Disparate temperature-dependent virus-host dynamics for SARS-CoV-2 and SARS-CoV in the human respiratory epithelium

Daniel Alpern, Elisa Cora, Bart Deplancke, Vincent Roland Julien Gardeux, Bastien Mangeat, Jörn Pezoldt, Julie Marie Russeil
PUBLIC LIBRARY SCIENCE, 2021
Journal paper

Abstract

Since its emergence in December 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally and become a major public health burden. Despite its close phylogenetic relationship to SARS-CoV, SARS-CoV-2 exhibits increased human-to-human transmission dynamics, likely due to efficient early replication in the upper respiratory epithelium of infected individuals. Since different temperatures encountered in the human upper and lower respiratory tract (37 degrees C and 33 degrees C, respectively) have been shown to affect the replication kinetics of several respiratory viruses, as well as host immune response dynamics, we investigated the impact of temperatures during SARS-CoV-2 and SARS-CoV infection using the primary human airway epithelial cell culture model. SARS-CoV-2, in contrast to SARS-CoV, replicated to higher titers when infections were performed at 33 degrees C rather than 37 degrees C. Although both viruses were highly sensitive to type I and type III interferon pretreatment, a detailed time-resolved transcriptome analysis revealed temperature-dependent interferon and pro-inflammatory responses specifically induced by SARS-CoV or SARS-CoV-2, which amplitude was inversely proportional to their replication efficiencies at 33 degrees C or 37 degrees C. These data provide crucial insight on pivotal virus-host interaction dynamics and are in line with characteristic clinical features of SARS-CoV-2 and SARS-CoV, as well as their respective transmission efficiencies.

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https://infoscience.epfl.ch/record/285244?ln=en

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Daniel Alpern, Elisa Cora, Bart Deplancke, Vincent Roland Julien Gardeux, Bastien Mangeat, Jörn Pezoldt, Julie Marie Russeil
PUBLIC LIBRARY SCIENCE, 2021
Journal paper

Abstract

Official source

https://infoscience.epfl.ch/record/285244?ln=en

About this result

Related concepts (16)

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The innate immune system has evolved to detect pathogens through germlineencoded pattern recognition receptors (PRRs). Nucleic acid sensors, a defined class of PRRs, bind to microbial and viral nucleic acids and trigger the production of type I interferons and cytokines which mediate the first line of host defense. In the past, these sensors have been primarily studied in the context of infections. Yet, the DNA sensor cyclic GMP-AMP synthase (cGAS) has been recently described to detect not only microbial and viral derived dsDNA but also self-DNA in a sequenceindependent manner. At steady state, the organization of nuclear self-DNA is tightly controlled by a complex network of multiple factors that can become imbalanced during genotoxic stress. Whether and how this stress can be sensed by cGAS in the absence of infection are the main questions of this thesis. Observing the fate of cGAS in space and time in the presence of several genotoxic insults including chemotherapeutics allowed me to gain novel insights into processes regulating the localization and activation of cGAS. In this thesis, I demonstrate that cGAS localizes to both nuclear and cytosolic compartments of the cell. We show that cGAS is inactive in the nucleus due to binding to the acidic patch on H2A-H2B heterodimers. Upon genotoxic stress, cGAS is removed from the nucleus in a manner that is dependent on histones and remains inactive. Moreover, with time cGAS transcription is repressed resulting in a gradual decrease of cGAS levels. On the other hand, cGAS-activating DNA substrates such as cytosolic chromatin fragments accumulate in the cytosol of senescent cells deficient in Lamin B1 when cGAS levels are already decreased. Along with the occurrence of these chromatin fragments, cGAS mediates an inflammatory response dependent on STING (Stimulator of interferon genes), referred to as the senescence-associated secretory phenotype (SASP). Overall, we conclude that acute genotoxic stress does not result in cGAS-STING signaling, whereas the chronic DNA damage response, senescence, activates the cGAS-STING pathway. Moreover, the results presented in this work suggest a new role for cGAS-STING signaling during senescence beyond the recognition of pathogens.

EPFL2020

The interplay between human genetic variation, chronic inflammation and persistent infection: relevance for cardiovascular morbidity

Flavia Aurelia Shoko Hodel

Contemporary genomic approaches allow us to seek answers to biological questions that were previously out of reach. Genome-wide association studies (GWAS) have identified numerous genetic polymorphisms associated with human diseases, providing new insight into the genes and pathways involved in pathogenesis. The work presented in this thesis aimed to harness the power of large-scale genomics, statistical methods and bioinformatic tools to explore the interactions between persistent infections, chronic low-grade inflammation, and coronary heart disease (CHD). To achieve this, we used data collected from large population-based studies of individuals of European ancestry.To identify human genetic determinants of the humoral immune response against persistent or frequently recurring infections, with a special focus on human polyomaviruses, we performed GWAS and meta-analyses of serostatus and quantitative immunoglobulin G responses. We identified NFKB1 as a common locus associated with antibody response to multiple pathogens. For polyomaviruses, we found strong associations of HLA class II, FUT2, STING1, and MUC1 genetic variants with the intensity of the humoral response. Together, these results demonstrate the modulating contribution of host genetic variation to the individual response against some of the most prevalent human viruses.Even when they are latent, chronic infections can trigger some degree of local or systemic immune response, resulting in low-grade inflammation. In an effort to better understand the variability of humoral immune response and inflammation patterns in response to pathogen exposure, we found evidence for an association between Chlamydia trachomatis and Helicobacter pylori seropositivity, and higher plasma levels of C-reactive protein (CRP), a sensitive indicator of inflammation. High polygenic risk was also significantly associated with CRP levels, confirming that human genetic variation plays a modulating role in systemic inflammation. These results improve our understanding of the relationship between persistent infections and chronic inflammation, an important determinant of long-term morbidity in humans.Finally, we developed statistical models to explore the influences of genetic variation, persistent infections and low-grade inflammation on incident CHD. We identified high polygenic risk and Fusobacterium nucleatum infection as associated with an increased risk of developing CHD, in addition to conventional risk factors. These results confirm that CHD is a multicomponent disease that is caused by demographic, genetic and environmental factors. Moreover, they might allow for better identification of individuals at high risk for CHD and provide a rationale for future anti-infective prevention trials.Together, this research demonstrates that current genomic and serological technology, bioinformatic analysis and functional follow-up studies have the potential to provide new insight into the molecular basis of host-pathogen interactions, and their role in chronic diseases. From a translational perspective, the results of this project include new targets for diagnosis and therapeutic development, new disease biomarkers, and better predictive models. Every advance in the understanding of complex disease has the potential to improve genomic and clinical medicine, and I am pleased to have had the opportunity to act at different levels to participate in this much needed transition to precision medicine.

EPFL2022

EPFL2020

The interplay between human genetic variation, chronic inflammation and persistent infection: relevance for cardiovascular morbidity

Flavia Aurelia Shoko Hodel

EPFL2022