November 8, 2023
Source: Nature
Photo / Image Source: Unsplash,
A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection
S. Anand Narayanan,
David A. Jamison Jr,
Joseph W. Guarnieri,
Victoria Zaksas,
Michael Topper,
Andrew P. Koutnik,
Jiwoon Park,
Kevin B. Clark,
Francisco J. Enguita,
Ana Lúcia Leitão,
Saswati Das,
Pedro M. Moraes-Vieira,
Diego Galeano,
Christopher E. Mason,
Nídia S. Trovão,
Robert E. Schwartz,
Jonathan C. Schisler,
Jordana G. A. Coelho-dos-Reis,
Eve Syrkin Wurtele &
Afshin Beheshti
Cardiovascular adaptations and changes The cardiovascular system includes the heart, arteries, veins, capillaries, and lymphatics, which are the organ systems responsible for the transport of blood, lymph, and their constituents to every organ in the body. Blood and lymph transport multiple components, including water, red blood cells, white blood cells, macromolecules (e.g., lipids, proteins, carbohydrates, macromolecule, etc.), micromolecules (e.g., nutrients, ions, etc.), of which are circulated systemically and transported to and from all organs of the body. Included in the transport of these components by blood and lymph are pathogens, such as the SARS-CoV-2 virus, which benefits from the cardiovascular system not only by binding to a cell-type expressing its cognate receptor (e.g., endothelial cells and ACE2 receptor), but also from the cardiovascular system’s function in transporting the virus and its replicants away from the host infected cell, tissue, and organ. In turn, the COVID-19 cardiovascular-related symptoms vary greatly, ranging from asymptomatic or mild respiratory symptoms to severe life-threatening respiratory and cardiac failure [33].
Early reports have described common symptoms of COVID-19 to include fever (88%), fatigue (38%), chills (11%), headache (14%), nasal congestion (5%), sore throat (14%), dry cough (68%), dyspnea (19%), nausea/emesis (5%), diarrhea (4–14%), and myalgias (15%). A meta-analysis of eight studies showed a higher prevalence of hypertension (17 ± 7%) and diabetes mellitus (8 ± 6%) followed by cardiovascular disease (5 ± 4%) in COVID-19 patients [33, 34]. Moreover, concomitant cardiovascular (CV) conditions may be occurring in 8–25% of COVID-19 infected population and an even greater proportion of those who die from the disease [33]. Indeed, evidence suggests that among the primary causes of death and overall mortality from COVID-19 infection are cardiac issues and respiratory failure [34].
These symptoms result from changes occurring at the molecular level from SARS-CoV-2 infection. A large autopsy study investigating multiple organs (heart, lung, kidney, liver, and lymph nodes) showed that the cellular and functional gene signatures from each organ’s major cell types (e.g., cardiomyocytes in the heart) decrease as a function of the viral load. More specifically in the heart (n = 41 from patient autopsy samples), despite no histological change, many heart functional markers (e.g., TNNI3, TNNT2, MYBPC3, PLN, and HAND1) showed decreased levels resulting from COVID-19 infection [35].
Another study showed the presence of SARS-CoV-2 in the myocardial heart tissue from autopsy cases, suggested to be tied to myocardial injury [36]. Indeed, these cellular adaptations extend into the vascular system (e.g., arteries, veins, etc.), with histopathological evidence from autopsy studies showing direct viral infection of endothelial cells and micro- and macrovascular thrombosis occurring in both the arterial and venous circulations. An autopsy study investigating COVID-19 in three patients showed SARS-CoV-2 viral components present in the endothelial cells from different autopsied organs, including the kidney, lung, heart, and liver were each infected with SARS-CoV-2 [37].
Inflammation of the endothelium was also observed, along with recruitment of neutrophils and mononuclear cells to the site of damage. In vitro studies also support SARS-CoV-2 being able to directly infect cardiovascular cells as seen from experiments showing viral infection of engineered human blood vessel organoids [38]. Severe COVID-19 has also been associated with endothelial specific changes and effects such as elevated endothelial activation, hypercoagulability, and increased presence of von Willebrand Factor [39, 40]. Endotheliitis from COVID-19 can occur, leading to a loss of cell–cell junctions, loss of endothelial cells, exposure of the basement membrane, abnormal cytokine release, abnormal reactive oxygen species release, and intussusceptive angiogenesis. Endothelin-1 has been suggested as a possible biomarker for those at risk with COVID-19 [34].
These cardiovascular adaptations from SARS-CoV-2 infection lead to a number of pathophysiological consequences including hypoxia, with prolonged ischemia leading to formation of hypoxanthine as an ATP breakdown product [36]. These effects may be from tissue remodeling caused by viral infection, as well as changes in blood viscosity, clotting, or inflammation, though more research of these areas would benefit our understanding of the effects of SARS-CoV-2 on the cardiovascular system and organ remodeling [33, 34, 36].
For example, a meta-analysis showed there are diverse cardiovascular complications including cardiac injury (e.g., myocardial injury, microinfarcts), heart failure, microembolic infarcts, acute coronary syndrome, arrhythmia, hypertension, and atrial and ventricular complications (e.g., fibrosis) [33, 34]. Autopsy and case reports from COVID-19 patients are also varied in their observations of cardiac tissue changes, highlighting the complexity of the disease and individual differences influencing pathophysiological progression and outcomes. Identifying cardiovascular specific biomarkers would help evaluate, as well as measure progression of disease, with troponin I as one example of a clinical marker evaluating myocardial injury is troponin I. Troponin I has been shown to be elevated in >10% of patients hospitalized with COVID-19, increasing with disease severity [41].
Identifying more markers with cardiovascular specific outcomes (i.e. metabolites, lipids, humoral factors, etc., mentioned in the above sections) would help evaluate, correlate, and triage patients and improve their outcomes, as well as facilitate identification of specific biochemical pathways that may mechanistically explain disease symptoms.
Indeed, with the metabolic and physiological adaptations seen with COVID-19 patients, understanding mitochondrial adaptations in these contexts is relevant, given mitochondrial function in bioenergetics. As discussed in our first review, the mitochondria is heavily dysregulated and suppressed in the host during SARS-CoV-2 infection [3].
One study specifically analyzed transcriptomic data on heart samples collected from deceased COVID-19 patients [6]. This analysis showed heavy suppression at the transcript level of the majority of mitochondrial pathways and genes [6]. The non-coding transcriptome response to SARS-CoV-2 may also play a significant response and regulatory role with the cardiovascular adaptations developing from COVID-19 disease.
Whether miRNA’s (e.g., hsa-miR-2392), lncRNA’s (e.g., NRIR and BISPR), or circRNA’s that are involved in suppressing mitochondrial gene expression, changing oxidative phosphorylation, mitochondrial structure (e.g., translation, metabolism, etc.), and causing inflammatory effects, may be involved with local cardiac adaptations or systemic vascular adaptations is unknown, but warrants future investigations to explore the specific roles of the transcriptome with cardiovascular adaptations. Furthermore, given the changes in cardiovascular structure, function, biochemical adaptations, that occur from SARS-CoV-2 infection, further study of cardiovascular mitochondrial adaptations is of relevance, and would help elucidate the underlying mechanisms impacting the cardiovascular system resultant from SARS-CoV-2 infection.
Immune adaptations and changes
The immune system includes the innate and adaptive immune systems. The innate system involves nonspecific responses to injury, and includes cell populations such as monocytes, macrophages, neutrophils, basophils, eosinophils, etc. The adaptive immune system involves specific response to pathogen infection, and includes cell populations such as T and B cells. The two arms of the immune system communicate, interact, and support each other in responding to injury, aided by humoral, circulating factors such as cytokines and chemokines, that provide information and context to immune cells as to how, where, and what to respond to, as well as the magnitude of the response. In turn, there are various feedback loops that provide guidance and direction to the immune system, both innate and adaptive, with SARS-CoV-2 activating both the innate and adaptive immune systems.
For the innate immune system, activation appears to be guided by neutrophils, which display increased levels of ROS and activated NETosis [42]. Additionally, the loss of ACE2 and DABK in the lungs of patients encourages neutrophil infiltration and inflammation. SARS-CoV-2 has also been suggested to dysregulate type 1 interferon signaling, which contributes to immune evasion early in infection. Consistent with this finding, bulk analysis of whole blood cell transcriptomes of severe COVID-19 patients compared with non-critically ill COVID-19 patients showed upregulation of Interferon alpha as the primary contributor to severe COVID-19. Activated monocytes and macrophages also migrate to the lungs (chemotaxis), further exacerbating lung inflammation and pulmonary fibrosis [43].
Several studies have reported disordered structure of the infected lung, along with extensive immune infiltration [35, 44]. For example, the lung alveoli in COVID-19 patients develop additional hyaluronan, forming a coating that can reduce oxygen exchange, as well as leading to pulmonary edema. Another study of COVID-19 patients showed chronic lung impairment accompanied by persistent respiratory immune alterations, showing specific memory T and B cells enriched at the site of infection [45].
With the significant neutrophil, macrophage, T and B cell infiltration and activation observed, and localized hyperinflammatory states of these immune cells around alveolar epithelial cells, this develops into more lung damage and loss of compartmental identity. When a timeline and pattern of the cytokine storm in tracheal aspirate samples was organized and reported, divergences in the systemic versus airway cytokine production during COVID-19 were observed [46].
Indeed, a study assessing lung function of critical COVID-19 patients showed 55% of them experienced persistent impairment three months after ICU discharge, including declines in patient lung function, exercise capacity, and quality of life [47]. This suggests respiratory failure is another significant factor involved with patient mortality with severe SARS-CoV-2 infection, with an investigation of single-nuclei RNA sequencing of COVID-19 patient lung samples identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, with the data showing COVID-19 patient lungs were highly inflamed, with dense infiltration of aberrantly activated macrophages, though with impaired T-cell responses and suggestions of impaired lung regeneration, based on alveolar type 1 cell phenotypes [48].
With regard to adaptive immune cell responses to SARS-CoV-2, these include lymphopenia (lowered CD4 and CD8 T-cell number) in COVID-19 patients, also seen in autopsy reports [49, 50]. There are case by case variations; for example, an influx of T cells and myeloid cells occurs into the myocardium. In response to this event, COVID-19’s pathogen-associated molecular patterns and damage-associated molecular patterns (PAMPs and DAMPs) are activated, as well as cytokines released by alveolar macrophages [51, 52]. These pathways are thought to contribute to the dysregulation of monocytes and macrophages in COVID-19 [53] and the subsequent dysfunction of T cells.
Changes also occur within the heart, as seen with gene expression analysis of cardiac tissue for TNF-ɑ, interferon-γ, chemokine ligand 5, interleukin-6, interleukin-8 (CXCL8), and interleukin-18. Severe COVID-19 is also associated with elevated endothelial activation, hypercoagulability, and the presence of von Willebrand Factor (vWF) [53, 54]. Indeed, COVID-19 induces a complex pattern of cytokine release as part of an overall dysregulated immune response that, in severe cases, injures the parenchyma of vital organs and leads to viremia and sepsis [55, 56].
Severe COVID-19 is characterized by an inflammatory profile that involves initial immune evasion by downregulation of Type I Interferon pathways along with significant upregulation of IL-6, IL-8 and TNF-α in the lungs that coincides with increased NF-κB activity [57, 58]. In one study of COVID-19 patients, a notable increase in multiple serum cytokines (e.g., TNF-α, IFN-γ, IL-2, IL-4, IL-6 and IL-10) was seen [59], while another study showed high plasma levels of IL-1β, IL-1RA, IL-7, IL-8, IL-9, IL-10, bFGF, GCSF, GM-CSF, IFN-γ, IP-10, MCP1, MIP-1α, MIP-1β, PDGF, TNF-α, and VEGF. A different study showed increased levels of inflammatory markers such as C-reactive protein, D-dimer, ferritin, IL-6 and lactate dehydrogenase (LDH) associated with higher mortality in COVID-19 patients [60].
These results suggest an overproduction of cytokines in response to lung damage, or as a compensatory response to attempt to re-direct, accelerate, or shutdown the immune response. These cytokine fluctuations also coincide with systemic inflammation and myocardial injury; in 137 patients admitted for COVID-19 disease in Hubei province, heart palpitations were noted as one of the presenting symptoms in 7.3% of patients [61].
Moreover, there have been reports of complete heart blockage and atrial fibrillation in patients with COVID-19 infection [62]. In patients diagnosed with severe COVID-19, increased levels of pro-inflammatory cytokines, (e.g., soluble IL-2R, IL-6, IL-8, and TNF-α) have been observed, with these cytokines disrupting endothelial cells antithrombotic and anti-inflammatory functions, leading to coagulation dysregulation, complement and platelet activation, and leukocyte recruitment in the microvasculature [63, 64].
While increased levels of circulating chemokines, pro-inflammatory cytokines, regulatory cytokines, and growth factors were observed in severe COVID patients who died as compared to surviving patients, a more restricted and selective increase of cytokines such as IL-10 was observed in the airway samples with actual decreased levels of pro-inflammatory cytokines such as IFN-γ, IL-17, IL-5, and IL-2 as compared to uninfected controls [46]. These results demonstrate that inflammation is also highly modulated in the airways as an attempt to decrease exacerbated inflammation. Figure 1 illustrates a snapshot of extracellular factors involved with immune adaptations during COVID-19 and the uniqueness of systemic versus airway inflammatory milieu.
Organ alterations from SARS-CoV-2 infection In addition to the cardiovascular system, SARS-CoV-2 infects and has an effect on many organ systems (e.g., cardiovascular, immune, and endocrine systems, as described above), including the lungs, lymph nodes, brain, liver, kidneys, gastrointestinal tract, testis (Fig. 3) [65,66,67]. COVID-19 is known to cause multi-organ dysfunction, though the burden of infection outside the respiratory tract and time to viral clearance is not well understood.
A recent postmortem study of 44 patients quantified and mapped the distribution, replication, and cell-type specificity of SARS-CoV-2 across the body, specifically the brain but other organs as well, from acute infection to more than seven months following symptom onset. It was seen that SARS-CoV-2 infection of the body was widely spread across respiratory and non-respiratory tissues (e.g., the brain) [68]. This spread of infection provides context for the different symptoms patients experience.
Neurological and psychiatric symptoms have been reported for acute, post-acute, and longer-term SARS-CoV-2 infection in human patients across the human lifespan [69]. Although neurological manifestations remain incompletely characterized in terms of etiology, severity, and incidence, they present signs of nonspecific (e.g., headache, dizziness, myalgia, fatigue, somnolence, insomnia, etc.) and specific (e.g., encephalopathy, encephalitis, stroke, status epilepticus, ataxia, anosmia, ageusia, demyelinating syndromes, etc.) deficits of the central nervous system, the peripheral nervous system, or both, with new-onset or relapsed associated prodromal, subthreshold, or fully expressed (i.e., suprathreshold) psychiatric conditions. The spectrum of presumed virogenic psychiatric disorders across age cohorts and other demographic classifications is broad and includes anxiety, depression, confusion or disordered thought (e.g., brain fogor psychosis).
Structural and functional changes in brain anatomy, such as brief to protracted alterations in gray and white matter volume, blood perfusion and oxygenation, and metabolic activity [70], often parallel and are consistent with onset and duration of mental health diagnoses in infected populations. Areas caudal to the neocortex tend to be most affected, with olfactory cortex, basal ganglia, hippocampus, amygdala, cerebellum, and brain stem abnormalities occurring in greater frequency and magnitude in COVID-19 patients. Uncertainty regarding the cause of COVID-19-related neuropathology centers on SARS-CoV-2 neuroinvasion, with the olfactory epithelium as a plausible entry point with subsequent retrograde transsynaptic propagation to other brain areas.
Astrocytes and Schwann cells infected by SARS-CoV-2 may also be negatively impacted with their neurotransmission, synapse modulation, reinnervation, metabolite and electrolyte homeostasis, and cell signaling functions. This may cause, contribute, or lead to observed central and peripheral nervous system trauma and dysfunction [70]. There is data that also supports hematogenous mechanisms enabling viral access to nervous tissue through infection of blood-brain-barrier (BBB) endothelial cells or epithelial cells of the choroid plexus blood–CSF barrier.
Indeed, a study examining SARS-CoV-2 interaction with brain organoids suggests a compromised blood-brain-barrier (BBB) as manifested by injured endothelial cells and increased BBB permeability [71]. Multisystem hyperinflammatory immunoreactions most appropriately describe for the diverse set of pathologies observed in post mortem autopsy analyses, as well as in live in vivo or in vitro tissue, the result of hemorrhagic, ischemic, and hypoxic injury, mitochondrial dysfunction, neuronal damage and apoptosis, and microglial and astrocytic activation.
With regard to gastrointestinal (GI) effects of SARS-CoV-2, an autopsy study of 29 cases showed the GI to be one of the primary organs infected by the virus, as well as being supported by the literature of postmortem organ analysis [65]. GI involvement and symptoms (e.g., diarrhea, anorexia, nausea/vomiting, abdominal pain, etc.) is associated with long hospital stays and severity of disease, with the rates of GI symptoms of the percent of individuals ranging from 11% to 53%. ACE2 is frequently found in human intestinal epithelial cells, with SARS-CoV-2 being detected in patient GI samples [72]. Indeed, while there is a paucity of data of SARS-CoV-2 effects on GI physiology, GI symptoms are common in patients with COVID-19, though and should be considered when evaluating patient conditions as well as treatment options.
Here we summarize a few examples of organ adaptations resulting from SARS-CoV-2 infection. These highlight the virus’s diverse biological targets and outcomes, though more studies are warranted given our comprehensive lack of understanding of these, and other, organ alterations, as well in particular, the biochemical pathways that are affected by viral infection. In addressing these knowledge gaps, patient care will improve as well as new treatment modalities will be identified. Moreover, these adaptations are related with long-term implications of SARS-CoV-2 infection, of which we describe in the next section.
Impact of circulating factors on post-acute sequelae of SARS-CoV-2 (PASC, long COVID-19)
In addition to COVID-19 from SARS-CoV-2 infection, patients may experience long-term symptoms as a result of organ or tissue damage due to SARS-CoV-2. This condition is referred to as post-acute sequelae of SARS-CoV-2 (PASC), or long COVID-19 [73, 74]. PASC patients are burdened with multiple symptoms, including more than a third of PASC patients continuing to experience lung fibrotic abnormalities following hospital discharge [75].
Many are also at risk of developing microemboli due to maladaptations with clotting physiology (e.g., massively increased levels of vWF which leads to increased platelet activation, etc.) [76]. Indeed, virus-driven cellular alterations have been suggested to contribute to the pathophysiology of PASC patients [3, 77]. Persistent viral presence and inflammation within the olfactory epithelium has been evident from histological analysis, as well as long-term impairments in taste and smell in the cells of the tongue’s taste buds [78].
PASC is also characterized by chronic fatigue, which has numerous underlying causes. As a comparison, the post-flu or fever fatigue that occurs (e.g., Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)) may have some similarities to the persistent fatigue in PASC. PASC symptoms may also be influenced by abnormalities of the central nervous system, such as brain hypometabolism [79].
A recent postmortem study also quantified and mapped the SARS-CoV-2 organ tropism, finding long-term signs of infection in the brain, as well as across the body within the tissue (e.g., respiratory, cardiovascular, lymphoid, gastrointestinal, genitourinary, endocrine, skin, and peripheral nervous systems) seven months following infection onset, confirmed through in situ hybridization, immunohistochemistry, and immunofluorescence analyses of the tissue, isolation of SARS-CoV-2 from tissue by cell culture, and detection of the spike sequence variants in non-respiratory sites [71].
While psychological and environmental factors are likely to be involved, long-term biochemical adaptations, including increased oxidative stress and muscle mitochondrial failure, may contribute to the chronic fatigue syndrome found in PASC patients [80]. In addition, due to the activation of the fibrosis pathway from persistent virus-induced inflammation, the heart may subsequently undergo structural remodeling that may also explain the PASC symptoms [81]. There are also long-term immune changes, with PASC patients having elevated expression of type I IFN (IFN-) and type III IFN (IFN-1), highly activated innate immune cells, while lacking naive T and B cells [82], which may also be related with the symptoms PASC patients experience, but also increase their risk of infection, etc.
Indeed, while many individuals recover from SARS-CoV-2, a significant number of patients continue to suffer with long-term disease symptoms (e.g., PASC) long term after recovery from the primary infection [73, 74]. The severity of the primary infection appears to be independent from the possibility and severity of long-term symptoms, though this requires further research. Indeed, it is critical to understand the systemic effects of PASC, its biological mechanism and symptoms, and to develop treatments that promote functional recovery in symptomatic individuals, given the negative health-effects of PASC, as well as the socioeconomic and healthcare burden this condition will impose. Further research on PASC will improve our knowledge and understanding of the condition, as well as enable identification of relevant treatments and interventions to improve patient outcomes.
Conclusion SARS-CoV-2 and its resultant acute and chronic diseases, COVID-19 and PASC, have caused significant impacts worldwide. Here we describe and review the latest knowledge about the viral effect on our physiology, as well as the latest research on relevant whole-body metabolism pathways, circulating biological components (e.g., RNA, cytokine, hormones, etc.), and affected organ systems and their physiological adaptations consequent to SARS-CoV-2 infection.
COVID-19 is a pleiotropic, complex, and dynamic condition (Fig. 4). The viral insults and cellular adaptations differ depending on the context, from cellular to organ systems, and intricate biochemistry ties and integrates these systems together. Herein, we have attempted to capture the prevalent host responses, as well as highlight gaps of knowledge that could be addressed with future research. We have also touched on relevant biochemical targets with potential for mitigating COVID-19 in the human host, and we will describe current and in-development treatment modalities that affect these in Part 3 of our review.
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