Exacerbated Innate Host Response to SARS-CoV in Aged Non-Human Primates

The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-κB as central player, whereas expression of type I interferon (IFN)-β is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI

Virus Identification in Unknown Tropical Febrile Illness Cases Using Deep Sequencing

Dengue virus is an emerging infectious agent that infects an estimated 50–100 million people annually worldwide, yet current diagnostic practices cannot detect an etiologic pathogen in ∼40% of dengue-like illnesses. Metagenomic approaches to pathogen detection, such as viral microarrays and deep sequencing, are promising tools to address emerging and non-diagnosable disease challenges. In this study, we used the Virochip microarray and deep sequencing to characterize the spectrum of viruses present in human sera from 123 Nicaraguan patients presenting with dengue-like symptoms but testing negative for dengue virus. We utilized a barcoding strategy to simultaneously deep sequence multiple serum specimens, generating on average over 1 million reads per sample. We then implemented a stepwise bioinformatic filtering pipeline to remove the majority of human and low-quality sequences to improve the speed and accuracy of subsequent unbiased database searches. By deep sequencing, we were able to detect virus sequence in 37% (45/123) of previously negative cases. These included 13 cases with Human Herpesvirus 6 sequences. Other samples contained sequences with similarity to sequences from viruses in the Herpesviridae, Flaviviridae, Circoviridae, Anelloviridae, Asfarviridae, and Parvoviridae families. In some cases, the putative viral sequences were virtually identical to known viruses, and in others they diverged, suggesting that they may derive from novel viruses. These results demonstrate the utility of unbiased metagenomic approaches in the detection of known and divergent viruses in the study of tropical febrile illness

Equine Torovirus (BEV) Induces Caspase-Mediated Apoptosis in Infected Cells

Toroviruses are gastroenteritis causing agents that infect different animal species and humans. To date, very little is known about how toroviruses cause disease. Here, we describe for the first time that the prototype member of this genus, the equine torovirus Berne virus (BEV), induces apoptosis in infected cells at late times postinfection. Observation of BEV infected cells by electron microscopy revealed that by 24 hours postinfection some cells exhibited morphological characteristics of apoptotic cells. Based on this finding, we analyzed several apoptotic markers, and observed protein synthesis inhibition, rRNA and DNA degradation, nuclear fragmentation, caspase-mediated cleavage of PARP and eIF4GI, and PKR and eIF2α phosphorylation, all these processes taking place after peak virus production. We also determined that both cell death receptor and mitochondrial pathways are involved in the apoptosis process induced by BEV. BEV-induced apoptosis at late times postinfection, once viral progeny are produced, could facilitate viral dissemination in vivo and contribute to viral pathogenesis

Virus genomes reveal factors that spread and sustained the Ebola epidemic.

The 2013-2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic 'gravity' model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics

Nieuw van de markt? Coronavirusuitbraak in Wuhan.

China kampt met de uitbraak van een nieuw coronavirus die vooralsnog niet onder controle is. Wat is er precies aan de hand, wat weten we wel en wat niet, en hoe moet het verder? In dit artikel zetten we de huidige stand van zaken op een rij en bespreken we de internationale aanpak

Foreign-body reaction to dermal sheep collagen in interferon-gamma-receptor knock-out mice

This study was performed to gain more insight into the role of interferon-gamma (IFN-gamma), a potent macrophage activator, in the foreign-body reaction to hexamethylenediisocyanate-crosslinked dermal sheep collagen (HDSC). Because the results of earlier studies aimed at modulating the foreign-body reaction in AO rats by local or systemic treatment with anti-IFN-gamma were not completely unambiguous, we extended our in investigations to IFN-gamma-receptor knock-out (KO) mice. Several parameters (i.e., macrophages, giant cells, T-cells, B-cells, granulocytes, expression of MHC class II, stroma formation, and degradation and calcification of the biomaterial) were compared between wild-type (WT) and KO mice. Remarkably, the foreign-body reaction was very similar in WT and KO mice. in both, giant cells were formed, but in contrast to previous results in AO rats, phagocytosis of HDSC bundles occurred hardly at all up to 9 weeks, and MHC class II expression was minimal. Stroma formation and vascularization were high and calcification occurred. T-cells comprised less than 1%; a few plasma cells were present in the KO mice at later time points. Granulocytes, mainly eosinophils, were present at all explantation time points. Because of the similar results in WT and KO mice, we question whether IFN-gamma plays a role at all in the foreign-body reaction in mice. (C) 2000 John Wiley & Sons, Inc

Foreign-body reaction to dermal sheep collagen in interferon-gamma-receptor knock-out mice

This study was performed to gain more insight into the role of interferon-gamma (IFN-gamma), a potent macrophage activator, in the foreign-body reaction to hexamethylenediisocyanate-crosslinked dermal sheep collagen (HDSC). Because the results of earlier studies aimed at modulating the foreign-body reaction in AO rats by local or systemic treatment with anti-IFN-gamma were not completely unambiguous, we extended our in investigations to IFN-gamma-receptor knock-out (KO) mice. Several parameters (i.e., macrophages, giant cells, T-cells, B-cells, granulocytes, expression of MHC class II, stroma formation, and degradation and calcification of the biomaterial) were compared between wild-type (WT) and KO mice. Remarkably, the foreign-body reaction was very similar in WT and KO mice. in both, giant cells were formed, but in contrast to previous results in AO rats, phagocytosis of HDSC bundles occurred hardly at all up to 9 weeks, and MHC class II expression was minimal. Stroma formation and vascularization were high and calcification occurred. T-cells comprised less than 1%; a few plasma cells were present in the KO mice at later time points. Granulocytes, mainly eosinophils, were present at all explantation time points. Because of the similar results in WT and KO mice, we question whether IFN-gamma plays a role at all in the foreign-body reaction in mice. (C) 2000 John Wiley & Sons, Inc