Immune responses to gp82 provide protection against mucosal Trypanosoma cruzi infection

The potential use of the Trypanosoma cruzi metacyclic trypomastigote (MT) stage-specific molecule glycoprotein-82 (gp82) as a vaccine target has not been fully explored. We show that the opsonization of T. cruzi MT with gp82-specific antibody prior to mucosal challenge significantly reduces parasite infectivity. In addition, we investigated the immune responses as well as the systemic and mucosal protective immunity induced by intranasal CpG-adjuvanted gp82 vaccination. Spleen cells from mice immunized with CpG-gp82 proliferated and secreted IFN-γ in a dose-dependent manner in response to in vitro stimulation with gp82 and parasite lysate. More importantly, these CpG-gp82-immunized mice were significantly protected from a biologically relevant oral parasite challenge.Saint Louis University Department of Molecular MicrobiologyUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Microbiologia, Imunologia e ParasitologiaUNIFESP, EPM, Depto. de Microbiologia, Imunologia e ParasitologiaSciEL

A treatment that eliminates SARS-CoV-2 replication in human airway epithelial cells and is safe for inhalation as an aerosol in healthy human subjects

Background: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense and worsens airway inflammation. Inhaled Optate is designed to safely to raise airway surface pH and is well-tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. Methods: Here, we grew primary normal human airway epithelial (NHAE) cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether it would prevent viral infection and replication. Cells were pre-treated with Optate or placebo prior to infection (MOI of 0.1) and viral replication was determined by plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. Results: Optate almost completely prevented viral replication at each time point between 24 and 120 hours, relative to placebo, both by plaque assay and by N protein expression (p < 0.001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs or oxygenation. Conclusions: Inhaled Optate may be well-suited for a clinical trial in patients with a pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regards to pH, isotonicity and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.Funded by NHLBI (P01 HL128192), the Lilly Endowment, and the Riley Children’s Foundation. Competing Interests: MDD and BG are funded by NIH P01 HL128192-01A1, are patent holders of Optate, and are co-Founders of Airbase Breathing Company. SDG and CMR are also patent holders of Optate

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Trans-sialidase recombinant protein mixed with CpG motif-containing oligodeoxynucleotide induces protective mucosal and systemic Trypanosoma cruzi immunity involving CD8(+) CTL and B cell-mediated cross-priming

The Trypanosoma cruzi trans-sialidase (TS) is a unique enzyme with neuraminidase and sialic acid transfer activities important for parasite infectivity. The T. cruzi genome contains a large family of TS homologous genes, and it has been suggested that TS homologues provide a mechanism of immune escape important for chronic infection. We have investigated whether the consensus TS enzymatic domain could induce immunity protective against acute and chronic, as well as mucosal and systemic, T. cruzi infection. We have shown that: 1) TS-specific immunity can protect against acute T. cruzi infection; 2) effective TS-specific immunity is maintained during chronic T. cruzi infection despite the expression of numerous related TS superfamily genes encoding altered peptide ligands that in theory could promote immune tolerization; and 3) the practical intranasal delivery of recombinant TS protein combined with a ssDNA oligodeoxynucleotide (ODN) adjuvant containing unmethylated CpG motifs can induce both mucosal and systemic protective immunity. We have further demonstrated that the intranasal delivery of soluble TS recombinant Ag combined with CpG ODN induces both TS-specific CD4(+) and CD8(+) T cells associated with vaccine-induced protective immunity. In addition, optimal protection induced by intranasal TS Ag combined with CpG ODN requires B cells, which, after treatment with CpG ODN, have the ability to induce TS-specific CD8(+) T cell cross-priming. Our results support the development of TS vaccines for human use, suggest surrogate markers for use in future human vaccine trials, and mechanistically identify B cells as important APC targets for vaccines designed to induce CD8(+) CTL responses.St Louis Univ, Hlth Sci Ctr, Dept Mol Microbiol, St Louis, MO 63104 USAUniv Fed Sao Paulo, Escola Paulista Med, CINTERGEN, Sao Paulo, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Immunol & Parasitol, Sao Paulo, BrazilUniv Fed Sao Paulo, Escola Paulista Med, CINTERGEN, Sao Paulo, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Microbiol Immunol & Parasitol, Sao Paulo, BrazilWeb of Scienc

Retrospective delirium ascertainment from case notes: a retrospective cohort study

Objectives This study sets out to ascertain if recognition of delirium impacts on patient outcomes. Design Retrospective cohort study. Setting Unscheduled admissions to acute care trust/secondary care UK hospitals. Participants Six hundred and fifty-six older adults aged ≥65 years admitted on 14 September 2018. Measurements Delirium was ascertained retrospectively from case notes using medical notes. Documented delirium was classified as recognised delirium and retrospectively ascertained delirium was classified as unrecognised delirium. Primary and secondary outcome measures Primary outcome measure: inpatient mortality. Secondary outcome measures: length of stay, discharge destination. Results Delirium was present in 21.1% (132/626) of patients at any point during admission. The presence of delirium was associated with increased mortality (HR 2.65, CI 1.40 to 5.01). Recognition of delirium did not significantly impact on outcomes. Conclusions Delirium is associated with adverse outcomes in hospitalised older adults. However, there is insufficient evidence that recognition of delirium affects outcomes. However, delirium recognition presents an opportunity to discuss a person’s overall prognosis and discuss this with the patient and their family. Further research is needed to assess the pathophysiology of delirium to enable development of targeted interventions towards improved outcomes in patients with delirium