Humanigen Inc (HGENQ)

[DonDonDonDon]

Below are some quotes from the paper. We already knew GM-CSF inhibition was the key to stopping severe Covid and Covid death but it seems GM-CSF inhibition is also the key to preventing Long Covid as well. Tomorrow is going to be very green!

full pdf of paper

While our data show that a broad range of cytokines remain deregulated
long after infection, IL-1ß, IL-6 and TNF-a represented a triad that was associated with
PASC. Blood profiling and single-cell data from early infection indicated that these
cytokines are induced in COVID-19 lung pro-inflammatory macrophages creating a
feedback loop that may trigger their long-term activation.

Conclusion: We provide evidence for a long-lasting cytokine signature potentially underlying many of the clinical symptoms of PASC that may be driven by macrophage primed during acute infection. This study demonstrates how the combination of digital epidemiology with selective biobanking can rapidly generate hints towards disease mechanisms.

Gene set analysis covering transcripts of response genes to these cytokines suggested that the pro-inflammatory macrophage not only produced this cytokine triad, but also responded to it

Mining of this single-cell sequencing dataset for cytokine response pathways revealed that such macrophages may not only be primed in the lung to produce the cytokine triad, but may also respond to it. The nature of response genes involved suggested chronic cytokine exposure. Based on this data, one may speculate that acute pro-inflammatory reprogramming of long-lived lung macrophages or their precursors may result in a vicious circle of IL-1ß, IL-6 and TNF-a production that self maintains this cellular compartment. This hypothesis may be supported by recent evidence showing epigenetic reprogramming of the monocyte/macrophage compartment in COVID-19 that results in pathological inflammasome engagement in these cells.

IL-1ß, IL-6 and TNF-a are cytokines which are mainly secreted by monocytes and macrophages upon inflammatory stimuli. The myeloid compartment and especially lung macrophages are strongly deregulated in COVID-19 patients as evidenced by previously published single cell analyzes on lung tissue, bronchoalveolar lavage fluid (BALF) and blood from patients with acute COVID-19 (20,25). To explore the potential cellular sources of IL-1ß, IL-6 and TNF-a in acute COVID-19, we analyzed previously published single-cell transcriptomics datasets from lung tissue, peripheral blood and BALF of patients in acute infection20-22. This analysis confirmed that this triad of cytokines was specifically expressed by the myeloid/macrophage compartment in the lungs (Figure 4B), but not or to a lesser extent by the myeloid/monocyte compartment in blood of patients with acute COVID-19 (Supplementary Figure 3). In a next step, we looked in-depth into macrophage subpopulations from bronchoalveolar fluid of patients with acute COVID-19. This analysis showed that the production of IL-1ß, TNF-a and to a lesser extent that of IL-6 was concentrated in the pro-inflammatory subset of lung macrophages.

20. Zhao Y, Kilian C, Turner JE, et al. Clonal expansion and activation of tissue-resident memorylike Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients. Sci Immunol 2021; 6(56).