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Modelling the linkage between influenza infection and cardiovascular events via thrombosis.

ABSTRACT: There is a heavy burden associated with influenza including all-cause hospitalization as well as severe cardiovascular and cardiorespiratory events. Influenza associated cardiac events have been linked to multiple biological pathways in a human host. To study the contribution of influenza virus infection to cardiovascular thrombotic events, we develop a dynamic model which incorporates some key elements of the host immune response, inflammatory response, and blood coagulation. We formulate these biological systems and integrate them into a cohesive modelling framework to show how blood clotting may be connected to influenza virus infection. With blood clot formation inside an artery resulting from influenza virus infection as the primary outcome of this integrated model, we demonstrate how blood clot severity may depend on circulating prothrombin levels. We also utilize our model to leverage clinical data to inform the threshold level of the inflammatory cytokine TNF? which initiates tissue factor induction and subsequent blood clotting. Our model provides a tool to explore how individual biological components contribute to blood clotting events in the presence of influenza infection, to identify individuals at risk of clotting based on their circulating prothrombin levels, and to guide the development of future vaccines to optimally interact with the immune system.

SUBMITTER: McCarthy Z

PROVIDER: S-EPMC7458909 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Modelling the linkage between influenza infection and cardiovascular events via thrombosis.

McCarthy Zachary Z Xu Shixin S Rahman Ashrafur A Bragazzi Nicola Luigi NL Corrales-Medina Vicente F VF Lee Jason J Seet Bruce T BT Neame Dion D Thommes Edward E Heffernan Jane J Chit Ayman A Wu Jianhong J

Scientific reports 20200831 1

There is a heavy burden associated with influenza including all-cause hospitalization as well as severe cardiovascular and cardiorespiratory events. Influenza associated cardiac events have been linked to multiple biological pathways in a human host. To study the contribution of influenza virus infection to cardiovascular thrombotic events, we develop a dynamic model which incorporates some key elements of the host immune response, inflammatory response, and blood coagulation. We formulate these ...[more]

PMID: 32868834

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Project description:More than 70 million people worldwide are still infected with the hepatitis C virus 30 years after its discovery, underscoring the need for a vaccine. To develop an effective prophylactic vaccine, detailed knowledge of the correlates of protection and an immunocompetent surrogate model are needed. In this study, we describe the minimum dose required for robust equine hepacivirus (EqHV) infection in equids and examined how this relates to duration of infection, seroconversion, and transcriptomic responses. To investigate mechanisms of hepaciviral persistence, immune response, and immune- mediated pathology, we inoculated eight EqHV naive horses with doses ranging from 1 to 2 to 1.3 106 RNA copies per inoculation. We characterized infection kinetics, pathology, and transcriptomic responses via new generation sequencing. The minimal infec- tious dose of EqHV in horses was estimated at 13 RNA copies, whereas 6 to 7 copies were insufficient to cause infection. Peak viremia did not correlate with infectious dose, while seroconversion and duration of infection appeared to be affected. Notably, sero- conversion was undetectable in the low-dose infections within the surveillance period (40 to 50 days). In addition, transcriptomic analysis revealed a nearly dose dependent effect, with greater immune activation and inflammatory response observed in high-dose infections than in low-dose infections. Interestingly, inoculation with 6 to 7 copies of RNA that did not result in productive infection was associated with a strong immune response, similar to that observed in the high-dose infections. IMPORTANCE We demonstrated that the EqHV dose of infection plays an important role for inducing immune responses, possibly linked to early clearance in high-dose and prolonged viremia in low-dose infections. In particular, pathways associated with innate and adaptive immune responses, as well as inflammatory responses, were more strongly upregulated in high-dose infections than in lower doses. Hence, inoculation with low doses may enable EqHV to evade strong immune responses in the early phase and therefore promote robust, long-lasting infection.

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Modelling the linkage between influenza infection and cardiovascular events via thrombosis.

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Modelling the linkage between influenza infection and cardiovascular events via thrombosis.

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