A CURIOSITY-DRIVEN SPECULATION IDENTIFYING A PARTICULAR INFLAMMATORY PROTEIN COMMON TO ALL OF THE DISPARATE COVID-19 COMPLICATIONS, AND POSSIBLE THERAPEUTICS
© William Alford 2020
* HMGB1 is a nuclear protein found in most cells and is primarily involved with transcription control, DNA repair, and response to infection and inflammation. HMGB1 rapidly moves from the nucleus into the cytoplasm and circulation during inflammation.
* When HMGB1 becomes extracellular, it can function as an inflammatory mediator, or a cytokine inflammation promoter, and is a primary component of the sepsis and cytokine storm cascades.
* Several inflammatory conditions can develop a positive feedback loop of HMGB1 and lead to a life-threatening stage in the pathological progression.
* HMGB1 release, unlike TNF-IL-1, and other pro-inflammatory cytokines, can be delayed by days before it is detected and becomes pathological, and can maintain a subclinical smoldering inflammatory state for years. Often patients are discharged before it emerges. The later stage emergence of HMGB1 could be associated with the dangerous “second week” of COVID-19 when patients have somewhat recovered only to quickly and suddenly have the illness re-emerge and become life threatening.
* HMGB1 is implicated in some way in most of the disparate and puzzling symptoms of the COVID-10 illness, such as age and gender differences, obesity, various organ involvement including eye, heart, gut, and lung, and systemic coagulation.
* Many existing FDA approved drugs and OTC compounds inhibit the release of HMGB1 and may be therapeutic for COVID-19 if repurposed.
News accounts continue to reveal new puzzling and disparate complications of COVID-19 that have been difficult to explain, and the evidence here will point to one rogue protein that is common to them all, and may suggest therapeutic options, many with repurposed existing safe medications and OTC compounds.
On February 27, 2020, I posted a link to the West Nile Virus (WNV) Survivors Facebook group for an article in Neuroscience News and Research about an investigation at the Karolinska Institutet of Sweden that had associated the residual cognitive impairment following Intensive Care (IC) to a particular pro-inflammatory protein. Long-term cognitive impairment is also a hallmark of WN Encephalitis and this study seemed important. The reasons for this impairment following IC have previously been unknown. The study followed 100 intensive care patients and found that they had elevated levels of the pro-inflammatory protein, High mobility group box 1 (HMGB1), as long as six months after discharge. HMGB1 is an important nuclear protein that organizes the DNA and regulates transcription. When released by glia and neurons it is a key initiator of neuroinflammation that acts both inside and outside of cells. Inside cells it is part of a complex that detects pathogens or injury stressors and activates pro-inflammatory cytokines, particularly IL-1β and IL-18. It can also be released from cells and then acts as a chemoattractant cytokine and can persist and contribute to development of autoimmune disorders, or drive inflammation further and thereby worsen symptoms. The Karolinska group hypothesized that even after quite a long time following discharge from hospital, there was some ongoing inflammation in IC patients supported by the persistent HMGB1 finding. This parallelled the long-term neurological dysfunction following WNV and so I began looking into the commonality of HMGB1 between the two groups.
The Neuroscience News and Research article was based on an original paper in the form of a letter to the editor of the journal Intensive Care Med (2020), that led to a conclusion that the proinflammatory properties of extracellular HMGB1 associated with the impairment merited further investigation for ameliorating the cognitive dysfunction, but did not suggest a therapy (Brück E, et al) . However it did give a reference to a prior publication that had looked at the issues of long-term nonresolving inflammation following survival of sepsis, a syndrome that is the leading cause of death of patients in hospital, noting the paucity of therapeutics, and particularly that the only FDA approved therapy had been pulled from the market (activated protein C, pulled in 2011) leaving only supportive and often ineffective treatment (Chavan, SS, et al). This ‘nonresolving inflammation’ has found interest for targeting certain molecules for therapy, and because of the fact that monoclonal anti-tumor necrosis factor (anti-TNF) antibodies have prevented fatal septic shock in primates, numerous papers have been published appreciating the role that cytokines play in organ damage during sepsis. Any anti-TNF therapeutic is limited by the fact that some cytokine production is only very early in the course of the infection and by the time of diagnosis, patients no longer have high TNF levels, but do have elevated levels of HMGB1. The group studied mice and found that administering HMGB1 to healthy mice produced cognitive impairment and that administering monoclonal antibodies to HMGB1 improved cognitive function. Given the recent better understanding of the interactions between the innate immune system of the brain and neurological dysfunctions affecting cognition, the brains of the mice were examined and dendritic spines of hippocampal neurons were found to be normal at two weeks following sepsis, but significant loss was observed over a four month period following onset, indicating that the degeneration progressed and was not part of the acute process of onset. The neutralizing antibodies gave a great protection against this dendritic spine loss which was associated with memory function.
HMGB1 may contribute to many inflammatory diseases where it regulates intracellular cascades influencing immune cell functions, including chemotaxis and immune modulation (Martinotti S). As reported above, HMGB1 is now appreciated to be a late mediator of sepsis in animal models and when sepsis is induced by endotoxin exposure, administering anti-HMGB1 antibodies before or after endotoxin exposure protects against lethality. Administration of HMGB1 itself was lethal. So, HMGB1 emerges as a primary player in various inflammatory processes and the role in persistent and even delayed degeneration is particularly important. In the following account we shall see that it is involved in a great many illnesses.
Figure 1. The association of late HMGB1 release and death following endotoxin exposure
Reprinted with permission of the American Thoracic Society.
Copyright © 2020 American Thoracic Society. All rights reserved.
Haichao Wang, Huan Yang, ChristopherJ. Czura, Andrew E. Sama,
and Kevin J. Tracey/2001/HMGB1 as a Late Mediator of Lethal
Systemic Inflammation/American Journal of Respiratory and Critical
Care Medicine/Vol 164/ pp 1768–1773. The American Journal of
Respiratory and Critical Care Medicine is an official journal of the
American Thoracic Society.
A role for HMGB1 in neurological disorders was suggested by other research showing that cytokines may stimulate release of HMGB1 from glial cells of the posterior pituitary called pituicytes, as well as astrocytes. HMGB1 has also been found to be highly expressed in mouse neurons and astrocytes and can be released during brain insults contributing to neuroinflammation and brain damage. Leis reported the resurrection of a severely neurologically dysfunctional patient after the appearance of neutralizing antibodies following West Nile Virus infection, when given methylprednisolone. The association of disease severity with an increase of various proinflammatory molecules, including glial protein 100B, HMGB1, and osteopontin was recognized and appreciated to indicate a persistent post-infectious neuroinflammatory response (Leis A). Wang had investigated the role of HMGB1 in viral disease in a paper published in Viral Immunology in 2005. In his study in murine models of endotoxemia and sepsis, serum HMGB1 was first detected at 8 hours post challenge, plateaued at 16 to 32 hr and remained elevated for around 72 hours (Wang, et al). Again, its release paralleled animal lethality from sepsis much later than other proinflammatory cytokines. Figure 1 in a 2012 Molecular Medicine paper shows HMGB1 from murine models of sepsis survivors remaining very elevated at 4 weeks and only declining to near baseline at 2 months (Chavan SS). HMGB1 can be actively released from innate immune cells or passively by necrotic or damaged cells and induce an inflammatory response, but not from apoptotic cells, which self-destruct without causing an inflammatory response (Scaffidi P) (a general consensus, although this has been challenged if cell type is considered (Bell C)). This distinction will be important when we examine such features of COVID-19 pneumonia and associations such as gender reponses. When HMGB1 was appraised as a target for treating sepsis, it was discovered that green tea could restrict HMGB1 release and rescue mice from lethal sepsis even when given as late as 24 hours post sepsis onset (Wang H). Green tea is a cultural norm in many Asian countries and contains many biologically active compounds, with epigallocatechin