases in antigen presentation, lipid handing, and inflammation that persisted with weight loss and weight cycling. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease. Thus, we have created an open-access interactive portal for our processed data to improve accessibility for the research community.

immunology↗

bioRxiv2021

Deep immune profiling of the maternal-fetal interface with mild SARS-CoV-2 infection

Pregnant women are an at-risk group for severe COVID-19, though the majority experience mild/asymptomatic disease. Although severe COVID-19 has been shown to be associated with immune activation at the maternal-fetal interface even in the absence of active viral replication, the immune response to asymptomatic/mild COVID-19 remains unknown. Here, we assessed immunological adaptations in both blood and term decidua from 9 SARS-exposed pregnant women with asymptomatic/mild disease and 15 pregnant SARS-naive women. In addition to selective loss of tissue-resident decidual macrophages, we report attenuation of antigen presentation and type I IFN signaling but upregulation of inflammatory cytokines and chemokines in blood monocyte derived decidual macrophages. On the other hand, infection was associated with remodeling of the T cell compartment with increased frequencies of activated CD69+ tissue-resident T cells and decreased abundance of Tregs. Interestingly, frequencies of cytotoxic CD4 and CD8 T cells increased only in the blood, while CD8 effector memory T cells were expanded in the decidua. In contrast to decidual macrophages, signatures of type I IFN signaling were increased in decidual T cells. Finally, T cell receptor diversity was significantly reduced with infection in both compartments, albeit to a much greater extent in the blood. The resulting aberrant immune activation in the placenta, even with asymptomatic disease may alter the exquisitely sensitive developing fetal immune system, leading to long-term adverse outcomes for offspring.

immunology↗

bioRxiv2021

Immunization with SARS-CoV-2 nucleocapsid protein triggers a pulmonary immune response in rats

The SARS-CoV-2 pandemic have been affecting millions of people worldwide, since the beginning of 2020. COVID-19 can cause a wide range of clinical symptoms, which varies from asymptomatic presentation to severe respiratory insufficiency, exacerbation of immune response, disseminated microthrombosis and multiple organ failure, which may lead to dead. Due to the rapid spread of SARS-CoV-2, the development of vaccines to minimize COVID-19 severity in the world population is imperious. One of the employed techniques to produce vaccines against emerging viruses is the synthesis of recombinant proteins, which can be used as immunizing agents. Based on the exposed, the aim of the present study was to verify the systemic and immunological effects of IM administration of recombinant Nucleocapsid protein (NP), derived from SARS-CoV-2 and produced by this research group, in 2 different strains of rats (Rattus norvegicus); Wistar and Lewis. For this purpose, experimental animals received 4 injections of NP, once a week, and were submitted to biochemical and histological analysis. Our results showed that NP inoculations were safe for the animals, which presented no clinical symptoms of worrying side effects, nor laboratorial alterations in the main biochemical and histological parameters, suggesting the absence of toxicity induced by NP. Moreover, NP injections successfully triggered the production of specific anti-SARS-CoV-2 IgG antibodies by both Wistar and Lewis rats, showing the sensitization to have been well sufficient for the immunization of these strains of rats. Additionally, we observed the local lung activation of the Bronchus-Associated Lymphoid Tissue (BALT) of rats in the NP groups, suggesting that NP elicits specific lung immune response. Although pre-clinical and clinical studies are still required, our data support the recombinant NP produced by this research group as a potential immunizing agent for massive vaccination, and may represent advantages upon other recombinant proteins, since it seems to induce specific pulmonary protection.

immunology↗

bioRxiv2021

Harnessing Matrix Completion to Unify and Extend Viral Serology Studies

The development of new vaccine strategies, as well as our understanding of key processes that shape viral evolution and host antibody repertoires, rely on measuring multiple antibody responses against large panels of viruses. Given the enormous diversity of circulating virus strains and antibody responses, exhaustive testing of all antibody-virus interactions is infeasible. Even within individual studies with limited panels, exhaustive testing is not always done, and there is no common framework for combining information across studies with partially overlapping panels, especially when the assay type or host species differ. Results from prior studies have demonstrated that virus-antibody interactions can be characterized in a vastly simpler and lower-dimensional space, suggesting that relatively few measurements could accurately predict unmeasured antibody-virus interactions. Here, we apply matrix completion to several of the largest-scale studies for both influenza and HIV-1. We explore how prediction accuracy evolves as the number of available measurements changes and approximate the number of additional measurements necessary in several highly incomplete datasets (suggesting [~]250,000 measurements could be saved). In addition, we show how the method can combine disparate datasets, even when the number of available measurements is below the theoretical limit that guarantees successful prediction. This approach can be readily generalized to other viruses or more broadly to other low-dimensional biological datasets. SignificanceOne of the central problems in immunology is to characterize how our vast array of antibodies inhibits the diverse pathogens we encounter in our lives. In this work, we apply a well-studied mathematical technique called matrix completion that leverages patterns in partially-observed antibody-virus inhibition data to infer unmeasured interactions. We predict the results of tens of thousands of missing experiments in influenza and HIV-1 studies and quantify the expected error of our estimates. By harnessing matrix completion, future experiments could be designed that only collect a fraction of measurements, saving time and resources while maximizing the information gained.

immunology↗

bioRxiv2021

Systems-level analysis of patients treated for acute P. falciparum malaria reveals a role for the humoral response and cytokine milieu in limiting γδ T cell expansion

The mechanism of acquisition and maintenance of natural immunity against Plasmodium falciparum malaria remains unclear. Although, clinical immunity develops over time with repeated malaria episodes, disease tolerance is more rapidly acquired compared to protective immunity. It remains unclear, how pre-existing immune responses impacts the mechanism responsible for disease tolerance. Here, we investigated a cohort of returning travelers treated for acute symptomatic P. falciparum malaria, either infected for the first time, or with a previous history of malaria. Through repeated sampling over one year in a malaria free setting, we were able to study the acute and longitudinal effects of the infection. We combined comprehensive immune cell and plasma protein profiling with integrated and data driven analysis, describing the immune landscape from acute disease to one year after infection. We identified a strong association between pro-inflammatory signatures and {gamma}{delta} T cell expansion. The association was significantly impacted by previous exposure to malaria, resulting in a dampened pro-inflammatory response, which translated to reduced V{delta}2+ {gamma}{delta} T cell expansion compared to primary infected individuals. The dampened inflammatory signal was associated with early expansion of Fc{gamma}RIII+ monocytes and parasite-specific antibodies of IgG1 and IgG3 isotypes. Our data suggest that the interplay of Fc{gamma}RIII+ monocytes and a cytophilic parasite-specific IgG during the early blood stage infection lead to lower parasitemia and a dampened pro-inflammatory response with reduced {gamma}{delta} T cell expansion. This enhanced control and reduced inflammation points to a potential mechanism on how tolerance is established following repeated malaria exposure. One Sentence SummaryA systems immunology analysis on natural malaria sheds light on disease tolerance mechanism associated with gamma delta T cell expansion

immunology↗

bioRxiv2021

Global anti-tumor immunity after localized, bioengineered Treg depletion

Over 90% of deaths from cancer occur due to solid tumors, occurring at a rate of [~]1,500 deaths per day in the US, highlighting a profound and unmet need for new therapies. Solid tumors evade clearance by T cells due to a variety of immunosuppressive properties of the tumor microenvironment. However, this immunosuppression cannot be easily blocked on a global level because systemic activation of the immune system elicits a host of complications. An ideal therapy for solid tumors would act locally to activate the immune response without evoking global adverse effects. Here we present a biodegradable, macroporous scaffold that is implanted adjacent to the tumor and suppresses the main obstacle to cancer immunosurveillance: intratumoral regulatory T cells. The scaffold also promotes the recruitment and activation of T cell effectors into the tumor, resulting in clearance of otherwise aggressive and fatal tumors in mice. Unexpectedly, the local depletion of Tregs results in an "immunological abscopal effect" acting on distant tumors. We demonstrate that this versatile platform can also deliver tumor-antigen-specific T cells directly to the peri-tumoral environment, bypassing difficulties in intravenous delivery including the environmental barriers imposed by the tumors vasculature. By orchestrating multiple local immunomodulatory treatments, this scaffold offers a general approach to engineer T-cell responses to solid tumors without systemic toxicities.

immunology↗

bioRxiv2021

Mathematical modelling of autoimmune myocarditis and the effects of immune checkpoint inhibitors

Autoimmune myocarditis is a rare, but frequently fatal, side effect of immune checkpoint inhibitors (ICIs), a class of cancer therapies. Despite extensive experimental work on the causes, development and progression of this disease, much still remains unknown about the importance of the different immunological pathways involved. We present a mathematical model of autoimmune myocarditis and the effects of ICIs on its development and progression to either resolution or chronic inflammation. From this, we gain a better understanding of the role of immune cells, cytokines and other components of the immune system in driving the cardiotoxicity of ICIs. We parameterise the model using existing data from the literature, and show that qualitative model behaviour is consistent with disease characteristics seen in patients in an ICI-free context. The bifurcation structures of the model show how the presence of ICIs increases the risk of developing autoimmune myocarditis. This predictive modelling approach is a first step towards determining treatment regimens that balance the benefits of treating cancer with the risk of developing autoimmune myocarditis.

immunology↗

bioRxiv2021

Intranasal administration of a VLP-based vaccine against COVID-19 induces neutralizing antibodies against SARS-CoV-2 and Variants of Concerns

BackgroundThe highly contagious SARS-CoV-2 is mainly transmitted by respiratory droplets and aerosols. Consequently, people are required to wear masks and maintain a social distance to avoid spreading of the virus. Despite the success of the commercially available vaccines, the virus is still uncontained globally. Given the tropism of SARS-CoV-2, a mucosal immune reaction would help to reduce viral shedding and transmission locally. Only seven out of hundreds of ongoing clinical trials are testing the intranasal delivery of COVID-19 vaccines. MethodsIn the current study, we tested in murine model the immunogenicity of a conventional vaccine platform based on virus-like particles (VLPs) displaying RBD of SARS-CoV-2 for intranasal vaccination. The candidate vaccine, CuMVTT-RBD, has been immunologically optimized to incorporate tetanus-toxin and is self-adjuvanted with TLR7/8 ligands. ResultsCuMVTT-RBD elicited strong RBD- and spike- specific systemic IgG and IgA antibody responses of high avidity. Local immune responses were assessed and results demonstrate strong mucosal antibody and plasma cell production in lung tissue. The induced systemic antibodies could efficiently recognize and neutralize different Variants of Concerns of mutated SARS-CoV-2 RBDs. ConclusionIn summary, intranasal vaccination with CuMVTT-RBD shows high immunogenicity and induces protective systemic and local specific antibody response against SARS-CoV-2 and its variants. One sentence summaryEvaluation of an intransal administrated conventional VLP-based vaccine against COVID-19 in a murine model.

immunology↗

bioRxiv2021

Identification of topoisomerase as a precision-medicine target in chromatin reader SP140-driven Crohns disease

How mis-regulated chromatin directly impacts human immunological disease is poorly understood. Speckled Protein 140 (SP140) is an immune-restricted PHD and bromodomain-containing chromatin reader whose loss-of-function associates with Crohns disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL). However, mechanisms underlying SP140-driven pathogenicity and therapeutic approaches that rescue SP140 remain unexplored. Using a global proteomic strategy, we identified SP140 as a repressor of topoisomerases (TOP) that maintains heterochromatin and immune cell fate. In humans and mice, SP140 loss resulted in unleashed TOP activity, genome instability, severely compromised lineage-defining and microbe-inducible innate transcriptional programs and defective bacterial killing. Pharmacological inhibition of TOP1 or TOP2 rescued these defects. Furthermore, exacerbated colitis was restored with TOP1 or TOP2 inhibitors in Sp140-/- mice, but not wild-type mice, in vivo. Collectively, we identify SP140 as a repressor of topoisomerases and reveal repurposing of TOP inhibition as a precision strategy for reversing SP140-driven immune disease.

immunology↗

bioRxiv2021

An innate immune activation state prior to vaccination predicts responsiveness to multiple vaccines

Many factors determine whether an individual responding to vaccination will generate an immune response that can lead to protection. Several studies have shown that the pre-vaccination immune state is associated with the antibody response to vaccines. However, the generalizability and mechanisms that underlie this association remain poorly defined. Here, we sought to identify a common pre-vaccination signature and mechanisms that could predict the immune response across a wide variety of vaccines. We leveraged the "Immune Signatures Data Resource" created by the NIH Human Immunology Project Consortium (HIPC) to integrate data from 28 studies involving 13 different vaccines and associate the blood transcriptional status of 820 healthy young adults with their responses. An unsupervised analysis of blood transcriptional profiles across studies revealed three distinct pre-vaccination states, characterized by the differential expression of genes associated with a pro-inflammatory response, cell proliferation, and metabolism alterations downstream of NF{kappa}B and IRF7. Innate and adaptive immune cell subset-specific genes were also associated with the three pre-vaccination states. Importantly, individuals whose pre-vaccination state was enriched in pro-inflammatory response genes known to be downstream of NF{kappa}B tended to have higher serum antibody responses one month after vaccination. A supervised analysis of the same data resulted in a single classifier, also enriched for NF{kappa}B regulated genes, that predicted the antibody response across most of the vaccines. Projection into single-cell RNA-sequencing data suggested that this pre-vaccination state was attributable to the signature of activation of non-classical monocytes and myeloid dendritic cells. Transcriptional signatures of acute responses to bacterial and not viral infections were enriched in the high pro-inflammatory pre-vaccination state and also included NF{kappa}B regulated genes. The pro-inflammatory pre-vaccination state was highly reminiscent of the innate activation state triggered by TLR ligands or adjuvants. These results demonstrate that wide variations in the transcriptional state of the immune system in humans can be a key determinant of responsiveness to vaccination. They also define a transcriptional signature NF{kappa}B activation at baseline, that is associated with a greater magnitude of antibody response to multiple vaccines, and suggest that modulation of the innate immune system by next-generation adjuvants targeting NF{kappa}B before vaccine administration may improve vaccine responsiveness.

systems biology↗

bioRxiv2021

Helminth infection is associated with dampened cytokine responses to viral and bacterial stimulations in Tsimane hunter-horticulturalists.

BackgroundSoil-transmitted helminth (STH) infections can catalyze immunological changes that affect the response to subsequent infections, particularly those that elicit strong inflammatory responses. As globalization heightens the risk that remote communities with high STH prevalence will encounter novel pathogens, understanding how STHs shape immune responses to these downstream infections becomes increasingly crucial. MethodologyWe worked with Tsimane forager-horticulturalists in the Bolivian Amazon, where STHs are prevalent. We tested whether STHs and eosinophil levels--most likely indicative of infection in this population--are associated with dampened immune responses to in vitro stimulation with H1N1 and lipopolysaccharide (LPS) antigens. Whole blood samples (n = 179) were treated with H1N1 vaccine and LPS and assayed for 13 cytokines (interferon gamma [INF-{gamma}], interleukin [IL]-1{beta}, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, Granulocyte-macrophage colony-stimulating factor [GM-CSF], and Tumor necrosis factor-alpha [TNF-]). We evaluated how STHs and eosinophil levels affected cytokine responses and T helper (Th) 1 and Th2-cytokine suite responses to stimulation. ResultsInfection with Ascaris lumbricoides was significantly (p [≤] 0.05) associated with lower response of some cytokines to H1N1 and LPS in women. Eosinophils were significantly negatively associated with some cytokine responses to H1N1 and LPS, with the strongest effects in women, and associated with a reduced Th1- and Th2-cytokine response to H1N1 and LPS in women and men. Conclusions and implicationsWe find that STHs were associated with dampened cytokine responses to certain viral and bacterial antigens, and suggest that this mitigation of host-induced damage may reduce the incidence of cytokine storms in populations with high STH prevalence.

immunology↗

bioRxiv2021

Measuring host immune response status by simultaneous quantitative measurement of activity of signal transduction pathways that coordinate functional activity of immune cells from innate and adaptive immune system

For many diseases, including cancer, viral infections such as COVID-19, bacterial infections, and auto-immune diseases, the immune response is a major determinant of progression, response to therapy, and clinical outcome. Innate and adaptive immune response are controlled by coordinated activity of multiple immune cell types. The functional activity state of immune cells is determined by cellular signal transduction pathways (STPs). A novel mRNA-based signaling pathway assay platform has been developed to quantitatively measure relevant STP activities in all types of immune cells and mixed immune cell samples for experimental and diagnostic purposes. We generated a STP activity profile, termed Immune-Pathway Activity Profile (I-PAP), for a variety of immune cell types in resting and activated state, and provide a first example for use in patient samples. MethodsThe technology to measure STP activity has been described for androgen and estrogen receptor, PI3K, MAPK, TGF{beta}, Notch, NF{kappa}B, JAK-STAT1/2, and JAK-STAT3 pathways. STP activity was measured on Affymetrix expression microarray data from preclinical studies containing public data from different types of immune cells, resting/naive or immune-activated in vitro, to establish I-PAPs. Subsequently data from a clinical study on rheumatoid arthritis were analyzed. ResultsI-PAPs of naive/resting and immune-activated CD4+ and CD8+ T cells, T helper cells, B cells, NK cells, monocytes, macrophages, and dendritic cells were established and in agreement with known experimental immunobiology. In whole blood samples of rheumatoid arthritis patients TGF{beta} pathway activity was increased; JAK-STAT3 pathway activity was selectively increased in female patients. In naive CD4+ Tregs TGF{beta} pathway activity was increased, while in memory T effector cells JAK-STAT3 pathway activity tended to increase, suggesting that these immune cell types contributed to whole blood analysis results. ConclusionSTP assay technology (currently being converted to qPCR-based assays) makes it possible to directly measure functional activity of cells of the innate and adaptive immune response enabling quantitative assessment of the immune response of an individual patient. Envisioned utility lies in (1) prediction and monitoring of response to immunomodulatory treatments for a variety of immune-mediated diseases, including RA; (2) uncovering novel treatment targets; (3) improvement and standardization of in vitro immunology research and drug development.

immunology↗

bioRxiv2021

Effect of Aeromonas hydrophila infected on metabolomic response and gut microbial 16S rRna of Charybdis japonica

The innate immune response of Charybdis japonica treated with Aeromonas hydrophila was explored using bioinformatics. Metabolomics data were integrated with a gut microbial 16S rRNA dataset, together with information on corresponding enzyme activity. The results of the study showed that after being infected with A. hydrophila, some beneficial genera of bacteria in the gut of C. japonica, such as Photobacterium, Rhodobacter, Polaribacter, Psychrilyobacter, Mesoflavibacter, Fusibacter and Phormidium, could directly inhibit Vibrio or produce extracellular polysaccharides with highly effective antibacterial properties. The intestinal probiotics of C. japonica such as Mesoflavibacter have a mutually reinforcing relationship with Phaeobacter, Colwellia, Bacillus, Psychrobacter and Cohaesibacter. Conditional pathogenic bacteria in the gut of healthy crabs may also have such a symbiotic relationship with intestinal probiotics, promoting their growth and reproduction. For example, Phormidium has a mutualistic relationship with Aeromonas and Azopira. Metabolites in the gut of C. japonica infected with A. hydrophila, including beta-alanine metabolism, nitrogen metabolism, inositol phosphate metabolism, galactose metabolism, histidine metabolism, ascorbate and arginine and proline metabolism were increased, with alanine metabolism being the most abundant. The activity of metabolite related enzymes such as lipid peroxidase, phenoloxidase, superoxide dismutase, nitric oxide synthase, glutathione transferase and mid-glutathione decreased and NO levels also decreased. The positive correlation with the probiotic flora suggests that metabolites increase with bacterial abundance and that microbial metabolites or co-metabolites can, in turn, achieve many pleiotropic effects to resist invasion by A. hydrophila. These results may contribute to further research in the resistance of C. japonica to invading pathogens. ImportanceWith the rapid development of the C. japonica farming industry, investors, in pursuit of economic benefits, have encountered problems such as frequent outbreaks of various diseases, resulting in high mortality and huge economic losses. The open water circulation system can give rise to several crab bacterial diseases. Among these, A. hydrophila is a pathogenic bacterium affecting fish and crustaceans, which leads to huge economic losses. Our results suggest that metabolites increased with the abundance of bacteria. It is possible that the autoimmune system and the entry of A. hydrophila into the intestinal tissues of C. japonica react immunologically and that the organism is producing certain metabolites which may be metabolised by various bacteria and absorbed into the circulation. In addition, some of these metabolites are modified or bound in the hepatopancreas to produce microbiota-host co-metabolites. These microbial metabolites or co-metabolites can resist invasion by A. hydrophila.

immunology↗

bioRxiv2021

Natural killer-like B cells promote Th17 cell differentiation and exacerbate rheumatoid arthritis

B cells are important participants in the pathogenesis of rheumatoid arthritis (RA). Besides classical B cells, novel B cell subsets are continually to be identified in recent years. Natural killer-like B (NKB) cells, a newly recognized B cell subset, are proved to be actively involved in the anti-infection immunity. However, their role in RA and the potential mechanism remain elusive. Here, we showed that NKB cells were expanded dramatically in collagen-induced arthritis (CIA) mice, demonstrating dynamic changes during the disease progression. These cells promoted CD4+ effector T cell proliferation and Th17 cell differentiation in vitro, while adoptive transfer of these cells exacerbated the arthritis severity of CIA mice. RNA Sequencing revealed that NKB cells displayed distinct differential gene expression profile under RA circumstance, potential perpetuating the disease progression. Moreover, the frequencies of NKB cells were significantly increased in RA patients, positively correlated with the clinical and immunological features. After effective therapy, these cells could be recovered to normal levels. Taken together, our results preliminarily revealed the pathogenic role of NKB cells in RA by promoting Th17 proinflammatory responses. Targeting these cells might provide potential therapeutic strategies for this persistent disease.

immunology↗

bioRxiv2021

SARS-CoV-2 mechanistic correlates of protection: insight from modelling response to vaccines

The definition of correlates of protection is critical for the development of next generation SARS-CoV-2 vaccine platforms. Here, we propose a new framework for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication. One Sentence SummaryA framework for modelling the immune control of viral dynamics is applied to quantify the effect of several SARS-CoV-2 vaccine platforms and to define mechanistic correlates of protection.

immunology↗