After the virus has cleared—Can preclinical models be employed for Long COVID research?

Abstract

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.

Migraine inhibitor olcegepant reduces weight loss and IL-6 release in SARS-CoV-2 infected older mice with neurological signs

“…In conclusion, in addition to the acute effects studied here, antagonizing CGRP signaling may be therapeutic against long COVID, as long COVID patients also show higher IL-6 plasma levels [37]. As long COVID has been demonstrated in mouse models [38], future plans include 15 investigating if antagonizing CGRP signaling in preclinical models can mitigate associated neurological symptoms of long COVID [39]. SARS-CoV-2 in the presence of placebo or CGRP-receptor antagonist olcegepant slow-release pellets (olcegepant, BIBN4096, Tocris; 2 mg/kg/day/SQ) or mice lacking CGRP were infected with the same virus; animals were then assessed for motion-induced nausea (dizziness) at 3 days after viral infection (dpi).…”

“…In conclusion, in addition to the acute effects studied here, antagonizing CGRP signaling may be therapeutic against long COVID, as long COVID patients also show higher IL-6 plasma levels [37]. As long COVID has been demonstrated in mouse models [38], future plans include investigating if antagonizing CGRP signaling in preclinical models can mitigate associated neurological symptoms of long COVID [39].…”

Role of the microbiota-gut-brain axis in postacute COVID syndrome

“…For example, mice engineered to express the human receptor for the COVID virus, angiotensin-converting enzyme 2 (hACE2), have allowed the study of COVID and its sequelae following both acute ( 21 ) and chronic ( 22 ) infection. In fact, multiple preclinical animal models, including those in mice, ferrets, hamsters, and nonhuman primates, exist that can develop postinfectious PASC-like disease ( 23 ) and have the potential to identify MGB axis deficits induced by acute infection that may contribute to chronic symptoms in patients.…”

Emerging Landscape of Preclinical Models for Studying COVID-19 Neurologic Diseases

“…This may be important in studying long COVID, as young patients who have only had mild symptoms during the acute infection phase can still develop long-COVID symptoms that impact their quality of life . For a more in-depth review of the implications of animal studies on studying the neural impact of long-COVID, Jansen et al provide a thorough overview and discussion …”

“…96 For a more indepth review of the implications of animal studies on studying the neural impact of long-COVID, Jansen et al provide a thorough overview and discussion. 97 2.3.1.2. Hamster.…”