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“You see, we have a kind of allergy to the past; it’s our national disease, and the very assurance with which you insist that the past is within the present is likely to seem quite repellent, even offensive, to these new readers.”
Early in the COVID-19 pandemic, the role of ‘cytokine storm’ in patients with severe course was raised. Indeed, this triggered multiple investigations centred around calming excessive inflammation with pharmacotherapies such as corticosteroids and interleukin-6 inhibition, among others. Not surprisingly, the editors of the Journal of the American Medical Association reported that over 9 months they received over 10,000 submissions on the topic of COVID-19 – many suggesting or observing novel therapies.
Even before the hydroxychloroquine debacle, intensivists were and are, appropriately, skeptical of sepsis immunomodulation. This is probably rooted in the multitudinous therapeutic failures in this space – ranging from heparin to anti-thrombin III, anti-TNF alpha therapies to non-steroidal anti-inflammatories and, of course, activated protein C. These flops seemingly, subconsciously, cemented themselves into the sepsis storage sulci of ICU practitioners – hardening clinicians to new tactics, pre-judging almost all new therapies as ‘doomed-to-fail.’
Though, with the positive results observed with corticosteroids in COVID-19, might we open the door, slightly, and allow in a small cleft of therapeutic light to illuminate our hardened convictions? Could the immune system still present itself as a target in COVID-19 and sepsis in general? With this, we turn our lonely eyes to X-box binding protein [XBP].
X-box Binding Protein
X-box binding protein [XBP] is a transcription factor that triggers the expression of pro-inflammatory cytokines such as tumour necrosis factor alpha [TNF-a], interleukin-6 [IL-6] and others. But if you recall the ‘central dogma’ of molecular biology, XBP generation, itself, is subject to regulation. This can occur via regulatory splicing of XBP messenger RNA [mRNA] by another protein, inositol-requiring enzyme 1 alpha [IRE1]. IRE1 is a ‘stress sensor’ and resides within the membrane of the endoplasmic reticulum. IRE1 may be thought of as a gate-keeper of XBP – when IRE1 is activated, as an endonuclease, it splices XBP mRNA which is then translated into a functional transcription factor.
So, to recap, the stress sensor IRE1 – living in the endoplasmic reticulum – splices XBP mRNA thereby allowing it to act as a template for generating XBP, a transcription factor that accentuates pro-inflammatory cytokines. What then activates IRE1? IRE1 endonuclease is triggered by pathogen-associated molecular patterns – especially lipopolysaccharide [LPS] but also by viral epitopes, for example by influenza. Accordingly, the pro-inflammatory cascade presents itself from exposure to pathogens, to expression of IL-6 and TNF-alpha via activation of IRE1 and the transcription factor XBP. This pathway is well-described in human dendritic cells and bone-marrow derived macrophages. This is anticipated as these ubiquitous cells are particularly important interfaces between innate and adaptive immunity.
Given the pathway above, it is rational to wonder if there are any specific inhibitors or mechanisms to break the throughput from pathogen to cytokine elaboration? One molecular lever to pull is to activate the sigma-1 receptor [S1R], an endoplasmic membrane chaperone protein that associates with and inhibits IRE1. Thus, S1R agonism inhibits XBP mRNA splicing which blunts expression of inflammatory cytokines. This pathway was originally characterized in the central nervous system as many neuroactive compounds – including some psychedelics – have been shown to modulate immune activity in microglia. Multiple investigations had explored these machinations for modulation of various neurodegenerative, psychiatric and cerebrovascular insults. More simply, pharmacological activation of SIR blunts IRE1 which attenuates XBP elaboration and, accordingly, down-regulates pro-inflammatory cytokines.
One relatively well-known, oral S1R agonist is fluvoxamine – the selective serotonin uptake inhibitor – initially used to treat major depression and obsessive-compulsive disorder. If the aforementioned signalling pathways play clinically-important contributions to infectious inflammation, might fluvoxamine soothe the septic cytokine surge?
Fluvoxamine in murine sepsis
In 2019 Rosen and colleagues published a deceptively influential paper in Science Translational Medicine. Given what was known about S1R agonism and neuro-inflammation, the authors wondered whether the oral S1R agonist fluvoxamine could attenuate the septic response in a murine model of sepsis and if fluvoxamine could diminish the inflammatory response of human peripheral blood, in vitro. Their data expanded upon that of Szabo and colleagues who investigated the effects of hallucinogen indole alkaloids [also S1R agonists] on human, monocyte-derived dendritic cells that were inflamed by incubation with bacterial and viral [i.e., influenza] pathogens.
Both groups showed remarkably consistent results in that S1R agonism significantly halted pro-inflammatory response and, per Szabo et al., enhanced the anti-inflammatory response. Further, in a 4-arm trial [12 mice per arm] of placebo versus fluvoxamine alone versus ceftriaxone alone versus fluvoxamine plus ceftriaxone for treating fecal slurry septicemia, Rosen and colleagues found that fluvoxamine had a similar mortality benefit as compared to ceftriaxone! Fairly convincingly, the authors showed that this mortality benefit was associated with the anti-inflammatory cytokine profile compelled by S1R agonism and, accordingly, IRE1 and XBP inhibition. Importantly, in both lipopolysaccharide challenge and fecal-induced peritonitis, fluvoxamine was administered relatively quickly [i.e., within 30 - 90 minutes after insult]. Lastly, the authors also demonstrated that in vitro inflammation of peripheral human blood was also reduced by treatment with fluvoxamine.
Given that fluvoxamine is inexpensive and FDA-approved, its potential for immediate study in sepsis and – more pressingly – COVID-19 was apparent to Dr. Angela Reiersen, a child psychiatrist at Washington University, early in the North American phase of the pandemic.