Biology subjects

Gat-Viks, I.

Publications and source records attributed to Gat-Viks, I..

3 recordsLinked to original sources

bioRxiv2022

The host transcriptional response to superinfection by influenza virus and streptococcus pneumonia

Secondary bacterial challenges during influenza virus infection ( superinfection) cause excessive mortality and hospitalization. Here we present a longitudinal study of gene-expression changes in murine lungs during superinfection, with an initial influenza A virus (IAV) infection and a subsequent Streptococcus pneumonia (SP) infection. In addition to the well-characterized impairment of the innate immune response, we identified superinfection-specific alterations in endothelial-related genes, including a previously uncharacterized rapid downregulation of particular angiogenic and vascular markers. Superinfection-specific alterations were also evident in the analysis of cellular states related to the hosts immune resistance against pathogens. We found that superinfected mice manifested an excessive rapid induction of immune resistance starting only a few hours after the secondary bacterial challenge. In addition, there was a substantial rewiring of the resistance program: interferon-regulated genes were switched from positive to negative correlations with resistance, whereas genes of fatty-acid metabolism were switched from negative to positive correlations with resistance. Thus, the transcriptional resistance state in superinfection is reprogrammed toward repressed interferon signaling and induced fatty acid metabolism. Our findings suggest new insights into the remodeling of the host defense upon superinfection, providing promising targets for future therapeutic interventions.

systems biology↗

bioRxiv2022

Pleural macrophages promote recovery from influenza virus infection

Seasonal influenza results in 3 to 5 million cases of severe disease and 250,000 to 500,000 deaths annually. Macrophages have been implicated in both the resolution and progression of the disease, but the drivers of these outcomes are poorly understood. We probed mouse lung transcriptomic datasets using the Digital Cell Quantifier algorithm to predict immune cell subsets that correlated with mild or severe influenza A virus (IAV) infection outcomes. We identified a novel lung macrophage population that transcriptionally resembled small serosal cavity macrophages and correlated with mild disease. Until now, the study of serosal macrophage translocation in the context of infections has been neglected. Here, we show that pleural macrophages (PMs) migrate from the pleural cavity to the lung after infection with pH1N1 A/California/04/2009 IAV. We found that the depletion of PMs increased morbidity and pulmonary inflammation. There were increased proinflammatory cytokines in the pleural cavity and an influx of neutrophils within the lung. Our results show PMs are recruited to the lung during IAV infection and contribute to recovery from influenza. This study expands our knowledge of PM plasticity and provides a new source of lung macrophages independent of monocyte recruitment and local proliferation. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/493482v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1e8880borg.highwire.dtl.DTLVardef@13b987dorg.highwire.dtl.DTLVardef@19856f9org.highwire.dtl.DTLVardef@76277d_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Distinct gene programs underpinning 'disease tolerance' and 'resistance' in influenza virus infection

When challenged with an invading pathogen, the host defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. We exploited transcriptional and physiological monitoring across 33 mouse strains, during in vivo influenza virus infection, to identify two host-defense gene programs - one is associated with hallmarks of disease tolerance and the other with hallmarks of resistance. Both programs constitute generic responses in multiple mouse and human cell types. Our study describes the organizational principles of these programs and validates Arhgdia as a regulator of disease-tolerance states in epithelial cells. We further reveal that the baseline disease-tolerance state in macrophages is associated with the pathophysiological response to injury and infection. Our framework provides a paradigm for the understanding of disease tolerance and resistance at the molecular level.

systems biology↗