Lowe, D. M. | bioRxiv Science

bioRxiv2021

Executable Network of SARS-CoV-2-Host Interaction Predicts Drug Combination Treatments

The COVID-19 pandemic has pushed healthcare systems globally to a breaking point. The urgent need for effective and affordable COVID-19 treatments calls for repurposing combinations of approved drugs. The challenge is to identify which combinations are likely to be most effective and at what stages of the disease. Here, we present the first disease-stage executable signalling network model of SARS-CoV-2-host interactions used to predict effective repurposed drug combinations for treating early- and late-stage severe disease. Using our executable model, we performed in silico screening of 9870 pairs of 140 potential targets and have identified 12 new drug combinations. Camostat and Apilimod were predicted to be the most promising combination in effectively supressing viral replication in the early stages of severe disease and were validated experimentally in human Caco-2 cells. Our study further demonstrates the power of executable mechanistic modelling to enable rapid pre-clinical evaluation of combination therapies tailored to disease progression. It also presents a novel resource and expandable model system that can respond to further needs in the pandemic.

systems biology↗

bioRxiv2021

The relationship between mucosal microbiota, colitis and systemic inflammation in Chronic Granulomatous Disorder

BackgroundChronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by an inflammatory colitis and is associated with systemic inflammation. ObjectiveTo investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation. MethodsWe performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients colons, and conducted compositional and functional pathway prediction analyses. ResultsThe microbiota in samples from colitis patients demonstrated reduced taxonomic alpha diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilisation were enriched in patients with colitis and correlated positively with faecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by faecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into High and Low systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta diversity analyses. ConclusionThe microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition. Key MessagesThe colonic mucosal microbiome and bacterial metabolic pathways in patients with CGD colitis differ from patients without colitis, even in macroscopically normal bowel segments. The mucosal microbiome and bacterial metabolic pathways in patients with CGD also differ according to the extent of systemic inflammation, independently from the presence of colitis, suggesting a role for the gut microbiota in the inflammatory phenotype of this condition. Capsule summaryThe pathogenesis of chronic granulomatous disorder (CGD)-associated colitis and other inflammatory complications is unclear. We demonstrate potentially treatable alterations in the mucosa-associated microbiome in CGD colitis and microbial differences which associate with systemic inflammation independently of colitis status.

immunology↗

bioRxiv2021

Eosinophils are an integral component of the pulmonary granulocyte response in Tuberculosis and promote host resistance in mice

Host resistance to Mycobacterium tuberculosis infection requires the activities of multiple leukocyte subsets, yet the roles of the different innate effector cells during tuberculosis are incompletely understood. Here we uncover an unexpected association between eosinophils and Mtb infection. In humans, eosinophils are decreased in the blood but enriched in resected human tuberculosis lung lesions and autopsy granulomas. Influx of eosinophils is also evident in infected zebrafish, mice, and nonhuman primate granulomas, where they are functionally activated and degranulate. Importantly, employing complementary genetic models of eosinophil deficiency, we demonstrate that, in mice, eosinophils are required for optimal pulmonary bacterial control and host survival after Mtb infection. Collectively, our findings uncover an unexpected recruitment of eosinophils to the infected lung tissue and a protective role for these cells in the control of Mtb infection in mice.

immunology↗