Asymptomatic Plasmodium falciparum infection in children is associated with increased auto-antibody production, high IL-10 plasma levels and antibodies to merozoite surface protein 3

Background Mechanisms of acquired protection to malaria in asymptomatic Plasmodium falciparum carriers are only partially understood. Among them, the role plays by the self-reactive antibodies has not been clarified yet. In this study, the relationship between repertoires of circulating self-reactive and parasite-specific immunoglobulin G (IgG), their correlation with cytokine levels, and their association with protection against malaria was investigated in asymptomatic Plasmodium falciparum-infected Gabonese children. Methods The diversity of P. falciparum-specific antibody repertoire was analysed using a protein micro-array immunoassay, the total auto-antibody repertoire by quantitative immunoblotting and circulating cytokine levels were measured by ELISA in endemic controls (EC) and P. falciparum-infected children from Gabon with asymptomatic (AM) or mild malaria (MM). The association of self- and parasite-specific antibody repertoires with circulating cytokines was evaluated using single linkage hierarchical clustering, Kruskal – Wallis tests and Spearman’s rank correlation. Results Children with AM exhibited an IgG response to merozoite surface protein 3 (MSP3) but not to MSP1-19, although their levels of total P. falciparum-specific IgG were similar to those in the MM group. Moreover, the asymptomatic children had increased levels of autoantibodies recognising brain antigens. In addition, a correlation between IL-10 levels and parasite load was found in AM and MM children. These two groups also exhibited significant correlations between plasma levels of IL-10 and IFN-γ with age and with total plasma IgG levels. IL-10 and IFN-γ levels were also associated with auto-antibody responses in AM. Conclusions Altogether, these results indicate that a self-reactive polyclonal response associated with increased IgG to MSP3 and high plasma levels of IL-10 and IFN-γ may contribute to protective immune mechanisms triggered in asymptomatic P. falciparum infection in Gabonese children

IgG autoantibody to brain beta tubulin III associated with cytokine cluster-II discriminate cerebral malaria in central India

We investigated the significance of these self-reactive antibodies in clinically well-defined groups of P. falciparum infected patients manifesting mild malaria (MM), severe non-cerebral malaria (SM), or cerebral malaria (CM) and in control subjects from Gondia, a malaria epidemic site in central India using quantitative immunoprinting and multivariate statistical analyses. A two-fold complete-linkage hierarchical clustering allows classifying the different patient groups and to distinguish the CM from the others on the basis of their profile of IgG reactivity to brain proteins defined by PANAMA Blot. We identified beta tubulin III (TBB3) as a novel discriminant brain antigen in the prevalence of CM. In addition, circulating IgG from CM patients highly react with recombinant TBB3. Overall, correspondence analyses based on singular value decomposition show a strong correlation between IgG anti-TBB3 and elevated concentration of cluster-II cytokine (IFNγ, IL1β, TNFα, TGFβ) previously demonstrated to be a predictor of CM in the same populatio

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org

An integrated cell atlas of the lung in health and disease.

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas

Abstract P2-05-08: Combined neoadjuvant iniparib and carboplatin in locally advanced or metastatic canine mammary tumors (MT) to support human clinical studies

Abstract INTRODUCTION Among breast cancers, the triple negative subtype (negative for hormone receptors and not overexpressing HER2) has the worst prognosis and its response to Iniparib has been investigated in clinical trials. Further investigations are needed to optimize drug schedule and patient selection criteria. Iniparib antitumor mechanism is not completely understood, as well as iniparib diffusion kinetic into tumoral tissues. We address these questions in spontaneous canine invasive mammary carcinomas, which are a good model for this cancer subtype (Ibisch et al., World Veterinary Cancer Congress 2012), in a neoadjuvant setting. To our knowledge, this is the first study of iniparib administration in cancer-bearing dogs. MATERIAL AND METHODS Twenty female dogs with spontaneous MT with malignant criteria (tumor size, speed of growth, ulceration, relapse, or metastasis) were included. All tumors were described as rapidly growing. Dogs received a first infusion of iniparib at day 0 and a combination of carboplatin and iniparib at day 7. Biological materials (tumor biopsies and blood) were collected before and 5 minutes after iniparib infusion for pharmacokinetic and metabolism studies. Tumor response was evaluated by caliper measurements and histopathological analysis of mammary tumors and draining lymph nodes. A chain mastectomy was performed 3 or 4 weeks later. Histological records included the subtype of carcinoma (WHO 1999), Elston &amp; Ellis grade, presence of emboli, lymph node metastasis and IHC stainings using ER, PR, Her2 (scored according to Wolff et al.2007), CK5/6, EGF-R and Ki67. Intensity of necrosis and apoptosis was evaluated using PAS coloration and immunohistochemistry for caspase 3, at DO on tumor biopsies and at surgery. Toxicity of the protocol was evaluated and its efficiency on invasive carcinomas was compared to surgery alone (control group of 27 female dogs with invasive mammary carcinomas treated by chain mastectomy alone). RESULTS Treated and control groups shared similar features concerning animal breeds, age, neutering status and tumor location. 75% of the treated MT were malignant. Necrosis and apoptosis were significantly increased in respectively 63 and 56% of iniparib treated tumors. Clinical evidence of toxicity was minimal (15% of dogs with nausea, 60% with transient polyuria-polydipsia). Tumor stabilization was observed before surgery in all dogs but one. Median survival has not been reached. CONCLUSION Iniparib at 35mg/kg combined with carboplatin at 300 mg/m2 seemed well tolerated in this study and deserves further investigations. The degree of necrosis and apoptosis in the treated tumors can be evaluated with these techniques. Iniparib pharmacokinetic and metabolism studies in cancer-bearing dogs are ongoing. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-08.</jats:p