Meningococcal disease refers to any illness caused by bacteria called Neisseria meningitidis. Meningococcal septicemia which is an infection of the bloodstream remains a serious, life threatening illnesses. For every 100 people who get sick in Western Europe, 7 – 10 will die, even if optimal treatment is given. Lipopolysaccharide (LPS) concentrations of up to 3,000 endotoxin units per milliliter of plasma are closely correlated with the exceptionally high levels of meningococcal DNA in the circulatory and perivascular region. The dramatic features of this illness may be explained by the fact that individuals with fulminant meningococcal septicemia have endotoxin levels that are noticeably greater than those seen in patients with sepsis brought on by other gram-negative bacteria. Analyses of postmortem materials and, more recently, blood and tissue samples have been used largely to figure out the fundamental pathogenesis of meningococcal septic shock and multiple organ failure. The molecular intricacy involving thousands of genes has become clear by employing transcriptomic approaches to assess the changes in gene expression in human immune cells, in vitro tests, and tissues from the lungs, heart, kidneys, liver, and spleen of deceased meningococcal shock patients. A more complete understanding of fulminant meningococcal sepsis has been hampered in the past by the lack of an appropriate animal model. To understand the pathophysiology of meningococcal sepsis a large animal porcine model simulating fulminant human meningococcal sepsis and multiple organ failure has been recently developed. This porcine model can also be a valuable tool to test new drug therapy.
In a new study published in the journal Frontiers in Cellular and Infection Microbiology, Oslo University Hospital researchers: Dr. Berit Brusletto, Dr. Bernt Hellerud, Dr. Ole Olstad, Dr. Reidun Øvstebø, and Professor Petter Brandtzaeg investigated the similar and different changes in the human transcriptomes acquired from meningococcal patients with fatal sepsis and multiple organ dysfunction with the transcriptomes from the porcine model of meningococcal shock and multiple organ dysfunction. The outcomes of their porcine model, which simulated the exponential development of N. meningitidis in patients with meningococcal septic shock, imply that the transcriptome alterations seen in the patients’ major organs are mirrored in the organs of the porcine model.
The research team looked at how N. meningitidis affects the heart, lungs, kidneys, liver, and spleen in addition to other organ systems. The activation and subsequent suppression of the coagulation systems and the overexpression of the complement system in the blood and major organs were all observed in the porcinis. The major cytokines, chemokines, and other proteins associated with inflammation were compared for changed gene expressions at the mRNA level in plasma and organ tissue. The authors simulated the development of meningococci in the blood and major organs using the porcine model and doubling dosages of the bacteria administered intravenously every 30 min. equal to the growth velocity measured in meningococcal shock patients. They consistently observed the animals during the 4-hour experiment and got enough blood samples for the longitudinal observation of various mediators. Researchers were able to get autopsy tissue samples for additional research right away after the animals were euthanized.
According to the authors the porcine model closely mirrors the alterations observed in patients when they compare the projected Z-scores of biofunctions, canonical pathways, and upstream regulators of the organs in the porcine model with the genes elevated in humans. The downregulation of organ death, morbidity, and mortality in patients and porcinis suggest that the regulation of the biofunctions is quite similar. Of the 18 canonical pathways that met the selection criteria and were present in the lung samples from the patients, 15 were elevated and 2 were downregulated in both humans and porcinis. One particular pathway (NF-kB signaling) was only elevated in the porcine model and downregulated in patients. Their findings imply that a fulminant meningococcal sepsis-simulating porcine model is indeed a qualified model to study the pathophysiology of this deadly illness in people. In comparison to human organs, the porcine organs often had greater measured gene transcription levels. The higher levels may be connected to larger bacterial populations at the start of the experiment which lasted 4 hours, as well as to interspecies variations in immune responses and susceptibility to bacterial antigens, particularly LPS. They noticed that the IL-17 signaling pathway, which appears to play a significant role in the pathophysiology of sepsis, was one of the key anticipated canonical pathways in both models. Moreover, a few important proteins were quantifiable in every organ. Notably, certain cytokine levels in the organs of meningococcal septic shock patients were greater than in the porcine experimental model.
In summary, Dr. Berit Brusletto and colleagues showed that a porcine model of the disease closely mimics the immune activation detected at the transcriptome level in the large organs of patients with fulminant meningococcal sepsis. This suggests that a redesigned porcine model of this infection can replicate crucial immunological systems and serve as a useful tool for further research into the inflammatory features of the illness and potential therapeutic possibilities.
Brusletto BS, Hellerud BC, Olstad OK, Øvstebø R, Brandtzaeg P. Transcriptomic changes in the large organs in lethal meningococcal shock is reflected in a porcine shock model. Frontiers in cellular and infection microbiology. 2022 :1087.