HMR/D
Dysregulation
Viral-induced HMR/D leads to new 'onset' Metabolic Syndromes
Several recoverees or survivors of COVID-19 (RT-PCR negative for SARS-CoV-2) continue to exhibit a plethora of clinical symptoms with impairment(s) of multiple organ systems. Accordingly, PASC or long-COVID is a virus-free, ‘new onset’ disease condition extending from an earlier viral-induced HMR/D. The HMR/D in PASC pathology is a cumulative clinical outcome of several causative mechanisms comprising of both SARS-CoV-2-derived virulence factors, as well as a multitude of host cellular dysfunctions and innate responses. A plethora of PASC clinical symptoms and related metabolic impairments indicate an involvement of different pathobiological mechanisms such as: i) viral-induced hypoxia/’Warburg’ effect, ii) iron (Fe)-redox dysregulation (FeRD), iii) m-Dys and altered bioenergetics, iv) oxidative stress (OxS), v) hyperinflammation, vi) autoimmunity, vii) dysbiosis, viii) latent viral re-activation, ix) persistent viral reservoirs, and x) virus-hijacked host factors. A wide range of pathophysiological mechanisms underlying the HMR/D are involved in the transition of SARS-CoV-2 Infection to virus-free PASC clinical condition.
1. Hypoxia/’Warburg’ Effect
SARS-CoV-2 hijacks host cellular metabolic machinery to extract adequate energy and carbon skeletons to facilitate viral entry and further molecular constructions for viral progeny inside a host cell for replication and propagation. The SARS-CoV-2 infection initiates complex human host-pathogen interactions and alters mitochondrial function with significant disruption of glycolysis/TCA cycle (Warburg effect), affecting several metabolic pathways of amino acid (AA), fatty acid (FA), nucleotide, and antioxidant synthesis. The viral-induced hypoxia/Warburg effect could potentially
compromise endocrinal, CV, CNS, GI, pulmonary, and reproductive functions that demand high levels of mitochondrial oxygen consumption, OXPHOS,and ATP reserve. Failure to reset hypoxia/Warburg effect after viral clearance in COVID-19 survivors, could eventually evoke PASC with metabolic impairments including new onset T2DM, myocardial infarction, CFS, brain fog, and blood clotting issues. Thus, PASC could be described as a SARS-CoV-2-induced chronic and self-perpetuating comprised state of m-Dys, where OxS potentially drives inflammation and shifts energy metabolism towards glycolysis while down-regulating OXPHOS. Long-term consequences of virus-induced hypoxia/Warburg effect could amplify potential risks of HMR/D with chronic multi-organ impairments in PASC.
2. Iron (Fe)-Redox Dysregulation (FeRD)
In SARS-CoV-2 infection, free iron released into the circulation could induce inflammation of alveolar macrophages and cause oxidative damage to lungs. Iron load increases blood viscosity with recurrent diffused micro/macro circulatory thrombosis leading to high levels of D-dimers in COVID-19 patients. Altered iron metabolism, iron-restricted erythropoiesis from hyperinflammation causes FeRD. In COVID-19, FeRD could trigger several clinical manifestations including: i) decrease functional hemoglobin (Hb), ii) increase cellular iron overload, iii) release free toxic heme into the
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circulation, iv) manifest hypoxemia and systemic hypoxia, v) reduce nitric oxide (NO•) synthesis, vi) activate coagulation pathway(s), vii) trigger ferroptosis with OxS and lipid peroxidation, and viii) induce mitochondrial degeneration. On the other hand, viral protein sequences could form complexes with porphyrin, affect heme on the 1-β chain of Hb, and release free iron. SARS-CoV-2 envelope (E) protein directly binds to heme (from Hb) released from damaged erythrocytes and lysed phagocytes. The viral genomic ORF8 protein could interact with the 1β-chain of Hb, capture the porphyrin and inhibit heme metabolism in the body. Such an array of SARS-CoV-2 interactions with Hb could induce hemolysis and/or form complexes with released heme, generate dysfunctional Hb (hemoglobinopathy) with reduced ability to transport O2/CO2 and lead to O2 deprived multi-faceted syndromes, including coagulation disorders. In severe stages of COVID-19, other Hb-associated markers such as bilirubin and ferritin progressively increase and worsen the clinical outcomes.nd PASC.
The FeRD-induced hyper-ferritinemia strongly correlates with different inflammatory phases of SARS-CoV-2 infection. In SARS-CoV-2 infected patients, the plasma levels of ferritin and IL-6 steadily decrease with gradual recovery from COVID-19. FeRD is highly prevalent among hospitalized COVID-19 patients and this clinical condition may continue for weeks or even months in PASC patients. Biomarkers of iron metabolism (i.e., ferritin, transferrin (TF), lactoferrin (LF), etc.) and Hb could provide risk stratification strategies for COVID-19 management. FeRD determinations are specific and sensitive to predict disease severity in COVID-19 and PASC.
3. Mitochondrial Dysfunction (m-Dys)
Mitochondrion is the cellular powerhouse involved in oxidative phosphorylation (OXPHOS), ATP synthesis, and regulation of calcium signaling, redox homeostasis, lipid metabolism, cell differentiation, immune system, apoptosis, and cellular senescence (aging). These vital processes are perturbed when the host cellular machinery is hijacked by SARS-CoV-2, which leads to mitochondrial dysfunction (m-Dys). COVID-19 patients with underlying primary mitochondrial disease and secondary m-Dys are prone to increased disease severity and case fatality rate compared to patients with healthy
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mitochondrial functions. Thus, m-Dys could heavily compromise host bioenergetics with detrimental consequences on COVID-19 and long-term PASC patients. Hyper-inflammation (with CRS or cytokine storm) due to massive outburst of ROS, is a prominent clinical feature of COVID-19. Mitochondrion is a significant source of ROS in human cellular metabolism that could trigger the onset and development of cytokine storm.
4. Oxidative Stress (OxS)
Oxidative stress (OxS) is a nonspecific patho-physiological condition that reflects a redox imbalance between increased production of ROS (free radicals) and inability of antioxidant defenses to neutralize the reactive intermediates or to repair the ensuing damage. ROS disrupts cellular metabolism by inflicting DNA strand breaks, protein degradation, lipid peroxidation, and cellular damage. Combined with inflammation, OxS contributes to cardinal patho-mechanisms of both COVID-19 and PASC. After SARS-CoV-2 infection, the viremia stage could increase OxS, elevate levels of
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ROS/inflammation markers (i.e., peroxide, NO•, carbonylated proteins, and IL-6) and inflict severe cellular/tissue damage. This clinical condition may compromise mitochondrial functions and trigger apoptosis of leukocytes. Hyper-inflammation, pro-oxidant cytotoxic milieu, and early apoptosis of leukocytes from SARS-CoV-2 infection, could cause severe endothelial-alveolar injury and multi-organ dysfunction syndrome (MODS). PASC patients exhibit a wide range of tissue/organ damage involving pulmonary, cardio-vascular, neuro-cognitive, gastro-intestinal, reproductive, and dermatological systems.
5. Hyper-inflammation
SARS-CoV-2 infection could disrupt host immune homeostasis, inflict tissue injury, and may persist during post-recovery phase of COVID-19 survivors and manifest as PASC. Cell-mediated immune responses with antigen-specific T cells decrease in COVID-19 patients and affect viral clearance from infected host cells. Cytotoxic T cells elevate in peripheral blood and bronchoalveolar lavage of PASC patients with severe airway dysfunction with persistent respiratory symptoms that last for 3 to 6 months. SARS-CoV-2 induced T-cell imbalance resolve over time; however, the markers upregulated from
T-cell exhaustion may remain up to 1 year in PASC patients. Elevated levels of neutrophils with neutrophil extracellular traps (NETs and NETosis) and associated immune-thrombosis, are prominent features of COVID-19 pathology. COVID-19 patients with severe disease exhibit increased monocyte counts with higher frequencies of classical monocytes, lower frequencies of intermediate/non-classical monocytes and elevated plasma levels of C-reactive protein (CRP) and serum TF in comparison to mild disease. This abnormal immune response may persist for >6 months after COVID-19 recovery. Cytokine storm or CRS’, a clinical state of hyper-inflammation, is a prominent feature of COVID-19 severity, linked to respiratory dysfunction, ARDS with adverse disease outcomes. About 10% of patients recovered from COVID-19 show persistent symptoms up to 6 months after initial SARS-CoV-2 infection. Hyperimmune activation an autoimmunity are considered as potential causative factors in the onset of PASC.
6. Autoimmunity
In COVID-19 patients, autoantibodies against nuclear bodies, auto-nuclear antibodies, (ANA), phospholipids, type I interferon (IFN), melanoma differentiation-associated protein 5 (MDA5), and ACE2 have been reported. These auto-antibodies against immuno-modulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins) could attack tissues of patients, thereby impair host cell signals, perturb immune function, damage organ systems, and increase COVID-19 severity. Human leukocyte antigen (HLA) genetic polymorphism has also been
observed in COVID-19 patients. HLA polymorphism plays a key role in the onset of several autoimmune diseases. Evidently, SARS-CoV-2 infection could elicit auto-inflammatory and autoimmune disorders such as Guillain-Barré syndrome (GBS), autoimmune hemolytic anemia, immune thrombocytopenic purpura, and Kawasaki disease (KD). Mechanisms of COVID-19-derived autoimmune disorders include: i) viral-mediated host hyper-immune response, ii) viral-induced excessive NETs formation with neutrophil-associated cytokine responses, and iii) the molecular mimicry between viral antigenic components and host molecules.
7. Dysbiosis
Gut dysbiosis is defined as reduction in diversity of GI microflora or depletion of autochthonous or host commensal beneficial bacteria with an enrichment of microbial pathogens that may alter host susceptibility to SARS-CoV-2 infection. Impairment of short-chain fatty acid (SCFA) and L-isoleucine biosynthesis in gut microbiome persists beyond 30 days after recovery from COVID-19, which could contribute to persistent leaky gut and dysbiosis in PASC patients. Notably, even after viral clearance, more than half of patients suffer from PASC with persistent dysbiosis, deregulated GI
metabolism and compromised host immune response. Gut dysbiosis and disrupted intestinal barrier function could worsen pulmonary symptoms, augment neurological or hepatic inflammation through translocation of endotoxins and bacteria via portal veins. Dysbiosis of gut microbiome with ensuing gut barrier dysfunction could severely impact patho-physiologies of both COVID-19 and PASC. GI tract is the largest immunological organ in the body and any aberrant immune response to SARS-CoV-2 infection induced by resident microflora could affect recovery from COVID-19. Dysbiosis may lead to GI impairment with persistent symptoms of diarrhea and abdominal pain. Gut dysbiosis could also increase susceptibility to respiratory infections, alter immune responses and affect lung homeostasis (the ‘Gut-Lung Axis’). Persistent gut dysbiosis after resolution of COVID-19 may be linked to PASC, particularly to neurological manifestations.
SARS‐CoV‐2 infection inflicts sustained metabolic damage to gut microbiome and GI function; therefore, opportunistic pathogens could selectively enrich in fecal microflora of COVID-19 patients. Accordingly, SARS-CoV-2 infection could inflict direct cytopathic injury to gut epithelia and elicit indirect immune-mediated damage to endothelial cells. SARS-CoV-2 could also induce GI inflammation, dysregulate intestinal ACE2 activity, and/or infect gut microflora (similar to bacteriophage-type transduction), as three potential inter-connected mechanisms in gut dysbiosis in PASC.
8. Latent Viral Reactivation
Since the onset of COVID-19 pandemic, a strong correlation between SARS-CoV-2 infection or COVID-19 vaccination and herpesvirus co-infection/reactivation has been reported. To date the reactivation of eight human herpesviruses (HHVs) have been identified, including Herpes Simplex Virus types 1 (HSV‐1) and 2 (HSV‐2), Varicella‐Zoster Virus (VZV or HHV‐3), Epstein-Barr Virus (EBV or HHV‐4), Cytomegalovirus (HCMV or HHV‐5), HHV‐6, HHV‐7, and Kaposi's Sarcoma‐associated Herpesvirus (KSHV or HHV‐8). Incidence of HHV reactivation was high among patients admitted to the ICU for severe
COVID-19 and among individuals administered with COVID-19 vaccine.Simultaneous occurrence of cytokine storm and immune-suppression during SARS-CoV-2 infection may lead to reactivation of latent HHV in the body. Lymphopenia with reduced CD8+ levels and elevated CD4+/CD8+ ratio indicate the severity of COVID-19. This clinical condition leads to an immune-suppressed state, which could ultimately trigger reactivation of latent HHV and aggravate SARS-CoV-2 infection. In addition to viral co-infection, anti‐COVID‐19 therapies (i.e., azithromycin, nafamostat mesylate, and remdesivir) could activate various cell signaling pathways and trigger viral lytic reactivation. Remdesivir, a widely administered anti‐COVID‐19 drug, is shown to induce lytic reactivation of KSHV and EBV, from virus‐associated lymphoma cells. SARS-CoV-2 infected patients demonstrate a wide spectrum of cutaneous manifestations, including maculopapular or perifollicular rash, urticaria, vesicles, petechiae, purpura, livedo racemosa, and pseudo-chilblains, often referred to as the ‘COVID toes’. These cutaneous manifestations of COVID-19 are reportedly associated with reactivation of latent HHVs. An exhausted dysfunctional antiviral immune response from SARS-CoV-2 infection could trigger reactivation of human adenovirus with a sequelae effect of ME/CFS in PASC patients.
9. Persistent Viral Reservoirs
Infectious viral particle clears out and remains undetectable in the body for most COVID-19 cases; however, among certain patients, SARS-CoV-2 could persist for months after post-recovery. Accordingly, total clearance of SARS-CoV-2 RNA or its protein antigens from host infected tissue may take longer time, while the virus and its antigenic fragments continue to remain dormant for extended periods of time in the body. Persistence of SARS-CoV-2 or its viral components in the body could trigger a dysregulated immune response and proinflammatory cytokine release, which may cause chronic
low-grade inflammation and MODS. These acute sequelae also have a genetic basis that may predispose COVID-19 survivors to a compromised immune status consequently affecting viral clearance.Multi-organ viral tropism predominantly in cells expressing ACE2, TMPRSS2, or both has been reported. Viral shedding (as detected by RT-PCR) may be prolonged in certain tissue of post-COVID patients for an extended duration in lower respiratory tract (59 days), serum (60 days), upper respiratory tract (83 days), and feces (126 days). Such viral persistence could serve as a chronic trigger for inflammation and cellular activation that may further inflict tissue damage and PASC-related symptoms. In long-term persistence of COVID-19-associated anosmia (loss of smell), viral transcripts are detected in the inflamed olfactory mucosa. Viral persistence and associated inflammation in olfactory neuro-epithelium may account for prolonged or relapsing symptoms such as anosmia. Delayed immune clearance of SARS-CoV-2 antigen(s) or duration of viral antigen burden in the upper respiratory tract and other anatomical sites during acute COVID-19 is linked to the development of PASC.
Long-term shedding of SARS-CoV-2 is widely reported, even after resolution of symptomatic COVID-19. The continuous replication of live SARS-CoV-2, its viral RNA, or viral protein fragments could play a major role in the clinical onset of PASC. Such SARS-CoV-2 antigen persistence in infected tissues could possibly trigger immune perturbations that may contribute to the development of PASC. Also, persistent viral RNA has been detected in multiple tissues of recovered patients even months after the onset of COVID-19. In a cohort of COVID-19 patients with persistent symptoms, about 45% showed detectable plasma SARS-CoV-2 RNA. Viral RNA was also found in blood, stool, and urine of PASC patients. Spike and/or viral RNA fragments could persist in COVID-19 recoverees up to 12 months or longer. The S1 antigen in peripheral blood monocytes could remain up to 15 months after SARS-CoV-2 infection. In summary, viral persistence could play a major role in PASC, considering the ability of SARS-CoV-2 pathogen to infect and reinfect individuals over a lifetime.
10. Viral-Hijacked Host Factors
Clinical outcomes of COVID-19 are directly related to the ability of SARS-CoV-2 to hijack host metabolic machinery and cellular factors of an infected individual, for viral invasion and internalization, followed by intra-cellular replication to assemble and release multiple viral copies for ultimate propagation and transmission. Each of the SARS-CoV-2 hijacked host cellular factor, is also a quintessential functional component of several key physiological pathways of human metabolism. In consequence, the virus-hijacked host cellular factors undergo HMR/D, with altered or compromised
function, which ultimately contribute to a plethora of organ/system impairments with detrimental effects on human metabolism. If not reversed or reset, the viral-induced HMR/D condition may persist in PASC for weeks or months even after viral clearance and recovery from COVID-19.