by Keyword: Immunity

Gawish R, Starkl P, Pimenov L, Hladik A, Lakovits K, Oberndorfer F, Cronin SJF, Ohradanova-Repic A, Wirnsberger G, Agerer B, Endler L, Capraz T, Perthold JW, Cikes D, Koglgruber R, Hagelkruys A, Montserrat N, Mirazimi A, Boon L, Stockinger H, Bergthaler A, Oostenbrink C, Penninger JM, Knapp S, (2022). ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFNy-driven immunopathology Elife 11, e74623

Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cyto-kines IFN? and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. © Gawish et al.

JTD Keywords: covid-19 mouse model, covid-19 therapy, cytokine storm, mavie16, mouse, program, recombinant soluble ace2, tmprss2, Adaptive immunity, Angiotensin converting enzyme 2, Angiotensin-converting enzyme 2, Animal, Animal cell, Animal experiment, Animal model, Animal tissue, Animals, Apoptosis, Article, Bagg albino mouse, Breathing rate, Bronchoalveolar lavage fluid, C57bl mouse, Cell composition, Cell infiltration, Controlled study, Coronavirus disease 2019, Coronavirus spike glycoprotein, Covid-19, Cytokeratin 18, Cytokine production, Dipeptidyl carboxypeptidase, Disease model, Disease models, animal, Disease severity, Drosophila-melanogaster, Enzyme linked immunosorbent assay, Expression vector, Flow cytometry, Gamma interferon, Gene editing, Gene expression, Gene mutation, Genetic engineering, Genetics, Glycosylation, High mobility group b1 protein, Histology, Histopathology, Immune response, Immunocompetent cell, Immunology, Immunopathology, Interferon-gamma, Interleukin 2, Metabolism, Mice, inbred balb c, Mice, inbred c57bl, Mouse-adapted sars-cov-2, Myeloperoxidase, Neuropilin 1, Nonhuman, Nucleocapsid protein, Pathogenicity, Peptidyl-dipeptidase a, Pyroptosis, Renin angiotensin aldosterone system, Rna extraction, Rna isolation, Sars-cov-2, Severe acute respiratory syndrome coronavirus 2, Spike glycoprotein, coronavirus, T lymphocyte activation, Trabecular meshwork, Tumor necrosis factor, Virology, Virus load, Virus replication, Virus transmission, Virus virulence

Cereta, AD, Oliveira, VR, Costa, IP, Guimaraes, LL, Afonso, JPR, Fonseca, AL, de Sousa, ART, Silva, GAM, Mello, DACPG, de Oliveira, LVF, da Palma, RK, (2021). Early Life Microbial Exposure and Immunity Training Effects on Asthma Development and Progression Frontiers Of Medicine 8, 662262

Asthma is the most common inflammatory disease affecting the lungs, which can be caused by intrauterine or postnatal insults depending on the exposure to environmental factors. During early life, the exposure to different risk factors can influence the microbiome leading to undesired changes to the immune system. The modulations of the immunity, caused by dysbiosis during development, can increase the susceptibility to allergic diseases. On the other hand, immune training approaches during pregnancy can prevent allergic inflammatory diseases of the airways. In this review, we focus on evidence of risk factors in early life that can alter the development of lung immunity associated with dysbiosis, that leads to asthma and affect childhood and adult life. Furthermore, we discuss new ideas for potential prevention strategies that can be applied during pregnancy and postnatal period.

JTD Keywords: asthma, dysbiosis, early life immunity, lung microbiome, Adulthood, Antibiotic exposure, Asthma, Childhood, Disease, Disease exacerbation, Dysbiosis, Early life immunity, Gut microbiome, Human, Immunity, Intestine flora, Lung development, Lung microbiome, Lung microbiota, Nonhuman, Perinatal period, Pregnancy, Prevention, Prevention strategies, Review, Risk, Risk factor, Sensitization, Supplementation, Vitamin-d, Wheeze

Cremonese, C., Schierwagen, R., Uschner, F. E., Torres, S., Tyc, O., Ortiz, C., Schulz, M., Queck, A., Kristiansen, G., Bader, M., Sauerbruch, T., Weiskirchen, R., Walther, T., Trebicka, J., Klein, S., (2020). Short-term western diet aggravates non-alcoholic fatty liver disease (NAFLD) with portal hypertension in TGR(mREN2)27 rats International Journal of Molecular Sciences 21, (9), 3308

Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.

JTD Keywords: ADGRE1, EMR1, F4/80, Immunity, Liver fibrosis, Macrophage, NAFLD, Portal hypertension, TGR(mREN2)27, Western diet