Abdominal symptoms of invasive meningococcal disease are associated with the induction of plasminogen activator inhibitor in omental adipocytes

Abstract

Abdominal symptoms are increasingly reported in invasive meningococcal disease (IMD), but the underlying mechanisms remain unclear. We aimed to explore the pathophysiology of these presentations using an animal model. We utilized a collection of 20 meningococcal isolates that were either associated or not associated with abdominal presentations, which were injected intraperitoneally into transgenic mice expressing human transferrin. We employed histological examination, RNA sequencing (RNAseq) transcriptomic analysis, and reverse transcriptase real-time PCR to analyze tissue preparations of the mices omentum. The 20 tested isolates induced similar levels of bacteremia in mice. However, isolates associated with abdominal presentations (mainly serogroup W isolates of clonal complex 11) caused thrombotic lesions in the blood vessels of the omentum, and they also induced a higher inflammatory response in the omentum with elevated levels of IL-6, TNF-alpha, and KC. Furthermore, these isolates induced higher expression of several genes, some of which are involved in coagulopathy, such as plasminogen activator inhibitor 1 (PAI-1). We also demonstrated that the PAI-1 encoding gene is overexpressed in adipocyte cells of the omentum. Lipopolysaccharide from the isolates associated with abdominal presentations, instead of whole bacteria, induced similar pathological findings. During IMD, thrombosis formation in the omentums blood vessels is associated with a local induction of an inflammatory response and overexpression of the plasminogen activator inhibitor 1 encoding gene. These lesions can lead to thrombosis and hypoperfusion in the omentum, resulting in clinical abdominal presentations Author summaryNeisseria meningitidis, commonly known as meningococci, is a bacterium that is transmitted directly from person to person through respiratory droplets. This bacterium causes invasive meningococcal disease (IMD), which can manifest in various symptoms beyond just meningitis. Notably, abdominal presentations, including abdominal pain and diarrhea, are increasingly being reported. The aim of our investigation was to elucidate the underlying mechanism of these abdominal symptoms. To achieve this, we employed several experimental approaches and provided evidence that these symptoms are caused by the coagulation (clotting) of blood in the microvessels that surround the abdominal organs, such as the intestine. This clotting is triggered by the bacteriums induction of a human enzyme that promotes coagulation. Notably, this is the first study to explore a mechanism underlying an extra-meningeal clinical form of N. meningitidis infection. The enzyme responsible for this coagulation, plasminogen activator inhibitor 1, is a potential target for modulating the host response to IMD. Our findings have significant implications for the understanding of meningococcal pathophysiology and reveal additional potential targets for treatment.