Research initiative to aid in healthy recovery from Long-COVID with ‘reset’ of Viral-induced Human Metabolic Reprogramming/Dysregulation
Human Metabolic Research & Development Organization (HMRDO)
The global pandemic Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Corona virus -2 (SARS CoV-2), has led to a dramatic loss of human life worldwide and overburdened the healthcare systems in many countries. Although most recover, some patients continue to experience persistent symptoms, a condition known as Long-COVID, a viral-induced human metabolic reprogram/ dysregulation (HMR/D). According to the World Health Organization (WHO) guidelines, Long-COVID is defined as:
"Post COVID-19 condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction but also others and have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time."
Due to diverse clinical manifestation of HMR/D in Long-COVID, reliance on self-reported symptoms, and a lack of diagnostic tests and consensus definition, several patients struggle to obtain a definitive diagnosis. Unfortunately, the effects of viral-induced HMR/D not only impacts quality of life (QOL) of patients but potentially contributes to a decline in life expectancy. Therefore, restoring or resetting the functional status of viral-induced HMR/D in Long COVID patients is a global health priority. Bringing the public awareness about disabilities associated with Long-COVID, alongside research and development of accurate diagnostic assays, effective intervention protocols, and precision nutritional regimens are need-of-the-hour to reset or resolve viral-induced HMR/D in Long-COVID recovery. Our global mission is bringing together a global team of multi-disciplinary scientific experts and health professionals to collectively brainstorm and develop effective strategies to combat the post-COVID ‘new onset’ metabolic syndrome – the viral-induced HMR/D, an ongoing global health crisis.
Coronavirus Disease (COVID-19) Pandemic
The COVID-19 pandemic is a global viral outbreak of an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). First detected in China in December 2019, with the coronavirus spreading rapidly to other countries across the world, prompted the WHO to declare this outbreak as a pandemic on March 11, 2020. The SARS-CoV-2 viral-induced human metabolic reprogramming/ dysregulation (HMR/D), also known as the ‘Long-COVID’, has emerged as a novel clinical condition in COVID-19 survivors or recoverees, with lingering symptoms (or develop new ones), which fail to return to their baseline health.
Thus, the pandemic has progressed into a more complex global health crisis with unprecedented social and economic disruption around the world. As of 2024, COVID-19 still continues to transmit among populations and experts remain uncertain on the pandemic status!
From the WHO COVID-19 Dashboard (June, 2024)
776+
Million
CASES
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7.1+
Million
DEATHS
5.5+
Billion
VACCINATIONS
What is viral-induced HMR/D?
LIFE is a highly organized genetic-program and a chemical processing thermo-dynamic system that self-sustains its operation by breaking chemical bonds (catabolism) to release and capture free energy to form complex macro-molecules (anabolism) for specific structure-function (metabolism) in a lipid-based envelope, known as the cell. Viruses are non-living enveloped chemical particles that infect almost every species and are the most abundant genomic (DNA or RNA) entities on the planet.
SARS-CoV-2, the newly emerged coronavirus has a unique genomic (29.9-kb RNA) ability to insert and ‘reprogram’ a mega-fold larger size human DNA (3.1-Mb) and its cellular metabolic machinery to prime, alter, and redirect host macro-molecules to favor (support) its own life cycle. The SARS-CoV-2 genome interacts with thousands of human metabolites in a specific manner to facilitate its infectious process. The virus particle hijacks vital human factors for its cell surface binding, host invasion, and viral RNA integration with human DNA. The SARS‐CoV‐2-mediated genomic ‘reprogramming’ of human DNA and its specific hijacking of host cellular factors cumulatively results in metabolic ‘dysregulation’ in the body. Ultimately, SARS-CoV-2 reprograms and dysregulates several host cellular pathways that involve metabolism, bioenergetics, iron-redox signaling, and immunity – collectively termed as viral-induced human metabolic reprogramming/ dysregulation (HMR/D). Genomic and meta-genomic data revealed that co-evolution between viral and cellular genomes involve frequent horizontal gene transfer(s) and occasional co-option of novel functions over evolutionary time, the viral-induced HMR/D - the post-acute sequelae of COVID-19 (PASC) or Long-COVID, is one such prominent example.
COVID-19: An acute onset of viral-induced HMR/D
Symptomatic progression of COVID-19 requires that a genetically competent SARS-CoV-2 viral pathogen i) infects a susceptible host via specific cell surface receptors (CSRs) invades and internalizes into the cell utilizing host membrane proteases, ii) induces HMR/D to ensure ready access to an active host cell metabolic machinery for an uninterrupted viral replication, iii) inactivates innate host defense to evade viral elimination, and iv) exits the infected host cell and repeats viral propagation cycle for its exponential growth and transmission.
During the infection cycle, SARS-CoV-2 hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2 and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases, TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL) for fuso-genic release of its viral genome. The viral-induced HMR/D results in FIVE possible infectious outcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acute COVID-19 condition could manifest into THREE clinical phases: Phase-1: Hypoxia/hypoxemia ('Warburg' effect), Phase-II: Hyper-ferritinemia (‘cytokine storm’), and Phase-III: Thromboembolism (coagulopathy).
Long COVID or PASC: A chronic clinical state of viral-induced HMR/D
The WHO estimates that after recovery from an acute phase of SARS-CoV-2 infection, about 25 to 75% of such population experience persistent or new-onset symptoms for extended period of time referred to as ‘post-acute sequalae of COVID’ (PASC) or Long COVID. Transition of post-COVID patients (after recovery from acute SARS-CoV-2 infection) to a virus-free disease state with lingering, persistent exacerbated, or new clinical manifestations lasting for weeks to months, has emerged as serious global health crisis – PASC, a virus-induced HMR/D. PASC affects asymptomatic, mild symptomatic or self-quarantined (at home) individuals infected with SARS-CoV-2, as well as moderately to severely inflicted COVID-19 patients that required hospitalization and/or intensive care. The incidence of PASC is estimated at 10–30% of non-hospitalized cases, 50–70% of hospitalized cases, and 10–12% of vaccinated cases. PASC is reported in all ages, with highest percentage of cases observed between the ages 36 to 50 years. Also PASC is frequently diagnosed in non-hospitalized patients with mild illness, and this population represents most COVID-19 cases. After two years post-recovery, PASC continues to affect the disability-adjusted life years (DALYs per 1,000 persons) 25.3% non-hospitalized and 21.3% hospitalized individuals. Accordingly, the substantial cumulative burden of health loss due to persistent Long-term PASC is overwhelming.
A prospective cohort study (n=9,764) conducted by Researching COVID to Enhance Recovery (RECOVER) consortium of the United States National Institutes of Health (NIH) proposed a symptom-based criteria to identify and differentiate PASC cases. The study identified SIX clinical manifestations, namely: post-exertion malaise (PEM) (87%), fatigue (85%), brain fog (64%), dizziness (62%), gastro-intestinal disorders (59%), and palpitations (57%), as the most prominent PASC symptoms; an additional SIX common symptoms such as changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements was observed. Other manifestations associated with selected symptoms such as dry mouth, weakness, headaches, tremor, muscle and abdominal pain, fever/sweats/chills, and sleep disturbance were also recognized.
The long-term sequelae of PASC could manifest with >200 different and overlapping clinical symptoms involving multiple organ/systems such as: Pulmonary-PASC (general fatigue, dyspnea, cough, throat pain); Cardiovascular-PASC (chest pain, tachycardia, palpitations); Gastrointestinal-PASC (diarrhea, abdominal pain, nausea vomiting); Neuro-cognitive-PASC (brain fog, dizziness, loss of attention, confusion); Renal-PASC (renal failure, electrolyte disorders; Hepato-biliary-PASC; Skeleto-muscular-PASC (myalgias, arthralgias); Psychological-related PASC (post-traumatic stress disorder, anxiety, depression, insomnia); and other PASC manifestations (ageusia, anosmia, parosmia, skin rashes).
Pathology of PASC or Long-COVID is a cumulative outcome of viral-induced HMR/D at different cellular levels. The burden of viral-induced HMR/D may vary by demography (age, race, and sex) but more severe among patients with existing metabolic syndromes and in survivors from severe acute infection. The FIVE most prominent long-term clinical manifestations of viral-induced HMR/D include:
58%
FATIGUE
44%
HEADACHE
27%
BRAIN FOG
25%
HAIR LOSS
24%
DYSPNEA
Long COVID Sub-phenotypes
Based on relapsing/remitting nature of acute- and post-COVID symptoms, an integrative classification has been proposed. i) SARS-CoV-2 infection-related acute COVID symptoms (up to 4–5 weeks), ii) acute post-COVID symptoms (from week 5 to 12), iii) long post-COVID symptoms (from week 12 to 24), and iv) persistent post-COVID symptoms (lasting >24 weeks). This classification includes time reference points with predisposing intrinsic/extrinsic factors and hospitalization data in relation to post-COVID symptoms. In hospitalized COVID-19 patients, about 50-70% cases may continue to PASC lasting up to 3 months after hospital discharge. In non-hospitalized subjects, about 50–75% may turn PASC-free one month after symptomatic onset. PASC patients may also experience exercise intolerance and impaired daily function and quality of life.
Based on plethora of symptoms affecting different organs/systems, PASC patients could be categorized into FOUR different clusters or sub-phenotypes: Sub-phenotype-1 (33.8%) with cardiac and renal manifestations, Sub-phenotype-2 (32.8%) with respiratory, sleep and anxiety disorders, Sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders, and Sub-phenotype-4 (10.1%) with digestive and pulmonary dysfunctions.
“Viral-induced human metabolic reprogramming/ dysregulation (Long-COVID or PASC) is affecting millions of people worldwide. Join our scientific mission to combat this global health crisis with evidence-based research in precision nutrition, genomics, and metabolomics."
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