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Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined, but could be direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory ‘cytokine-storm’, a cocktail of interferon gamma, interleukin 1β and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids and hearts of SARS-CoV-2 infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCO and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the FDA breakthrough designated drug apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage., A combination of phosphoproteomics, drug screening and single-cell sequencing approaches identifies how cytokines elevated in COVID-19 patients drives cardiac dysfunction, with BET inhibitors serving as potential lead candidates decrease ACE2 cardiac expression and infection.

The isolation of broadly neutralising antibodies against the influenza haemagglutinin has spurred investigation into their clinical potential, and has led to advances in influenza virus biology and universal influenza vaccine development. Studies in animal models have been invaluable for demonstrating the prophylactic and therapeutic efficacy of broadly neutralising antibodies, for comparisons with antiviral drugs used as the standard of care, and for defining their mechanism of action and potential role in providing protection from airborne infection.

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing pancreatic β cells. Therapies need to incorporate strategies to overcome the genetic defects that impair induction or maintenance of peripheral T-cell tolerance and contribute to disease development. We tested whether the enforced expression of an islet autoantigen in antigen-presenting cells (APC) counteracted peripheral T-cell tolerance defects in autoimmune-prone NOD mice. We observed that insulin-specific CD8

Background Application of genetically modified hematopoietic stem cells is increasingly mooted as a clinically relevant approach to protein replacement therapy, immune tolerance induction or conditions where both outcomes may be helpful. Hematopoietic stem and progenitor cell (HSPC)-mediated gene therapy often requires highly toxic pretransfer recipient conditioning to provide a ‘niche’ so that transferred HSPCs can engraft effectively and to prevent immune rejection of neoantigen-expressing engineered HSPCs. For widespread clinical application, reducing conditioning toxicity is an important requirement, but reduced conditioning can render neoantigen-expressing bone marrow (BM) and HSC susceptible to immune rejection if immunity is retained. Methods BM or HSPC-expressing OVA ubiquitously (actin.OVA) or targeted to MHC II+ cells was transferred using low-dose (300 cGy) total body irradiation. Recipients were administered rapamycin, cyclosporine or vehicle for 3 weeks commencing at BM transfer. Engraftment was determined using CD45 congenic donors and recipients. Induction of T-cell tolerance was tested by immunising recipients and analysing in-vivo cytotoxic T-lymphocyte (CTL) activity. The effect of rapamycin on transient effector function during tolerance induction was tested using an established model of tolerance induction where antigen is targeted to dendritic cells. Results Immune rejection of neoantigen-expressing BM and HSPCs after low-dose irradiation was prevented by a short course of rapamycin, but not cyclosporine, treatment. Whereas transient T-cell tolerance developed in recipients of OVA-expressing BM administered vehicle, only when engraftment of neoantigen-expressing BM was facilitated with rapamycin treatment did stable, long-lasting T-cell tolerance develop. Rapamycin inhibited transient effector function development during tolerance induction and inhibited development of CTL activity in recipients of OVA-expressing BM. Conclusions Rapamycin acts to suppress acquisition of transient T-cell effector function during peripheral tolerance induction elicited by HSPC-encoded antigen. By facilitating engraftment, short-course rapamycin permits development of long-term stable T-cell tolerance. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0508-3) contains supplementary material, which is available to authorized users.

Type 1 diabetes (T1D) results from T-cell-mediated autoimmune destruction of pancreatic β cells. Effector T-cell responses emerge early in disease development and expand as disease progresses. Following β-cell destruction, a long-lived T-cell memory is generated that represents a barrier to islet transplantation and other cellular insulin-replacement therapies. Development of effective immunotherapies that control or ablate β-cell destructive effector and memory T-cell responses has the potential to prevent disease progression and recurrence. Targeting antigen expression to antigen-presenting cells inactivates cognate CD8

Vaccination by intranasal (IN) inoculation with a replication-competent virus forms the basis of licensed and novel candidate respiratory viral vaccines (e.g., the cold-adapted influenza virus vaccine). A positive global impact of vaccination depends on vaccine efficacy in developing countries where dietary deficiencies are commonplace. The current study was designed using Sendai virus (SeV) as a model respiratory viral vaccine to test antibody-forming cell (AFC) residence and isotype expression in the context of a vitamin A deficiency (VAD). Samples were taken 1 mo after vaccination when AFCs generally reach their peak in healthy animals. In control animals on a healthy diet, SeV induced an antibody response with a relative bias toward IgA in the upper respiratory tract (URT, as sampled by nasal wash), and IgG in the lower respiratory tract (LRT, as sampled by bronchoalveolar lavage [BAL]). In the context of VAD, the SeV-specific IgA antibodies in the nasal wash were significantly reduced in favor of enhanced IgG antibodies in the BAL. When AFCs were examined in diffuse nasal-associated lymphoid tissues (d-NALT), lungs, cervical lymph nodes (CLN), and mediastinal lymph nodes (MLN), a similar pattern emerged. AFCs were most frequent in the d-NALT and most expressed IgA in control mice. In the context of VAD, these IgA-producing AFCs were significantly reduced in number, skewing the natural balance of IgA and IgG. Taken together, the results show that the VAD diet, which is well known for its association with immune defects in the gut, significantly alters AFC induction and isotype expression in the respiratory tract.

Lymphocytes of the diffuse nasal-associated lymphoid tissue (d-NALT) are uniquely positioned to tackle respiratory pathogens at their point-of-entry, yet are rarely examined after intranasal (i.n.) vaccinations or infections. Here we evaluate an i.n. inoculation with Sendai virus (SeV) for elicitation of virus-specific antibody forming cells (AFCs) and CD8+ T cells in the d-NALT. Virus-specific AFCs and CD8+ T cells each appeared by day 7 after SeV inoculation and persisted for 8months, explaining the long-sustained protection against respiratory virus challenge conferred by this vaccine. AFCs produced IgM, IgG1, IgG2a, IgG2b and IgA, while CD8+ T cells were cytolytic and produced low levels of cytokines. Phenotypic analyses of virus-specific T cells revealed striking similarities with pathogen-specific immune responses in the intestine, highlighting some key features of adaptive immunity at a mucosal site.

Significant safety issues have emerged concerning the general use of DRYVAX® vaccine. Vaccination with replication-defective recombinant adenovirus (rAd) vaccines may offer a safer and effective alternative to live vaccinia virus (VV) vaccination. Six individual poxvirus glycoproteins: A33R, A34R, A36R, B5R, A27L or L1R that are normally expressed on the surface of infectious vaccinia virus were encoded in rAd vaccines and tested in mice in this study. A single-shot intramuscular injection of rAd encoding A27L protected mice against a lethal intranasal challenge with VV at 4 weeks post vaccination. By 10 weeks post vaccination, a significant decrease in post-challenge morbidity was observed that correlated with potent neutralizing antibody responses and the emergence of specific polyfunctional T cell responses. The immunogenicity and protective efficacy of rAd-A27L immunization persisted for at least 35 weeks post-vaccination. This study is the first demonstration that a single-shot subunit vaccine encoding a poxvirus protein confers protection against the mortality and morbidity associated with poxvirus infection.

Vitamin A deficiency (VAD) is a leading cause of pediatric morbidity and mortality due to infectious diseases. Recent pre-clinical studies have revealed that VAD impairs mucosal IgA-producing antibody forming cell (AFC) responses toward a paramyxovirus vaccine in the upper respiratory tract (URT), thus impeding a first line of defense at the pathogen's point-of-entry. The studies described here tested the hypothesis that VAD may also impair immune responses after FluMist vaccinations. Results show that (i) IgA-producing antibody forming cells (AFCs) are significantly reduced following FluMist vaccination in VAD mice, and (ii) oral doses of either retinyl palmitate or retinoic acid administered on days 0, 3, and 7 relative to vaccination rescue the response. Data encourage the conduct of clinical studies to determine if there are FluMist vaccine weaknesses in human VAD populations and to test corrective supplementation strategies. Improvements in vaccine efficacy may ultimately reduce the morbidity and mortality caused by influenza virus worldwide.

Vitamin A deficiency (VAD) has profound effects on immune responses in the gut, but its effect on other mucosal responses is less well understood. Sendai virus (SeV) is a candidate human parainfluenza virus type 1 (hPIV-1) vaccine and a candidate vaccine vector for other respiratory viruses. A single intranasal dose of SeV elicits a protective immune response against hPIV-1 within days after vaccination. To define the effect of VAD on acute responses toward SeV, we monitored both antibodies and CD8+T cells in mice. On day 10 following SeV infection, there was a trend toward lower antibody activities in the nasal washes of VAD mice than in those of controls, while bronchoalveolar lavage (BAL) fluid and serum antibodies were not reduced. In contrast, there was a dramatic reduction of immunodominant CD8+T cell frequencies in the lower respiratory tract (LRT) airways of VAD animals. These T cells also showed unusually high CD103 (the αE subunit of αEβ7) expression patterns. In both VAD and control mice, E-cadherin (the ligand for αEβ7) was better expressed among epithelial cells lining the upper respiratory tract (URT) than in LRT airways. The results support a working hypothesis that the high CD103 expression among T cell populations in VAD mice alters mechanisms of T cell cross talk with URT and LRT epithelial cells, thereby inhibiting T cell migration and egress into the lower airway. Our data emphasize that the consequences of VAD are not limited to gut-resident cells and characterize VAD influences on an immune response to a respiratory virus vaccine.