A biomathematical model of atherosclerosis in mice.

Atherosclerosis is one of the leading causes of death worldwide. Biomathematical modelling of the underlying disease and therapy processes might be a useful aid to develop and improve preventive and treatment concepts of atherosclerosis. We here propose a biomathematical model of murine atherosclerosis under different diet and treatment conditions including lipid modulating compound and antibiotics. The model is derived by translating known biological mechanisms into ordinary differential equations and by assuming appropriate response kinetics to the applied interventions. We explicitly describe the dynamics of relevant immune cells and lipid species in atherosclerotic lesions including the degree of blood vessel occlusion due to growing plaques. Unknown model parameters were determined by fitting the predictions of model simulations to time series data derived from mice experiments. Parameter fittings resulted in a good agreement of model and data for all 13 experimental scenarios considered. The model can be used to predict the outcome of alternative treatment schedules of combined antibiotic, immune modulating, and lipid lowering agents under high fat or normal diet. We conclude that we established a comprehensive biomathematical model of atherosclerosis in mice. We aim to validate the model on the basis of further experimental data.

Altered fibrin clot structure and dysregulated fibrinolysis contribute to thrombosis risk in severe COVID-19.

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. In this study, we determined the altered levels of factor XII (FXII) and its activation products in critically ill patients with COVID-19 in comparison with patients with severe acute respiratory distress syndrome related to the influenza virus (acute respiratory distress syndrome [ARDS]-influenza). Compatible with those data, we found rapid consumption of FXII in COVID-19 but not in ARDS-influenza plasma. Interestingly, the lag phase in fibrin formation, triggered by the FXII activator kaolin, was not prolonged in COVID-19, as opposed to that in ARDS-influenza. Confocal and electron microscopy showed that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggered formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, clot lysis was markedly impaired in COVID-19 as opposed to that in ARDS-influenza. Dysregulated fibrinolytic system, as evidenced by elevated levels of thrombin-activatable fibrinolysis inhibitor, tissue-plasminogen activator, and plasminogen activator inhibitor-1 in COVID-19 potentiated this effect. Analysis of lung tissue sections revealed widespread extra- and intravascular compact fibrin deposits in patients with COVID-19. A compact fibrin network structure and dysregulated fibrinolysis may collectively contribute to a high incidence of thrombotic events in COVID-19.

Pulmonary fibrosis in Fra-2 transgenic mice is associated with decreased numbers of alveolar macrophages and increased susceptibility to pneumococcal pneumonia.

Idiopathic pulmonary fibrosis (IPF) is a deadly condition characterized by progressive respiratory dysfunction. Exacerbations due to airway infections are believed to promote disease progression, and presence of Streptococcus in the lung microbiome has been associated with the progression of IPF and mortality. The aim of this study was to analyze the effect of lung fibrosis on susceptibility to pneumococcal pneumonia and bacteremia. The effects of subclinical (low dose) infection with Streptococcus pneumoniae were studied in a well characterized fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of spontaneous, progressive pulmonary fibrosis. Forty-eight hours after transnasal infection with S. pneumoniae, bacterial load was assessed in lung tissue, bronchoalveolar lavage (BAL), blood, and spleen. Leukocyte subsets and cytokine levels were analyzed in BAL and blood. Lung compliance and arterial blood gases were assessed. In contrast to wildtype mice, low dose lung infection with S. pneumoniae in Fra-2 TG mice resulted in substantial pneumonia including weight loss, increased lung bacterial load, and bacteremia. BAL alveolar macrophages were reduced in Fra-2 TG mice compared to the corresponding WT mice. Proinflammatory cytokines and chemokines (IL-1ß, IL-6, TNF-α, and CXCL1) were elevated upon infection in BAL supernatant and plasma of Fra-2 TG mice. Lung compliance was decreased in Fra-2 TG mice following low dose infection with S. pneumoniae. Pulmonary fibrosis increases susceptibility to pneumococcal pneumonia and bacteremia possibly via impaired alveolar bacterial clearance.

Preclinical Assessment of Bacteriophage Therapy against Experimental Acinetobacter baumannii Lung Infection.

Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of clinical development of phages as therapeutic agents. Therefore, we tested the efficacy of a purified lytic phage, vB_AbaM_Acibel004, against multidrug-resistant A. baumannii clinical isolate RUH 2037 infection in immunocompetent mice and a human lung tissue model. Sham- and A. baumannii-infected mice received a single-dose of phage or buffer via intratracheal aerosolization. Group-specific differences in bacterial burden, immune and clinical responses were compared. Phage-treated mice not only recovered faster from infection-associated hypothermia but also had lower pulmonary bacterial burden, lower lung permeability, and cytokine release. Histopathological examination revealed less inflammation with unaffected inflammatory cellular recruitment. No phage-specific adverse events were noted. Additionally, the bactericidal effect of the purified phage on A. baumannii was confirmed after single-dose treatment in an ex vivo human lung infection model. Taken together, our data suggest that the investigated phage has significant potential to treat multidrug-resistant A. baumannii infections and further support the development of appropriate methods for preclinical evaluation of antibacterial efficacy of phages.

Cardiovascular sequelae of pneumonia.

PURPOSE OF REVIEW: In this brief review, we discuss the current epidemiological data and latest results from basic research on the cardiovascular sequelae after lower respiratory tract infection. RECENT FINDINGS: Novel epidemiological evidence substantiates the association between pneumonia and subsequent cardiovascular events (CVEs) in the short- and long-term after viral or bacterial acute infection. Biomarkers such as cardiac troponin or coronary artery calcium may represent useful predictive tools for the detection of cardiac involvement during and after pneumonia. Particularly, Streptococcus pneumoniae directly cause cardiac damage by invasion into the myocardium and formation of microscopic lesions finally leading to the development of cardiac scarring in rodents and nonhuman primates. In addition, a causal relationship between pulmonary inflammation and atherosclerotic plaque formation in systemic arteries has emerged that appears to involve a mechanistic role for neutrophil granulocytes. However, many key pathomechanisms by which pneumonia may trigger or promote subsequent CVEs still remain unclear. SUMMARY: Pneumonia may deleteriously impact cardiovascular function. Direct cardiomyocyte destruction by pathogens as well as host inflammatory response associated effects including atherosclerotic plaque development and/or rupture have been observed. Details of underlying mechanisms need to be further investigated to deliver future perspectives for the prevention of CVEs subsequent to pneumonia.

Spectrum of pathogen- and model-specific histopathologies in mouse models of acute pneumonia.

Pneumonia may be caused by a wide range of pathogens and is considered the most common infectious cause of death in humans. Murine acute lung infection models mirror human pathologies in many aspects and contribute to our understanding of the disease and the development of novel treatment strategies. Despite progress in other fields of tissue imaging, histopathology remains the most conclusive and practical read out tool for the descriptive and semiquantitative evaluation of mouse pneumonia and therapeutic interventions. Here, we systematically describe and compare the distinctive histopathological features of established models of acute pneumonia in mice induced by Streptococcus (S.) pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Legionella pneumophila, Escherichia coli, Middle East respiratory syndrome (MERS) coronavirus, influenza A virus (IAV) and superinfection of IAV-incuced pneumonia with S. pneumoniae. Systematic comparisons of the models revealed striking differences in the distribution of lesions, the characteristics of pneumonia induced, principal inflammatory cell types, lesions in adjacent tissues, and the detectability of the pathogens in histological sections. We therefore identified core criteria for each model suitable for practical semiquantitative scoring systems that take into account the pathogen- and model-specific patterns of pneumonia. Other critical factors that affect experimental pathologies are discussed, including infectious dose, time kinetics, and the genetic background of the mouse strain. The substantial differences between the model-specific pathologies underscore the necessity of pathogen- and model-adapted criteria for the comparative quantification of experimental outcomes. These criteria also allow for the standardized validation and comparison of treatment strategies in preclinical models.