Role of the lung/gut/bone marrow axis and of the microbiota during influenza A virus infection – ACROBAT

Severe bacterial (pneumococcal) infections are commonly associated with influenza and are significant contributors to the excess morbidity and mortality of influenza. Today’s treatments of secondary bacterial infections are still not effective enough. Moreover, antibiotic resistance is a major issue. Hence, there is an urgent need for novel therapies. Defective innate immunity is one of the key factors favoring susceptibility to bacterial superinfection. The novelty of our project is to postulate that gut disorders during severe influenza contributes to altered pulmonary host defenses against secondary infection. This hypothesis stems from solid and convergent data (mouse) showing that influenza triggers intestinal inflammation and alters the composition and the metabolic activity of the gut microbiota. These changes are severe enough to confer susceptibility to bacterial infection as our preliminary data (based on fecal transfer experiments) show. Our project has the ambition to decipher mechanisms involved in gut-lung crosstalk during influenza in mice and in primates and to restore pulmonary host defenses via the manipulation of intestinal microbiota. Our motto is how to describe, understand and manipulate the gut physiology during influenza in order to favour lung defenses. We will proceed in four steps.

(i) We will gain further insights on gut disorders, which include inflammation, barrier function and microbiota composition/metabolism, during severe influenza by combining two experimental models: the mouse and the nonhuman primate system cynomolgus macaque, a relevant model to study influenza outcomes. We will combine targeted analyses, unbiased (omics) approaches and multi-parameter correlation analysis to identify mechanisms leading to gut disorders and to discover predictive markers of superinfection post-influenza.

(ii) We will determine the reciprocal links between lung inflammation due to influenza, intestinal disorders and disturbance of myelopoiesis. To correlate the severity of lung inflammation with gut disorders and myelopoiesis, we will lower pneumonia by inflammatory cell depletion. We will also investigate whether loss of appetite, which is an important hallmark of severe influenza, infers on disease outcomes. In these two settings (diminished pneumonia and reduced food intake), gut composition/fermentation activity, intestinal homeostasis/barrier functions and myelopoiesis will be studied.

(iii) We will investigate how changes in gut microbiota composition/metabolic activity during influenza shape lung immunity. To do so, influenza-experienced microbiota will be transferred both in recipient germ-free and in conventional animals (after antibiotic-treatment). In colonized mice, we will study myelopoiesis and pulmonary immune cell functions. We aim to identify molecular and cellular mechanisms leading to altered anti-pneumococcal responses in transplanted animals.

(iv) We will compare the efficiency of different strategies to boost pulmonary host defenses during severe influenza (mouse). We will use antibodies to reduce inflammation, regimen rich in fermentable fibers and probiotics to restore the disturbance of gut microbiota and to boost intestinal microbiota activity. In each protocol, we will establish the bacterial profiling, myelopoiesis and pulmonary host defense against Streptococcus pneumoniae.

This program will provide novel information on lung/gut interplays and might identify susceptibility factors to post-influenza bacterial superinfections. It might also lead to novel interventional approaches for the control of these superinfections.