Animal Models of Non-Respiratory, Post-Acute Sequelae of COVID-19.

Post-acute sequelae of COVID-19 (PASC) are a diverse set of symptoms and syndromes driven by dysfunction of multiple organ systems that can persist for years and negatively impact the quality of life for millions of individuals. We currently lack specific therapeutics for patients with PASC, due in part to an incomplete understanding of its pathogenesis, especially for non-pulmonary sequelae. Here, we discuss three animal models that have been utilized to investigate PASC: non-human primates (NHPs), hamsters, and mice.

Prediction of facial nerve outcomes after surgery for vestibular schwannoma using machine learning-based models: a systematic review and meta-analysis.

Postoperative facial nerve (FN) dysfunction is associated with a significant impact on the quality of life of patients and can result in psychological stress and disorders such as depression and social isolation. Preoperative prediction of FN outcomes can play a critical role in vestibular schwannomas (VSs) patient care. Several studies have developed machine learning (ML)-based models in predicting FN outcomes following resection of VS.

Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice.

The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to antigen recognition by the T cell receptor (TCR) in the thymus and are implicated in clonal deletion, but the mechanisms by which they operate are not clear. Moreover, their role in central tolerance is obscured by redundancy among the Nr4a family members and by their reported functions in Treg generation and maintenance. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to show that Nr4a1 and Nr4a3 are essential for the upregulation of Bcl2l11/BIM and thymic clonal deletion by self-antigen.

RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia.

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation.

Hypomorphic RAG2 Deficiency Promotes Selection of Self-Reactive B Cells.

Reduced function or hypomorphic variants in recombination-activating genes (RAG) 1 or 2 result in a broad clinical phenotype including common variable immunodeficiency (CVID) and even adult-onset disease. Milder RAG variants are less characterized. Here we describe the longitudinal course of a milder combined RAG deficiency in 3 of 7 siblings sharing the same RAG2 mutations over a 50-year study.

Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis.

Regulatory T cells (T) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT T under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2 VAT T subsets.

An early precursor CD8 T cell that adapts to acute or chronic viral infection.

This study examines the origin and differentiation of stem-like CD8+ T cells that are essential for sustained T cell immunity in chronic viral infections and cancer and also play a key role in PD-1 directed immunotherapy. These PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells, also referred to as precursors of exhausted T cells, have a distinct program that allows them to adapt to chronic antigen stimulation. Using the mouse model of chronic LCMV infection we found that virus specific stem-like CD8+ T cells are generated early (day 5) during chronic infection suggesting that this crucial fate commitment occurs irrespective of infection outcome.

System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans.

We performed a systems vaccinology analysis to investigate immune responses in humans to an H5N1 influenza vaccine, with and without the AS03 adjuvant, to identify factors influencing antibody response magnitude and durability. Our findings revealed a platelet and adhesion-related blood transcriptional signature on day 7 that predicted the longevity of the antibody response, suggesting a potential role for platelets in modulating antibody response durability. As platelets originate from megakaryocytes, we explored the effect of thrombopoietin (TPO)-mediated megakaryocyte activation on antibody response longevity.

Defining a highly conserved B cell epitope in the receptor binding motif of SARS-CoV-2 spike glycoprotein.

SARS-CoV-2 mRNA vaccines induce robust and persistent germinal centre (GC) B cell responses in humans. It remains unclear how the continuous evolution of the virus impacts the breadth of the induced GC B cell response. Using ultrasound-guided fine needle aspiration, we examined draining lymph nodes of nine healthy adults following bivalent booster immunization.

SARS-CoV-2: The Interplay Between Evolution and Host Immunity.

The persistence of SARS-CoV-2 infections at a global level reflects the repeated emergence of variant strains encoding unique constellations of mutations. These variants have been generated principally because of a dynamic host immune landscape, the countermeasures deployed to combat disease, and selection for enhanced infection of the upper airway and respiratory transmission. The resulting viral diversity creates a challenge for vaccination efforts to maintain efficacy, especially regarding humoral aspects of protection.

Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis.

During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG).

Single-cell analyses reveal that monocyte gene expression profiles influence HIV-1 reservoir size in acutely treated cohorts.

Elimination of latent HIV-1 is a major goal of AIDS research but the host factors determining the size of these reservoirs are poorly understood. Here, we investigated whether differences in host gene expression modulate the size of the HIV-1 reservoir during suppressive ART. Peripheral blood mononuclear cells (PBMC) from fourteen individuals initiating ART during acute infection who demonstrated effective viral suppression but varying magnitude of total HIV-1 DNA were characterized by single-cell RNA sequencing (scRNA-seq).

RSK1 dependency in FLT3-ITD acute myeloid leukemia.

Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines.

A trivalent mucosal vaccine encoding phylogenetically inferred ancestral RBD sequences confers pan-Sarbecovirus protection in mice.

The continued emergence of SARS-CoV-2 variants and the threat of future Sarbecovirus zoonoses have spurred the design of vaccines that can induce broad immunity against multiple coronaviruses. Here, we use computational methods to infer ancestral phylogenetic reconstructions of receptor binding domain (RBD) sequences across multiple Sarbecovirus clades and incorporate them into a multivalent adenoviral-vectored vaccine. Mice immunized with this pan-Sarbecovirus vaccine are protected in the upper and lower respiratory tracts against infection by historical and contemporary SARS-CoV-2 variants, SARS-CoV, and pre-emergent SHC014 and Pangolin/GD coronavirus strains.

Sialylated IgG induces the transcription factor REST in alveolar macrophages to protect against lung inflammation and severe influenza disease.

While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model.

The epigenetic trajectory of type 1 regulatory T cells.

The epigenome of T follicular helper cells prepares them for conversion into type 1 regulatory T cells.

Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients.

Background: Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence.

Methods: Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing.

Type I interferon signaling in dendritic cells limits direct antigen presentation and CD8 T cell responses against an arthritogenic alphavirus.

Ross River virus (RRV) and other alphaviruses cause chronic musculoskeletal syndromes that are associated with viral persistence, which suggests deficits in immune clearance mechanisms, including CD8 T-cell responses. Here, we used a recombinant RRV-gp33 that expresses the immunodominant CD8 T-cell epitope of lymphocytic choriomeningitis virus (LCMV) to directly compare responses with a virus, LCMV, that strongly induces antiviral CD8 T cells. After footpad injection, we detected fewer gp33-specific CD8 T cells in the draining lymph node (DLN) after RRV-gp33 than LCMV infection, despite similar viral RNA levels in the foot.

Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE.

Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine.

Transient anti-interferon autoantibodies in the airways are associated with recovery from COVID-19.

Preexisting anti-interferon-α (anti-IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti-IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti-IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19.

Endogenous self-peptides guard immune privilege of the central nervous system.

Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system. In fact, it remains physically connected to, and can be influenced by, the peripheral immune system. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding question.