TY - JOUR
T1 - A MULTI-HIT MODEL OF LONG COVID PATHOPHYSIOLOGY
T2 - THE INTERACTION BETWEEN IMMUNE TRIGGERS AND NERVOUS SYSTEM SIGNALING
AU - Brock, Malcolm V
AU - Bosmans, Frank
N1 - © 2024 The American Clinical and Climatological Association.
PY - 2024
Y1 - 2024
N2 - Early in the pandemic, clinicians recognized an overlap between Long COVID symptoms and dysautonomia, suggesting autonomic nervous system (ANS) dysfunction. Our clinical experience at Johns Hopkins with primary dysautonomia suggested heritability of sympathetic dysfunction, manifesting primarily as hyperhidrosis and as other dysautonomia symptoms. Whole exome sequencing revealed mutations in genes regulating electrical signaling in the nervous system, thus providing a genetic basis for the sympathetic overdrive observed. We hypothesize that dysautonomia in Long COVID requires two molecular hits: a genetic vulnerability to prime the ANS and a SARS-CoV-2 infection, as an immune trigger, to further disrupt ANS function resulting in increased sympathetic activity. Indeed, Long COVID patients show signs of chronic inflammation and autoimmunity. We have translated this two-hit concept to the clinic using ion channel inhibitors to target genetic susceptibility and immunomodulators to treat inflammation. This multi-hit hypothesis shows promise for managing Long COVID and merits further study.
AB - Early in the pandemic, clinicians recognized an overlap between Long COVID symptoms and dysautonomia, suggesting autonomic nervous system (ANS) dysfunction. Our clinical experience at Johns Hopkins with primary dysautonomia suggested heritability of sympathetic dysfunction, manifesting primarily as hyperhidrosis and as other dysautonomia symptoms. Whole exome sequencing revealed mutations in genes regulating electrical signaling in the nervous system, thus providing a genetic basis for the sympathetic overdrive observed. We hypothesize that dysautonomia in Long COVID requires two molecular hits: a genetic vulnerability to prime the ANS and a SARS-CoV-2 infection, as an immune trigger, to further disrupt ANS function resulting in increased sympathetic activity. Indeed, Long COVID patients show signs of chronic inflammation and autoimmunity. We have translated this two-hit concept to the clinic using ion channel inhibitors to target genetic susceptibility and immunomodulators to treat inflammation. This multi-hit hypothesis shows promise for managing Long COVID and merits further study.
KW - Humans
KW - COVID-19/immunology
KW - Post-Acute COVID-19 Syndrome
KW - SARS-CoV-2/immunology
KW - Signal Transduction
KW - Genetic Predisposition to Disease
KW - Primary Dysautonomias/physiopathology
KW - Inflammation/immunology
M3 - Article
C2 - 39135572
VL - 134
SP - 149
EP - 164
JO - Transactions of the American Clinical and Climatological Association
JF - Transactions of the American Clinical and Climatological Association
SN - 0065-7778
ER -