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Results for “immunology”

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bioRxiv2022

PPAR-γ regulates the effector function of human TH9 cells by promoting glycolysis

T helper 9 cells (TH9) are key drivers of allergic tissue inflammation. They are characterized by the expression of type 2 cytokines, such as IL-9 and IL-13, and the peroxisome proliferator-activated receptor gamma (PPAR-{gamma}) transcription factor. However, the functional role of PPAR-{gamma} in human TH9 cells remains unknown. Here, we demonstrate that PPAR-{gamma} drives activation-induced glycolysis, which, in turn, specifically promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments on skin samples of allergic contact dermatitis showed that the PPAR-{gamma}-mTORC1-IL-9 pathway was active in TH9 cells in human skin inflammation. Additionally, we found that tissue glucose levels were dynamically regulated in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological signals in vivo. Furthermore, paracrine IL-9 induced the lactate transporter MCT1 in IL-9R+ TH cells, where it increased aerobic glycolysis and proliferative capacity. Taken together, our findings delineate a hitherto unknown relationship between PPAR-{gamma}-dependent glucose metabolism and the pathogenic effector function of human TH9 cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/503972v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@ce684borg.highwire.dtl.DTLVardef@12121acorg.highwire.dtl.DTLVardef@29d712org.highwire.dtl.DTLVardef@e71117_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Sex-specific T cell exhaustion drives differential immune responses in glioblastoma

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunological sex differences are not fully understood. Using GBM models, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased T cell infiltration and increased T cell exhaustion. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD1 treatment. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, which was further corroborated by in vitro exhaustion assays. Moreover, increased T cell exhaustion was observed in male GBM patients. These findings demonstrate sex-specific pre-determined behavior of T cells is critical in inducing sex differences in GBM progression and immunotherapy response. Statement of significanceImmunotherapies in GBM patients have been unsuccessful due to a variety of factors including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-specific T cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve therapeutic efficacy of immunotherapy in GBM.

immunology↗

bioRxiv2022

Single-cell RNA sequencing highlights a reduced function of natural killer and cytotoxic T cells in recovered COVID-19 pregnant women

Pregnancy is a complex phenomenon during which women undergo immense immunological change throughout this period. Having an infection with the SARS-CoV-2 virus leads to an additional burden on the highly stretched immune response. Some studies suggest that age-matched pregnant women are more prone to SARS-CoV-2 infection compared with normal healthy (non-pregnant) women, while alternative evidence proposed that pregnant women are neither susceptible nor develop severe symptoms. This discrepancy in different findings regarding the immune responses of pregnant women infected with SARS-CoV-2 virus is not well understood. In this study, we investigated how SARS-CoV-2 viral infection could modulate the immune landscape during the active infection phase and recovery in pregnant females. Using flow cytometry, we identified that intermediate effector CD8+ T cells were increased in pregnant women who had recovered from COVID-19 as opposed to those currently infected. Similarly, an increase in CD4+ T helper cells (early or late) during the recovered phase was observed during the recovery phase compared with infected pregnant women or healthy pregnant women, whilst infected pregnant women had a reduced number of late effector CD4+ T cells. CD3+CD4- CD8-NKT cells that diminished during active infection in contrast to healthy pregnant women were significant increase in recovered COVID-19 recovered pregnant women. Further, our single-cell RNA sequencing data revealed that infection of SARS-CoV-2 had changed the gene expression profile of monocytes, CD4+ effector cells and antibody producing B cells in convalescent as opposed to healthy pregnant women. Additionally, several genes with cytotoxic function, interferon signalling type I & II, and pro- and anti-inflammatory functions in natural killer cells and CD8+ cytotoxic T cells were compromised in recovered patients compared with healthy pregnant women. Overall, our study highlights that SARS-CoV-2 infection deranged the adaptive immune response in pregnant women and could be implicated in pregnancy complications in ongoing pregnancies.

immunology↗

bioRxiv2022

Differences in the inflammatory proteome of East African and Western European adults and associations with environmental and dietary factors

Non-communicable diseases (NCDs) are rising rapidly in urbanizing populations in sub-Saharan Africa. Assessment of inflammatory and metabolic characterstics of an urbanizing African population and the comparison with populations outside Africa could provide insight in the pathophysiology of the rapidly increasing epidemic of NCDs, including the role of environmental and dietary changes. Using a proteomic plasma profiling approach comprising 92 inflammation-related molecules, we examined differences in the inflammatory proteome in healthy Tanzanian and healthy Dutch adults. We show that healthy Tanzanians display a pro-inflammatory phenotype compared to Dutch subjects, with enhanced activity of the Wnt/{beta}-catenin signalling pathway and higher concentrations of different metabolic regulators such as 4E-BP1 and fibroblast growth factor 21. Among the Tanzanian volunteers, food-derived metabolites were identified as an important driver of variation in inflammation-related molecules, emphasizing the potential importance of lifestyle changes. These findings endorse the importance of the current dietary transition in the NCDs epidemic in sub-Saharan Africa and the inclusion of underrepresented populations in systems immunology studies.

immunology↗

bioRxiv2022

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load and total HIV-1 DNA in HIV-1 infected humanized mice

BackgroundHIV-1 infection results in the activation of inflammasome involving NLRP3, IFI16, caspase-1 and release of IL-1 {beta} and IL-18. Early inflammasome activation may facilitate viral spread and establishment of the viral reservoir. We evaluated the effect of the caspase-1 inhibitor VX-765 on virological and immunological parameters after HIV-1 infection in humanized mice. MethodsNSG mice were engrafted with human CD34+ hematopoietic stem cells and were infected with HIV-1 JRCSF. 15 mice were first sacrificed serially to investigate kinetics of the HIV-1 related inflammasome activation. Infected mice (n=24) were then treated with VX-765 or vehicle from day 1 post infection for 21 days. Blood and organs were collected at different time points, and analysed for inflammasome genes expression, cytokines levels, viral load, CD4 cell count, and total HIV-1 DNA. ResultsExpression of caspase-1, NLRP3 and IL1-{beta} was increased in lymph nodes and bone marrow on day 1 and 3 post infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p< 0.001 respectively between day 1 and 3). IFI16 expression peaked at D24 in lymph node and bone marrow (FC 1.49 and 1.64, p<0.05) and coincides with increased IL-18 levels in plasma (6.89 vs. 83.19 pg/ml, p=0.004). AIM2 and IFI16 expression correlated with increased viral load in tissues (p<0.005 for the spleen) and loss of CD4+ T cells percentage in blood (p<0.0001 for the spleen). Treatment with VX-765 significantly reduced TNF- at day 11 (0.47 vs. 2.2 pg/ml, p=0.045), IL-18 at day 22 (7.8 vs 23.2 pg/ml, p=0.04), CD4+ T cells (44.3% vs 36,7%, p=0.01) and the CD4/CD8 ratio (0.92 vs 0.67, p=0.005) in plasma. Importantly, viral load (4.26 vs. 4.89 log 10 copies/ml, p=0.027) and total HIV-1 DNA (1 054 vs. 2 889 copies /106 cells, p=0.029) were decreased in VX-765-treated mice as compared to vehicle-treated mice. Discussionwe report here an early inflammasome activation before detectable viral dissemination in humanized mice. We demonstrated that targeting inflammasome activation early after HIV-1 infection may represent a potential therapeutic strategy to prevent CD4+ T cell depletion as well as to reduce immune activation, viral load and the HIV-1 reservoir formation.

immunology↗

bioRxiv2022

Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection

The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFN{varepsilon}) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs , {beta} and {lambda}. We show the necessity of IFN{varepsilon} for Zika Virus (ZIKV) protection by: increased susceptibility of IFN{varepsilon}-/- mice; their "rescue" by intravaginal recombinant IFN{varepsilon} treatment and blockade of protective endogenous IFN{varepsilon} by neutralising antibody. Complementary studies in human FRT cell lines showed IFN{varepsilon} had potent anti-ZIKV activity, associated with transcriptome responses similar to IFN{lambda} but lacking the proinflammatory gene signature of IFN. IFN{varepsilon} activated STAT1/2 pathways similar to IFN and {lambda} that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFN{varepsilon} exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFN{varepsilon}. However, the IFN{varepsilon} expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFN{beta} or {lambda}. Thus, the constitutive expression of IFN{varepsilon} provides cellular resistance to viral strategies of antagonism and maximises the antiviral activity of the FRT. These results show that the unique spatiotemporal properties of IFN{varepsilon} provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy. Author SummaryThe female reproductive tract (FRT) is vulnerable to sexually transmitted infections and therefore a well-tuned immune surveillance system is crucial for maintaining a healthy FRT. However, our understanding of the factors that impact viral infection of the FRT and the host response are not well understood. In this work we investigate the role of a hormonally regulated type I interferon, IFN epsilon (IFN{varepsilon}) in control of Zika virus (ZIKV) infection of the FRT. IFN{varepsilon} is unique compared to other canonical type-I IFNs in that it is constitutively expressed by epithelial cells of the FRT with expression levels controlled by progesterone and not in response to viral infection. We demonstrate that IFN{varepsilon} has anti-ZIKV properties using a combination of IFN{varepsilon} KO mice, blockade of endogenous IFN{varepsilon} by neutralising Abs and rescue of IFN{varepsilon} KO mice by recombinant IFN{varepsilon} administered directly to the FRT. Furthermore, we complemented our in vivo studies using human FRT derived cell lines. Importantly, ZIKV NS proteins did not block IFN{varepsilon} expression despite their ability to antagonise the expression of IFN{beta} or {lambda}. Collectively this work implicates IFN{varepsilon} as a key type-I IFN that provides a distinct homeostatic antiviral environment in the FRT.

immunology↗

bioRxiv2022

Novel 'GaEl antigenic patches' identified by 'reverse epitomics' approach to design multi-patch vaccines against NIPAH infection, a silent threat to global human health

BackgroundNipah virus (NiV) is a zoonotic virus that causes lethal encephalitis and respiratory disease with the symptom of endothelial cell-cell fusion. Several NiV outbreaks have been reported since 1999 with nearly annual occurrences in Bangladesh. The outbreaks had high mortality rates ranging from 40 to 90%. No specific vaccine has yet been reported against NiV. MethodologyRecently, several vaccine candidates and different designs of vaccines composed of epitopes against NiV were proposed. Most of the vaccines target single protein or protein complex subunits of the pathogen. The Multi-epitope vaccines proposed also cover a largely limited number of epitopes and hence their efficiency is still pending. To address the urgent need for a specific and effective vaccine against NiV infection in the present study, we have utilized the Reverse Epitomics approach ("overlapping-epitope-clusters-to-patches" method) to identify antigenic patches (Ag-Patches) and utilize them as immunogenic composition for Multi-Patch vaccine (MPV) design. The designed MPVs were analyzed for immunologically crucial parameters, physiochemical properties and interaction with Toll-like receptor 3 ectodomain. ResultsIn total 30 CTL (Cytotoxic T lymphocyte) and 27 HTL (Helper T lymphocytes) antigenic patches were identified from the entire NiV proteome based on the clusters of overlapping epitopes. These identified Ag-Patches cover a total of discreet 362 CTL and 414 HTL epitopes from entire proteome of NiV. The antigenic patches were utilized as immunogenic composition for the design of two CTL and two HTL multi-patch vaccines. The 57 antigenic patches utilized here cover 776 overlapping epitopes targeting 52 different HLA class I and II alleles providing a global ethnically distributed human population coverage of 99.71%. Such large number of epitope coverage resulting in large human population coverage cannot be reached with single protein/subunit or multi-epitope based vaccines. The reported antigenic patches also provide potential immunogenic composition for early detection diagnostic kits for NiV infection. Further, all the MPVs & Toll-Like Receptor ectodomain complexes show stable nature of molecular interaction with numerous hydrogen bonds, salt bridges and non-bounded contacts formation and acceptable root mean square deviation and fluctuation. The cDNA analysis show a favorable large scale expression of the MPV constructs in human cell line. ConclusionBy utilizing the novel Reverse epitomics approach highly immunogenic novel GaEl antigenic patches (GaEl Ag-Patches) a synonym term for antigenic patches, were identified and utilized as immunogenic composition to design four MPVs against NiV. We conclude that the novel Multi-Patch Vaccines is a potential candidate to combat NiV, with greater effectiveness, high specificity and large human population coverage worldwide.

immunology↗

bioRxiv2022

A new and highly effective method for predicting T-cell response targets implemented on SARS-CoV-2 data

Computational T-cell epitope prediction is essential in many immunological projects, including the development of vaccines. T-cells of immunocompetent vertebrate hosts can recognize as non-self only peptides which are present in the parasites proteins and absent in the hosts proteins. This basic principle allows us to predict which peptides can elicit T-cells response. We built on the fact that the specificity of T-cells reacting to SARS-CoV-2 antigens has been recently mapped in detail. Using Monte Carlo tests, we found that empirically confirmed peptides that stimulate T-cells contain an increased fraction of pentapeptides, hexapeptides, and heptapeptides which are not found in the human proteome (p < 0.0001). Similarly, hexapeptides absent in human proteins were overrepresented in peptides that elicited T-cell response in a published empirical study (p = 0.027). The new theory-based method predicted T-cell immunogenicity of SARS-CoV-2 peptides four times more effectively than current empirically based methods.

immunology↗

bioRxiv2022

Transiently heritable fates and quorum sensing drive early IFN-I response dynamics

Type I Interferon (IFN-I)-mediated antiviral responses are central to host defense against viral infections. Crucial is the tight and well-orchestrated control of cellular decision-making leading to the production of IFN-Is. Innovative single-cell approaches revealed that the initiation of IFN-I production is only limited to a fraction of 1-3% of the total population, both found in vitro and in vivo, which were thought to be stochastically regulated. To challenge this dogma, we addressed the influence of various host-intrinsic factors, both stochastic and epigenetic, on dictating early IFN-I responses. Hypomethylating drugs increased the percentage of responding cells. Next, with the classical Luria-Delbruck fluctuation test, we provided evidence that the fate of becoming a responding cell is transiently heritable. Finally, while studying varying cell-densities, we substantiated an important role for quorum sensing, which was verified by mathematical modeling. Together, this systems immunology approach opens up new avenues to progress the fundamental understanding of cellular decision-making during early IFN-I responses, which can be translated to other (immune) signaling systems, and ultimately will improve IFN-I based immune therapies.

immunology↗

bioRxiv2022

Schistosoma mansoni cercarial invadolysin cleaves complement C3 and suppresses proinflammatory cytokine production

Schistosoma mansoni employs immune evasion and immunosuppression to overcome immune responses mounted by its snail and human hosts. Myriad immunomodulating factors underlie this process, some of which are proteases. Here, we demonstrate that one protease, an invadolysin we have termed SmCI-1, is released from the acetabular glands of S. mansoni cercaria and is involved in creating an immunological milieu favorable for survival of the parasite. We confirm the presence of SmCI-1 in the cercarial stage of S. mansoni and demonstrate that it is released during transformation into the schistosomula. We confirm SmCI-1 functions as a metalloprotease with the capacity to cleave collagen type IV, gelatin and fibrinogen. We also show that complement component C3b is cleaved by this protease, resulting in inhibition of the classical and alternative complement pathways. Finally, we assess the effect of SmCI-1 on cytokine release from human peripheral blood mononuclear cells, providing compelling evidence that SmCI-1 promotes an anti-inflammatory microenvironment by enhancing production of IL-10 and suppressing the production of inflammatory cytokines like IL-1B and IL-12p70 and those involved in eosinophil recruitment and activation, like eotaxin-1 and IL-5.

immunology↗

bioRxiv2022

Mycobacterial exposure remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection

Alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells in the lung to encounter bacteria. We previously showed that AMs initially respond to Mtb in vivo by mounting a cell-protective, rather than pro-inflammatory response. However, the plasticity of the initial AM response was unknown. Here, we characterize how previous exposure to mycobacterium, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb) that mimics aspects of concomitant immunity, impacts the initial response by AMs. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory response to Mtb in vivo by AMs. Within the lung environment, AMs from scBCG vaccinated mice mount a robust interferon-associated response, while AMs from coMtb mice produce a broader inflammatory response that is not dominated by Interferon Stimulated Genes. Using scRNAseq, we identify changes to the frequency and phenotype of airway-resident macrophages following mycobacterium exposure, with enrichment for both interferon-associated and pro-inflammatory populations of AMs. In contrast, minimal changes were found for airway-resident T cells and dendritic cells after exposures. Ex vivo stimulation of AMs with Pam3Cys, LPS and Mtb reveal that scBCG and coMtb exposures generate stronger interferon-associated responses to LPS and Mtb that are cell-intrinsic changes. However, AM profiles that were unique to each exposure modality following Mtb infection in vivo are dependent on the lung environment and do not emerge following ex vivo stimulation. Overall, our studies reveal significant and durable remodeling of AMs following exposure to mycobacterium, with evidence for both AM-intrinsic changes and contributions from the altered lung microenvironments. Comparisons between the scBCG and coMtb models highlight the plasticity of AMs in the airway and opportunities to target their function through vaccination or host-directed therapies. Author SummaryTuberculosis, a disease caused by the bacteria Mycobacterium tuberculosis (Mtb), claims around 1.6 million lives each year, making it one of the leading causes of death worldwide by an infectious agent. Based on principles of conventional immunological memory, prior exposure to either Mtb or M. bovis BCG leads to antigen-specific long-lasting changes to the adaptive immune response that can be effective at protecting against subsequent challenge. However, how these exposures may also impact the innate immune response is less understood. Alveolar macrophages are tissue-resident myeloid cells that play an important role during Mtb infection as innate immune sentinels in the lung and the first host cells to respond to infection. Here, we examined how prior mycobacterium exposure, either through BCG vaccination or a model of contained Mtb infection impacts the early innate response by alveolar macrophages. We find that prior exposure remodels the alveolar macrophage response to Mtb through both cell-intrinsic changes and signals that depend on the altered lung environment. These findings suggest that the early innate immune response could be targeted through vaccination or host-directed therapy and could complement existing strategies to enhance the host response to Mtb.

immunology↗

bioRxiv2022

Transcription coactivator OCA-B/Pou2af1 is necessary and sufficient to promote T cell-intrinsic CD4 memory

The molecular mechanisms leading to the establishment of immunological memory are inadequately understood, limiting the development of effective vaccines and durable anti-tumor immune therapies. Here we show that ectopic OCA-B expression is sufficient to improve antiviral memory recall responses, while having minimal effects on primary effector responses. At peak viral response short lived effector T cell populations are expanded but show increased Gadd45b and Socs2 expression, while memory precursor effector cells show increased expression of Bcl2, Il7r and Tcf7 on a per-cell basis. Using an OCA-B mCherry reporter mouse line, we observe high OCA-B expression in CD4+ TCM cells. We show that early in viral infection, endogenously elevated OCA-B expression prospectively identifies memory precursor cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is both necessary and sufficient to promote CD4 T cell memory in vivo and can be used to prospectively identify memory precursor cells. SignificanceCD4+ T cell memory is incompletely defined and memory progenitors difficult to identify. Here, we show that expression of the OCA-B transcription coactivator in CD4+ T cells is necessary and sufficient to drive productive memory. Using a novel mCherry reporter mouse line, we show that OCA-B expression enriches for responding effector cells with elevated memory potential. The results show that OCA-B expression in T cells is sufficient to promote CD4+ memory formation and marks memory precursor cells.

immunology↗

bioRxiv2022

Profound immunomodulatory effects of 225Ac-NM600 drive enhanced anti-tumor responsein prostate cancer

An immunosuppressive tumor microenvironment has hampered the efficacy of immunotherapy in prostate cancer. However, radiation-induced immunological effects can partly mediate anti-tumor effects by promoting a pro-inflammatory environment potentially responsive to immunotherapy. Herein, we examined the immunomodulatory properties of a radiopharmaceutical therapy (RPT) with NM600 radiolabeled with either a beta or alpha emitter in two prostate cancer models. 225Ac-NM600, but not 177Lu-NM600, promoted significant anti-tumor effects and improved overall survival. Immunomodulatory effects were dose, radionuclide, and tumor type-dependent. 225Ac-NM600 elicited an array of immunomodulatory effects such as increased CD8/Treg ratio, activation of effector and memory T cells, abrogation of infiltrating suppressor cells (e.g., Tregs and MDSCs), and increased levels of Th1 cytokine and pro-inflammatory chemokines. Importantly, we demonstrate the need to carefully characterize the immune responses elicited by RPT both pre-clinically and clinically to maximize tumor control and avoid potential counterproductive immunosuppressive effects. TeaserTargeted alpha therapy can create a pro-inflammatory tumor micro-environment that partly explains stronger anti-tumor responses in prostate cancer

immunology↗

bioRxiv2022

Major Contribution of Myeloid Cells In TB specific Host Gene Signature: Revelations from Re-Analysis of Publicly Available Datasets

IntroductionInteraction of human host and its pathogen M.tuberculosis drives tuberculosis disease, resulting in dysregulation of host gene expression. We re-analyzed host gene expression datasets of TB to identify and validate a cellular circuit by interlinking the DEGs with their target miRNAs, GWAS hits associated with immunological phenotypes mapping to the DEGs and associated cellular subtypes through bioinformatic and experimental approaches. MethodologyDEGs were identified systematically through re-analysis of whole blood host transcriptomic datasets of treatment-naive TB patients, obtained from public repositories having at least 1.2 fold change of expression and FDR corrected p-value <0.05. Using well characterized M.tb antigens: Ag85 complex, LAM, CFP10 and ESAT6, we evaluated their effect on the expression of a subset of the top DEGs with at least two fold change of expression in a monocytic cell line THP1 with or without differentiation into a macrophage-like state with PMA and a T cell line Jurkat E6-1. ResultsWe discovered 305 DEGs (236 up and 69 down-regulated genes) out of which 23 (21 up and 2 down-regulated genes) were top DEGs. Overall, innate immune and myeloid cell associated pathways were enriched for up-regulated genes while T cell associated pathways were enriched for down-regulated genes. Among top DEGs, EPSTI1 was predominantly up-regulated in macrophages while SERPING1 was universally up-regulated in the monocyte model by all antigens. The down-regulation of gene expression was replicated by ESAT6 in T cell line by significantly down-regulating a top down-regulated gene LRRN3.

immunology↗

bioRxiv2022

Intranasal delivery of NS1-deleted influenza virus vectored COVID-19 vaccine restrains the SARS-CoV-2 inflammatory response

The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) variants and "anatomical escape" characteristics threaten the effectiveness of current coronavirus disease (COVID-19) vaccines. There is an urgent need to understand the immunological mechanism of broad-spectrum respiratory tract protection to guide broader vaccines development. In this study, we investigated immune responses induced by an NS1-deleted influenza virus vectored intranasal COVID-19 vaccine (dNS1-RBD) which provides broad-spectrum protection against SARS-CoV-2 variants. Intranasal delivery of dNS1-RBD induced innate immunity, trained immunity and tissue-resident memory T cells covering the upper and lower respiratory tract. It restrained the inflammatory response by suppressing early phase viral load post SARS-CoV-2 challenge and attenuating pro-inflammatory cytokine (IL-6, IL-1B, and IFN-{gamma}) levels, thereby reducing excess immune-induced tissue injury compared with the control group. By inducing local cellular immunity and trained immunity, intranasal delivery of NS1-deleted influenza virus vectored vaccine represents a broad-spectrum COVID-19 vaccine strategy to reduce disease burden.

immunology↗

bioRxiv2022

Design and Immunogenicity of SARS-CoV-2 DNA vaccine encoding RBD-PVXCP fusion protein

The potential of immune evasive mutations accumulation of the SARS-CoV-2 virus has led to its rapid spread causing over 600 million confirmed cases and more than 6.5 million confirmed deaths. Huge demand for the rapid development and deployment of low-cost and effective vaccines against emerging variants renews interest in DNA vaccine technology. Here we report a rapid generation and immunological evaluation of novel DNA vaccine candidates against Wuhan-Hu-1 and Omicron variants, based on the RBD protein fused with the Potato virus X coat protein (PVXCP). Delivery of DNA vaccines using electroporation in a two-doses regimen induced high antibody titers and profound cellular response in mice. Antibody titers induced against Omicron variant of the vaccine were sufficient for the effective protection against both the Omicron and Wuhan-Hu-1 virus infections. PVXCP protein in the vaccine construct shifted immune response to the favorable Th1-like type and provided oligomerization of RBD-PVXCP protein. A naked DNA delivery by the needle-free injection device allowed us to achieve antibody titers comparable with the mRNA-LNP delivery in rabbits. This data identifies the RBD-PVXCP DNA vaccine platform as a promising solution for robust and effective SARS-CoV-2 protection, supporting further translational study.

immunology↗

bioRxiv2022

An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection

Zika virus (ZIKV), an arbovirus transmitted by mosquitoes, was identified as a cause of congenital disease during a major outbreak in the Americas in 2016. Vaccine design strategies relied on limited available isolate sequence information due to the rapid response necessary. The first-generation ZIKV mRNA vaccine, mRNA-1325, was initially generated and, as additional strain sequences became available, a second mRNA vaccine, mRNA-1893, was developed. Herein, we compared the immune responses following mRNA-1325 and mRNA-1893 vaccination and reported that mRNA-1893 generated comparable neutralizing antibody titers to mRNA-1325 at 1/20th of the dose and provided complete protection from ZIKV challenge in non-human primates. In depth characterization of these vaccines indicated that the observed immunologic differences could be attributed to a single amino acid residue difference that compromised mRNA-1325 virus-like particle formation.

immunology↗

bioRxiv2022

Early immunomodulatory program triggered by pro-tolerogenic Bifidobacterium pseudolongum drives cardiac transplant outcomes

BackgroundDespite ongoing improvements in regimens to prevent allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes. MethodsIn this study, we further detailed the multifaceted immunomodulatory properties of pro-tolerogenic and pro-inflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation. ResultsIn addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum (Bifido) induced an early anti-inflammatory phenotype within 7 days, while Desulfovibrio desulfuricans (Desulfo) resulted in a pro-inflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that Bifido and Desulfo acted directly on primary innate immune cells. However, by 40 days after treatment, these two bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with Bifido treatment. ConclusionsThese dynamic effects suggest a critical role for early microbiota-triggered immunological events such as innate immune cell engagement, T cell differentiation, and LN architectural changes in the subsequent modulation of pro-tolerant versus pro-inflammatory immune responses in organ transplant recipients.

immunology↗