Differential Cytokine Responses in Hospitalized COVID-19 Patients Limit Efficacy of Remdesivir

A significant proportion of COVID-19 patients will progress to critical illness requiring invasive mechanical ventilation. This accentuates the need for a therapy that can reduce the severity of COVID-19. Clinical trials have shown the effectiveness of remdesivir in shortening recovery time and decreasing progression to respiratory failure and mechanical ventilation. However, some studies have highlighted its lack of efficacy in patients on high-flow oxygen and mechanical ventilation. This study uncovers some underlying immune response differences between responders and non-responders to remdesivir treatment. Immunological analyses revealed an upregulation of tissue repair factors BDNF, PDGF-BB and PIGF-1, as well as an increase in ratio of Th2-associated cytokine IL-4 to Th1-associated cytokine IFN-γ. Serological profiling of IgG subclasses corroborated this observation, with significantly higher magnitude of increase in Th2-associated IgG2 and IgG4 responses. These findings help to identify the mechanisms of immune regulation accompanying successful remdesivir treatment in severe COVID-19 patients

Linear B-cell epitopes in the spike and nucleocapsid proteins as markers of SARS-CoV-2 exposure and disease severity

BACKGROUND Given the unceasing worldwide surge in COVID-19 cases, there is an imperative need to develop highly specific and sensitive serology assays to define exposure to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). METHODS Pooled plasma samples from PCR positive COVID-19 patients were used to identify linear B-cell epitopes from a SARS-CoV-2 peptide library of spike (S), envelope (E), membrane (M), and nucleocapsid (N) structural proteins by peptide-based ELISA. Hit epitopes were further validated with 79 COVID-19 patients with different disease severity status, 13 seasonal human CoV, 20 recovered SARS patients and 22 healthy donors. FINDINGS Four immunodominant epitopes, S14P5, S20P2, S21P2 and N4P5, were identified on the S and N viral proteins. IgG responses to all identified epitopes displayed a strong detection profile, with N4P5 achieving the highest level of specificity (100%) and sensitivity (>96%) against SARS-CoV-2. Furthermore, the magnitude of IgG responses to S14P5, S21P2 and N4P5 were strongly associated with disease severity. INTERPRETATION IgG responses to the peptide epitopes can serve as useful indicators for the degree of immunopathology in COVID-19 patients, and function as higly specific and sensitive sero-immunosurveillance tools for recent or past SARS-CoV-2 infections. The flexibility of these epitopes to be used alone or in combination will allow for the development of improved point-of-care-tests (POCTs)

Whole blood immunophenotyping uncovers immature neutrophil-to-VD2 T-cell ratio as an early marker for severe COVID-19

COVID-19 severity is associated with cytokine levels and lymphopenia, but the role of immune cell subsets is not well understood. Here the authors immunophenotype whole blood samples from 54 COVID-19 patients and find that the immature neutrophil-to-VD2 T-cell ratio is associated with severe COVID-19

Insights into Antibody-Mediated Alphavirus Immunity and Vaccine Development Landscape.

Alphaviruses are mosquito-borne pathogens distributed worldwide in tropical and temperate areas causing a wide range of symptoms ranging from inflammatory arthritis-like manifestations to the induction of encephalitis in humans. Historically, large outbreaks in susceptible populations have been recorded followed by the development of protective long-lasting antibody responses suggesting a potential advantageous role for a vaccine. Although the current understanding of alphavirus antibody-mediated immunity has been mainly gathered in natural and experimental settings of chikungunya virus (CHIKV) infection, little is known about the humoral responses triggered by other emerging alphaviruses. This knowledge is needed to improve serology-based diagnostic tests and the development of highly effective cross-protective vaccines. Here, we review the role of antibody-mediated immunity upon arthritogenic and neurotropic alphavirus infections, and the current research efforts for the development of vaccines as a tool to control future alphavirus outbreaks

The proteobacterial species Burkholderia pseudomallei produces ergothioneine, which enhances virulence in mammalian infection

10.1096/fj.201800716FASEB JOURNAL32126395-640

The proteobacterial species Burkholderia pseudomallei produces ergothioneine, which enhances virulence in mammalian infection

Bacteria use various endogenous antioxidants for protection against oxidative stress associated with environmental survival or host infection. Although glutathione (GSH) is the most abundant and widely used antioxidant in Proteobacteria, ergothioneine (EGT) is another microbial antioxidant, mainly produced by fungi and Actinobacteria. The Burkholderia genus is found in diverse environmental niches. We observed that gene homologs required for the synthesis of EGT are widely distributed throughout the genus. By generating gene-deletion mutants and monitoring production with isotope-labeled substrates, we show that pathogenic Burkholderia pseudomallei and environmental B. thailandensis are able to synthesize EGT de novo. Unlike most other bacterial EGT synthesis pathways described, Burkholderia spp. use cysteine rather than γ-glutamyl cysteine as the thiol donor. Analysis of recombinant EgtB indicated that it is a proficient sulfoxide synthase, despite divergence in the active site architecture from that of mycobacteria. The absence of GSH, but not EGT, increased bacterial susceptibility to oxidative stresses in vitro. However, deletion of EGT synthesis conferred a reduced fitness to B. pseudomallei, with a delay in organ colonization and time to death during mouse infection. Therefore, despite the lack of an apparent antioxidant role in vitro, EGT is important for optimal bacterial pathogenesis in the mammalian host.-Gamage, A. M., Liao, C., Cheah, I. K., Chen, Y., Lim, D. R. X., Ku, J. W. K., Chee, R. S. L., Gengenbacher, M., Seebeck, F. P., Halliwell, B., Gan, Y.-H. The proteobacterial species Burkholderia pseudomallei produces ergothioneine, which enhances virulence in mammalian infection

Persistent Symptoms and Association With Inflammatory Cytokine Signatures in Recovered Coronavirus Disease 2019 Patients.

10.1093/ofid/ofab156Open Forum Infect Dis86ofab156

Longitudinal [18F]FB-IL-2 PET Imaging to Assess the Immunopathogenicity of O'nyong-nyong Virus Infection

10.3389/fimmu.2020.00894Frontiers in Immunology1189

CD8+ T Cells Trigger Auricular Dermatitis and Blepharitis in Mice after Zika Virus Infection in the Absence of CD4+ T Cells.

Zika virus (ZIKV) became a public health concern when it re-emerged in 2015 owing to its ability to cause congenital deformities in the fetus and neurological complications in adults. Despite extensive data on protection, the interplay of protective and pathogenic adaptive immune responses toward ZIKV infection remains poorly understood. In this study, using a T-cell‒deficient mouse model that retains persistent ZIKV viral titers in the blood and organs, we show that the adoptive transfer of CD8+ T cells led to a significant reduction in viral load. This mouse model reveals that ZIKV can induce grossly visible auricular dermatitis and blepharitis, mediated by ZIKV-specific CD8+ T cells. Single-cell RNA sequencing of these causative CD8+ T cells from the ears shows an overactivated and elevated cytotoxic signature in mice with severe symptoms. Our results strongly suggest a role for CD8+ T-cell‒associated pathologies after ZIKV infection in CD4+ T-cell‒immunodeficient patients