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Published on: April 3, 2017
The Central Role of Macrophages in Long COVID Pathophysiology
Philip Mcmillan1, Anthony J Turner2, Bruce D Uhal3
1McMillan Research Ltd., 71-75 Shelton Street, Covent Garden, London WC2H 9JQ, UK.
Insights
Long COVID, or Postacute Sequelae of COVID, may stem from persistent immune dysregulation and chronic macrophage activation. This sustained inflammatory response, driven by factors like spike protein and epigenetic changes, offers new therapeutic targets.
Area of Science:
- Immunology
- Virology
- Pathophysiology
Background:
- Postacute Sequelae of COVID (PASC), or Long COVID, presents diverse symptoms.
- Existing explanations for Long COVID are fragmented.
- A unifying hypothesis is needed to understand Long COVID's underlying mechanisms.
Purpose of the Study:
- To propose a unifying hypothesis for Postacute Sequelae of COVID (PASC).
- To identify chronic macrophage activation as the core pathophysiology of Long COVID.
- To elucidate the drivers of sustained immune response in Long COVID.
Main Methods:
- Review of existing literature on PASC and viral syndromes.
- Hypothesizing a central role for immune dysregulation.
- Integrating evidence of persistent viral elements and epigenetic modifications.
Main Results:
- Long COVID is hypothesized as a disorder of persistent immune dysregulation.
- Chronic macrophage activation is proposed as the fundamental pathophysiology.
- Sustained innate immune response is driven by persistent spike protein, epigenetic imprinting, and viral reservoirs.
Conclusions:
- Macrophage activation is central to Long COVID pathology.
- This framework allows for personalized risk assessment.
- Targeted interventions and therapeutic recalibration are suggested for Long COVID.
Abstract:
This review article attempts to provide a unifying hypothesis to explain the myriad of symptoms and predispositions underlying the development of PASC (Postacute Sequelae of COVID), often referred to as Long COVID. The hypothesis described here proposes that Long COVID is best understood as a disorder of persistent immune dysregulation, with chronic macrophage activation representing the fundamental underlying pathophysiology. Unlike transient post-viral syndromes, Long COVID involves a sustained innate immune response, particularly within monocyte-derived macrophages, driven by persistent spike protein (peripherally in MAIT cells and centrally in Microglial cells), epigenetic imprinting, and gut-related viral reservoirs. These macrophages are not merely activated temporarily but also become epigenetically "trained" into a prolonged inflammatory state, as demonstrated by enduring histone acetylation markers such as H3K27acDNA Reprogramming. It is proposed that recognizing macrophage activation as the central axis of Long COVID pathology offers a framework for personalized risk assessment, targeted intervention, and therapeutic recalibration.
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