A recent publication demonstrates the close connection between immune dysfunction in T cells and neutrophils that can be targeted by interfering with microbial sequestration in the spleen or by eliminating circulating chromatin. The presence of G-CSF and circulating histones in many conditions suggests that they may be critical drivers of immune dysfunction that could be targeted therapeutically. A study was published on Aug. 9 in Nature. It is also co-authored by Prof Sascha David, Dr Klaus Stahl and Dr Christian Bode, who will take part in the future of Santersus as Principle Investigators (PIs) of our upcoming clinical trial of NucleoCapture in critically unwell patients with sepsis in the ICU.
The authors showed that by controlling fungi and bacteria captured by splenic macrophages, neutrophil-derived myeloperoxidase attenuates sepsis by suppressing histone release. In systemic candidiasis, microbial capture via the phagocytic receptor SIGNR1 neutralizes myeloperoxidase by facilitating marginal zone infiltration and T cell death-dependent histone release. Histones and hyphae induce cytokines in adjacent CD169 macrophages including G-CSF that selectively depletes mature Ly6G(high) neutrophils by shortening their lifespan in favour of immature Ly6G(low) neutrophils with a defective oxidative burst. In sepsis patient plasma, these mediators shorten mature neutrophil lifespan and correlate with neutrophil mortality markers. Consequently, high G-CSF levels and neutrophil lifespan shortening activity are associated with sepsis patient mortality. Hence, by exploiting phagocytic receptors, pathogens degrade innate and adaptive immunity through the detrimental impact of downstream effectors on neutrophil lifespan. Hyperinflammation and immune dysfunction are key drivers of immunopathology in sepsis.
Hence, this important study reveals how microbial exploitation of phagocytic receptors is linked to triggering of sepsis and the immune cell mediated reduction in neutrophil life span. The explored pathway creates a novel therapeutic opportunity for NucleoCapture, which would eliminate circulating chromatin and aid with immune dysfunction without compromising the defensive function of neutrophils.