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bioRxiv2020

Human antigen-specific memory natural killer cell responses develop against HIV-1 and influenza virus and are dependent on MHC-E restriction

For over a decade, multiple studies have disputed the notion of natural killer (NK) cells as purely innate lymphocytes by demonstrating that they are capable of putative antigen-specific immunological memory against multiple infectious agents including two critical global health priorities - HIV and influenza. However, the mechanisms underlying antigen specificity remain unknown. Herein, we demonstrate that antigen-specific human NK cell memory develops upon exposure to both HIV and influenza, unified by a conserved and epitope-specific targetable mechanism firmly dependent on the activating CD94/NKG2C receptor and its ligand HLA-E, and confirm these findings by three rigorous and novel assays. We validated the permanent acquisition of antigen-specificity by individual memory NK cells by single-cell cloning. We identified biomarkers of antigen-specific NK cell memory through RNA-Seq transcriptomic fingerprints and complex immunophenotyping by 30-parameter flow cytometry showing elevated expression of KLRG1, 4{beta}7 and NKG2C. Finally, we show individual HLA-E-restricted peptides that may constitute the dominant response in HIV-1- and influenza-infected persons in vivo. Our findings clarify the mechanisms behind formation of antigen-specific memory NK cells, and suggest they could be targeted for future vaccines, cure strategies, or other therapeutic interventions.

immunology↗

bioRxiv2020

Integrative Transcriptomic Analysis Reveals the Immune Mechanism for A CyHV-3-Resistant Common Carp Strain

Anti-disease breeding is becoming the most promising solution to cyprinid herpesvirus-3 (CyHV-3) infection, the major threat to common carp aquaculture. Virus challenging studies suggested that a breeding strain of common carp is resistant to this disease. This study illustrates the immune mechanisms involved in anti-CyHV-3 ability. An integrative analysis of the protein-coding genes and long non-coding RNAs (lncRNAs) using transcriptomic data was performed. Tissues from the head kidney of common carp were extracted at day 0 (the healthy control) and day 7 after CyHV-3 infection (the survivors), and used to analyze the transcriptome through both Illumina and PacBio sequencing. Following analysis of the GO terms and KEGG pathways involved, the immune-related terms and pathways were merged. In order to dig out details in the immune aspect, The DEGs were filtered using the current common carp immune gene library. Immune gene categories and their corresponding genes in different comparison groups were revealed. Also, the immunological Gene Ontology terms for lncRNA modulation were retained. The weighted gene co-XSexpression network analysis was used to reveal the regulation of immune genes by lncRNA. The results demonstrated that the breeding carp strain develops marked resistance to CyHV-3 through a specific innate immune mechanism. The featured biological processes were autophagy, phagocytosis, cytotoxicity, and virus blockage by lectins and MUC3. Moreover, the immune suppressive signals, such as suppression of IL21R on STAT3, PI3K mediated inhibition on inflammation by dopamine upon infection, as well as the inhibition of NLRC3 on STING during a steady state. Possible susceptible factors for CyHV-3, such as ITGB1, TLR18, and CCL4, were also revealed from the non-breeding strain. The results of this study also suggested that Nramp and PAI regulated by LncRNA could facilitate virus infection and proliferation for infected cells respectively, while T cell leukemia homeobox 3 (TLX3) as well as galectin 3 function by lncRNA may play a role in the resistance mechanism. Therefore, immune factors that are immunogenetically insensitive or susceptible to CyHV-3 infection have been revealed.

immunology↗

bioRxiv2020

A Whole Virion Vaccine for COVID-19 Produced Via a Novel Inactivation Method: Results from Animal Challenge Model Studies

The COVID-19 pandemic has generated intense interest in the rapid development and evaluation of vaccine candidates for this disease and other emerging diseases. Several novel methods for preparing vaccine candidates are currently undergoing clinical evaluation in response to the urgent need to prevent the spread of COVID-19. In many cases, these methods rely on new approaches for vaccine production and immune stimulation. We report on the use of a novel method (SolaVAX) for production of an inactivated vaccine candidate and the testing of that candidate in a hamster animal model for its ability to prevent infection upon challenge with SARS-CoV-2 virus. The studies employed in this work included an evaluation of the levels of neutralizing antibody produced post-vaccination, levels of specific antibody sub-types to RBD and spike protein that were generated, evaluation of viral shedding post-challenge, flow cytometric and single cell sequencing data on cellular fractions and histopathological evaluation of tissues post-challenge. The results from this study provide insight into the immunological responses occurring as a result of vaccination with the proposed vaccine candidate and the impact that adjuvant formulations, specifically developed to promote Th1 type immune responses, have on vaccine efficacy and protection against infection following challenge with live SARS-CoV-2. This data may have utility in the development of effective vaccine candidates broadly. Furthermore, the results suggest that preparation of a whole virion vaccine for COVID-19 using this specific photochemical method may have utility in the preparation of one such vaccine candidate. Author SummaryWe have developed a vaccine for COVID-19 which is prepared by a novel method for inactivation of a whole virion particle and tested it in a hamster animal model for its ability to protect against SARS-CoV-2 infection.

immunology↗

bioRxiv2020

Immune Checkpoint Blockade induces peripheral cytotoxicity and persistence of large effector CD8+ T cell clones

Immune checkpoint blockers (ICB) exert their anti-cancer effects via CD8+ T cells, although how responses vary over sub-populations and across clones is incompletely understood. We performed single-cell RNA-sequencing of CD8+ T cells and their receptors pre- and post-ICB across eight patients, integrating results with bulk-sequencing data (n=209). We identify seven subsets with divergent responses to ICB, finding the effector cluster demonstrates the most pronounced changes. Likewise, transcriptomic response to ICB relates to clone size, with large clones demonstrating increased numbers of regulated genes of higher immunological pertinence. Cytotoxic effector clones were more likely to persist long-term following ICB and overlapped with public tumour-infiltrating lymphocyte clonotypes. Notably, pre-treatment CD8+ cytotoxicity associated with progression-free survival, highlighting the importance of the baseline CD8+ immune landscape in long-term response. This work further advances understanding of the molecular determinants of ICB response and assists in the search for peripheral prognostic biomarkers. ONE SENTENCE SUMMARYUsing single-cell and bulk RNA sequencing we explore checkpoint immunotherapy activity on peripheral CD8+ T cells in metastatic melanoma; demonstrating that cell subset and clone size determine gene expression responses to treatment, and that pre-treatment cytotoxicity and clonality of peripheral CD8+ T cells is clinically prognostic.

immunology↗

bioRxiv2020

Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells

The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While toll-like receptor ligation relies on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFN{gamma}). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in macrophages to identify the regulators of IFN{gamma}-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFN{gamma} signaling pathway. We report that the IFN{gamma} response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFN{gamma} and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.

immunology↗

bioRxiv2020

Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-{kappa}B control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10. IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.

immunology↗

bioRxiv2020

Deconvoluting the T cell response to SARS-CoV-2: specificity versus chance- and cognate cross-reactivity

SARS-CoV-2 infection takes a mild or clinically inapparent course in the majority of humans who contract this virus. After such individuals have cleared the virus, only the detection of SARS-CoV-2-specific immunological memory can reveal the exposure, and hopefully the establishment of immune protection. With most viral infections, the presence of specific serum antibodies has provided a reliable biomarker for the exposure to the virus of interest. SARS-CoV-2 infection, however, does not reliably induce a durable antibody response, especially in sub-clinically infected individuals. Consequently, it is plausible for a recently infected individual to yield a false negative result within only a few months after exposure. Immunodiagnostic attention has therefore shifted to studies of specific T cell memory to SARS-CoV-2. Most reports published so far agree that a T cell response is engaged during SARS-CoV-2 infection, but they also state that in 20-81% of non-SARS-CoV-2-exposed individuals, T cells respond to SARS-CoV-2 antigens (mega peptide pools), allegedly due to T cell cross-reactivity with coronaviruses causing Common Cold (CCC), or other antigens. Here we show that by introducing irrelevant mega peptide pools as negative controls to account for chance cross-reactivity, and by establishing the antigen dose-response characteristic of the T cells, one can clearly discern between cognate T cell memory induced by SARS-CoV-2 infection vs. cross-reactive T cell responses in individuals who had not been infected with SARS-CoV-2.

immunology↗

bioRxiv2020

Mucosal Associated Invariant T (MAIT) Cell Responses Differ by Sex in COVID-19

Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, yet the mechanisms governing this disparity remain incompletely understood. We carried out sex-balanced sampling of peripheral blood mononuclear cells from confirmed COVID-19 inpatients and outpatients, uninfected close contacts, and healthy controls for 36-color flow cytometry and single cell RNA-sequencing. Our results revealed a pronounced reduction of circulating mucosal associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets implicate that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, female MAIT cells possessed an immunologically active gene signature, whereas male counterparts were pro-apoptotic. Collectively, our findings uncover a female-specific protective MAIT profile, potentially shedding light on reduced COVID-19 susceptibility in females.

immunology↗

bioRxiv2020

Nucleated Cell Death by a Single Hole Generated by C5b-9

Cell death is essential for tissue regeneration and removal of pathogenic cells. Immunological cell death is caused by membrane attack complex (MAC) or bacterial perforins. A complete understanding of nucleated cell death or bacterial cell death by MAC is essential for therapeutic interventions. The mechanism of MAC mediated cell death in nucleated cell is controversial. We know show that MAC causes cell death in nucleated cells by creating a large single hole in the membrane. Our results are contrary to the current paradigm that states "MAC kills nucleated cell by multiple hits". MAC deposition on the cell membrane also trigger clustering of membrane rafts, which will have relevant consequences for enhanced cell signaling. Significance StatementProteins of late complement pathway that form membrane attack complex, cause death of undesirable nucleated cells such as lymphocytes. The structure of these proteins and their similarity to bacterial cytolysins has been studied. How C9 pore forming protein assemble with rest of C5b-8 on nucleated cell membrane remains controversial. We thus examined and now show the structures formed by these proteins on nucleated cell membranes. Formation of MAC occurs during complement activation during infection and autoimmunity. Largely, our current knowledge of the membrane pore formation is gained using ghost cells, lipid micelles, and erythrocytes. Understanding of how MAC kills nucleated cells will enhance our ability to design new therapies for selective killing of pathogens.

immunology↗

bioRxiv2020

Profound Treg perturbations correlate with COVID-19 severity

The hallmark of severe COVID-19 disease has been an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We explored the hypothesis that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in both Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, which correlated with poor outcomes. Accordingly, these Tregs over-expressed a range of suppressive effectors, but also pro-inflammatory molecules like IL32. Most strikingly, they acquired similarity to tumor-infiltrating Tregs, known to suppress local anti-tumor responses. These traits were most marked in acute patients with severe disease, but persisted somewhat in convalescent patients. These results suggest that Tregs may play nefarious roles in COVID-19, via suppressing anti-viral T cell responses during the severe phase of the disease, and/or via a direct pro-inflammatory role.

immunology↗

bioRxiv2020

Microbiome and Metabolome driven differentiation of TGF-β producing Tregs leads to Senescence and HIV latency

Current therapeutic interventions to eradicate latent HIV ("reservoir") and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-responders, "INRs") and high frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence and immune dysfunction, peripheral blood leukocytes from these subjects have enhanced expression of a network of genes regulated by cellular senescence driving transcription factors (TFs) FOXO3, SMAD2 and IRF3. In these subjects, increased frequencies of regulatory T cells and expression of the TGF-{beta} signaling cascade are complimented by the downregulation of cell cycle, metabolic and pro-inflammatory pathways. Lactobacillaceae family and metabolites (members of the butyrate family - i.e. -ketobutyrate) were correlated with Treg frequencies in "Senescent-INRs" ex vivo, triggered the differentiation of TGF-{beta} producing Tregs and promoted HIV latency establishment in vitro. These cascades, downstream of PD-1/TGF-{beta}, prevent memory T cell differentiation and are associated with an increase in frequencies of cells with inducible HIV ex vivo. Our findings identify cellular senescence responses that can be targeted by PD-1 or TGF-{beta} specific interventions that have shown safety and efficacy in cancer, and may prove to be crucial for HIV eradication.

immunology↗

bioRxiv2020

Combining an alarmin HMGN1 peptide with PD-L1 blockade facilitates stem-like CD8+ T cell expansion and results in robust antitumor effects

BackgroundThe expansion of intratumoral stem-like CD8+ T (Tstem) cells provides a potential approach to improving the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, here we demonstrate a strategy to facilitate Tstem cell expansion by combining an alarmin high-mobility group nucleosome binding domain 1 (HMGN1) peptide with programmed death-ligand 1 (PD-L1) blockade. MethodsThe antitumor effects of HMGN1, anti-PD-L1 antibody, and their combined treatment were monitored in the B16F10, LLC, Colon26, or the EO771 tumor-bearing mice. The comprehensive immunologic analyses, such as high-dimensional flow cytometry, transcriptome analysis, and single-cell RNA sequencing, were used to investigate the cellular and molecular mechanisms of antitumor immune responses after treatments. ResultsThe HMGN1 peptide synergizes with PD-L1 blockade in augmenting the number of mature DCs enriched in immunoregulatory molecules (mregDCs) in tumors, and enhancing their MHC class I antigen-presenting program, which is correlated with the expansion of intratumoral Tstem cells, specifically promoting the Tstem cells but restricting terminally exhausted CD8+ T (Tex) cells, owing to the regulatory molecules expressed on mregDCs. ConclusionOur results indicate that HMGN1 peptide serves as an immunoadjuvant to promote effective anti-PD-L1 immunotherapy and implicate that mregDCs play a role beyond facilitating Tstem cell expansion.

immunology↗

bioRxiv2020

Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Tuberculosis (TB) remains a major public health problem with host-directed therapeutics offering potential as novel treatment strategies. However, their successful development still requires a comprehensive understanding of how Mycobacterium tuberculosis (M.tb) infection impacts immune responses. To address this challenge, we applied standardised immunomonitoring tools to compare TB antigen, BCG and IL-1{beta} induced immune responses between individuals with latent M.tb infection (LTBI) and active TB disease, at diagnosis and after cure. This revealed distinct responses between TB and LTBI groups at transcriptomic, proteomic and metabolomic levels. At baseline, we identified pregnane steroids and the PPAR{gamma} pathway as new immune-metabolic drivers of elevated plasma IL-1ra in TB. We also observed dysregulated induced IL-1 responses after BCG stimulation in TB patients. Elevated IL-1 antagonist responses were explained by upstream differences in TNF responses, while for IL-1 agonists it was due to downstream differences in granzyme mediated cleavage. Finally, the immune response to IL-1{beta} driven signalling was also dramatically perturbed in TB disease but was completely restored after successful antibiotic treatment. This systems immunology approach improves our knowledge of how immune responses are altered during TB disease, and may support design of improved diagnostic, prophylactic and therapeutic tools.

immunology↗

bioRxiv2020

Type I and III IFNs produced by the nasal epithelia and dimmed inflammation are key features of alpacas resolving MERS-CoV infection

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, provoking the induction of interferon stimulated genes (ISGs) along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-{kappa}B control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, is central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10. Author summaryMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a respiratory disease causing high mortality in humans. In camelids, the main MERS-CoV reservoir host, viral infection leads to subclinical disease. Our study describes transcriptional regulations of innate immunological pathways underlying asymptomatic clinical manifestations of alpacas in response to MERS-CoV. Concomitant to the peak of infection, these animals elicited a strong transient interferon response and induction of the anti-inflammatory cytokine IL10 in the nasal mucosa. This was associated to a dimmed regulation of pro-inflammatory cytokines and induction of interferon stimulated genes along the whole respiratory mucosa, leading to the rapid clearance of the virus. Thus, innate immune responses occurring in the nasal mucosa appear to be the key in controlling MERS-CoV disease by avoiding a cytokine storm. Understanding on how asymptomatic host reservoirs counteract MERS-CoV infection will aid in the development of antiviral drugs and vaccines.

immunology↗

bioRxiv2020

Identification of molecular candidates which regulate calcium-dependent CD8+ T-cell cytotoxicity

Cytotoxic CD8+ T lymphocytes (CTL) eliminate infected cells or transformed tumour cells by releasing perforin-containing cytotoxic granules at the immunological synapse. The secretion of such granules depends on Ca2+-influx through store operated Ca2+ channels, formed by STIM-activated Orai proteins. Whereas molecular mechanisms of the secretion machinery are well understood, much less is known about the molecular machinery that regulates the efficiency of Ca2+-dependent target cell killing. Here, we isolated total RNA from natural killer (NK) cells, non-stimulated CD8+ T-cells, and from Staphylococcus aureus enterotoxin A (SEA) stimulated CD8+ T-cells (SEA-CTL) and conducted whole genome expression profiling by microarray experiments. Based on differential expression analysis of the transcriptome data and analysis of master regulator genes, we identified 31 candidates which potentially regulate Ca2+-homeostasis in CTL. To investigate a putative function of these candidates in CTL cytotoxicity, we transfected either SEA-stimulated CTL (SEA-CTL) or antigen specific CD8+ T-cell clones (CTL-MART-1) with siRNAs specific against the identified candidates and analyzed the killing capacity using a real-time killing assay. In addition, we complemented the analysis by studying the effect of inhibitory substances acting on the candidate proteins if available. Finally, to unmask their involvement in Ca2+ dependent cytotoxicity, candidates were also analyzed under Ca2+-limiting conditions. Overall, this strategy led to the identification of KCNN4, RCAN3, CCR5 and BCL2 as potential candidates to regulate the efficiency of Ca2+-dependent target cell killing.

immunology↗

bioRxiv2020

Direct measurement of B lymphocyte gene expression biomarkers in peripheral blood enables early prediction of seroconversion after vaccination

Vaccination is a common and efficient means to reduce the mortality and morbidity of emerging infectious diseases. Among responders, injected antigen induces acquired immunity pathways and leads to the final production of antigen-specific antibodies. The whole process may take weeks to months, depending on the antigen. Typically, seroconversion to influenza vaccine is expected after one month with a responder rate of ~50%. An early biomarker to predict response is desirable. Peripheral blood gene expression (or transcript abundance, TA) datasets in the public domain were analyzed for early biomarkers among responders. As peripheral blood samples (such as peripheral blood mononuclear cells, PBMC) are cell mixture samples containing various blood cell-types (leukocyte subpopulations, LS). We first develop a model that enables the determination of TA in B lymphocytes of certain genes directly in PBMC samples without the need of prior cell isolation. These genes are called B cell informative genes. Then a ratio of two B cell informative genes (a target gene and a stably expressed reference gene) measured in PBMC was used as a new biomarker to gauge the target gene expression in B lymphocytes. This method having an obvious advantage over conventional methods by eliminating the tedious procedure of cell sorting and enables directly determining TA of a leukocyte subpopulation in cell mixture samples is called Direct LS-TA method. By using a B lymphocyte-specific gene such as TNFRSF17 or TXNDC5 as target genes with either TNFRSF13C or FCRLA as reference genes, the B cell biomarkers were determined directly in PBMC which was highly correlated with TA of target genes in purified B lymphocytes. These Direct LS-TA biomarkers in PBMC increased significantly early after vaccination in both the discovery dataset and a meta-analysis of 7 datasets. Responders had almost a 2-fold higher Direct LS-TA biomarker level of TNFRSF17 (SMD=0.84, 95% CI=0.47-1.21 after log2). And Direct LS-TA biomarkers of TNFRSF17 and TXNDC5 measured at day 7 predict responder with sensitivity values of higher than 0.7. The Area-under curves (AUC) in receiver operation curve (ROC) analysis were over 0.8. Here, we report a straightforward approach to directly analyses B lymphocyte gene expression in PBMC, which could be used in a routine clinical setting as it avoids the labor-intensive procedures of B lymphocyte isolation. And the method allows the practice of precision medicine in the prediction of vaccination response. Furthermore, response to vaccination could be predicted as early as on day 7. As vaccination response is based on the similar acquired immunology pathway in the upcoming worldwide vaccination campaign against COVID-19, these biomarkers could also be useful to predict seroconversion for individuals.

immunology↗

bioRxiv2021

COVID-19 virtual patient cohort reveals immune mechanisms driving disease outcomes

To understand the diversity of immune responses to SARS-CoV-2 and distinguish features that predispose individuals to severe COVID-19, we developed a mechanistic, within-host mathematical model and virtual patient cohort. Our results indicate that virtual patients with low production rates of infected cell derived IFN subsequently experienced highly inflammatory disease phenotypes, compared to those with early and robust IFN responses. In these in silico patients, the maximum concentration of IL-6 was also a major predictor of CD8+ T cell depletion. Our analyses predicted that individuals with severe COVID-19 also have accelerated monocyte-to-macrophage differentiation that was mediated by increased IL-6 and reduced type I IFN signalling. Together, these findings identify biomarkers driving the development of severe COVID-19 and support early interventions aimed at reducing inflammation. Author summaryUnderstanding of how the immune system responds to SARS-CoV-2 infections is critical for improving diagnostic and treatment approaches. Identifying which immune mechanisms lead to divergent outcomes can be clinically difficult, and experimental models and longitudinal data are only beginning to emerge. In response, we developed a mechanistic, mathematical and computational model of the immunopathology of COVID-19 calibrated to and validated against a broad set of experimental and clinical immunological data. To study the drivers of severe COVID-19, we used our model to expand a cohort of virtual patients, each with realistic disease dynamics. Our results identify key processes that regulate the immune response to SARS-CoV-2 infection in virtual patients and suggest viable therapeutic targets, underlining the importance of a rational approach to studying novel pathogens using intra-host models.

immunology↗

bioRxiv2021

SLTRiP induces long lasting and protective T-cell memory response

Major developments have been made in the past many years to characterize and explore potential vaccine candidates that can induce host immune responses against parasite. These advances were based on the fact that the induction of host immune responses could effectively target parasite at different stages of its life cycle and thus, abrogate Plasmodium infections. The role of T-cells against malaria comes from initial studies on rodents showing these cells could inhibit parasite development during pre-erythrocytic stages. Since then, the importance of the cellular immune responses against malaria has been increasingly emphasized, especially for vaccine development against pre-erythrocytic stages. Previous work in our laboratory has confirmed that SLTRiP confers protection against the pre-erythrocytic stage of Plasmodium growth in rodents. Here we report that the protection is mainly due to cell mediated immune responses and PbSLTRiP specific cellular memory responses could be efficiently recalled in mice challenged with P. berghei parasites even after a year following immunization. Our results thereby, highlight the role of the T cell response involved in protection. Characterization of T-cells by intracellular cytokine staining (ICS) revealed that the induced T cells were polyfunctional and involved in secretion of pro-inflammatory cytokines which mediate anti-parasitic activity. The findings contribute to our understanding of the immunological mechanisms underlying the protective vaccines.

immunology↗