The Effects of Preceding LPS Administration on the Fluenz-induced Immune Response

Overview

To evaluate the bacterial-viral interactions between LPS and Fluenz as a model for sepsis (bacterial) and Influenza (viral) infections which are common and associated with high mortality rates in the ICU. To understand these interactions is important for the development of preventive and therapeutic interventions.

The Influenza virus is known for its severe course of infection and systemic effects, associated with high mortality rates. Recent work has shown that influenza promotes susceptibility for secondary bacterial infections, thereby worsening the prognosis. While it has become clear that bacterial infections induce an immunosuppressed state in which the immune response against viral infections is attenuated1, it is unknown how a bacterial infection, such as in sepsis, influences the susceptibility and immune response to influenza. The sepsis-induced immunosuppressive state, called "immunoparalysis", may be a major contributor to this increased vulnerability. Because of the high mortality rates of both sepsis and influenza, it is of main importance to understand this interaction for the development of putative preventive and therapeutic interventions in ICU patients. Human endotoxemia represents a model of systemic inflammation, mimicking bacterial sepsis and subsequent development of immunoparalysis. The live, attenuated, quadrivalent influenza vaccine "Fluenz™" is registered in the European Union and can be used as a surrogate for an actual influenza infection. In this study, we want to investigate the effects of an endotoxemia challenge on the Fluenz™-induced inflammatory response to present unique in vivo data on mechanistic interactions of systemic LPS followed by mucosal Fluenz™, thereby providing clues regarding the increased vulnerability towards viral infections in septic patients and open up new avenues to investigate therapeutic measures to prevent this. Furthermore, it provides important implications regarding the safety and efficacy of the vaccine in (post)septic or immunocompromised patients. Objective: Our primary objective is to investigate the effects of endotoxin-induced systemic inflammation and subsequent development of endotoxin tolerance on the inflammatory response following Fluenz administration in vivo. To evaluate whether these effects involve local and/or systemic inflammation, symptoms, temperature and peak expiratory flow will be measured. Next, local inflammatory parameters are measured in nasal wash and systemic inflammatory parameters are measured in blood. Furthermore, we want to evaluate whether preceding endotoxemia influences the viral shedding of influenza in nasal wash. Also, changes in the mucosal microbiome, transcriptome and metabolome will be assessed. Finally, mitochondrial function and mental strength during human endotoxemia will be assessed.

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