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High-dose intravenous vitamin C treatment for COVID-19

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COVID-19 pneumonia seems to be a lung injury caused by the hyperactivation immune effector cells. High-dose vitamin C may result in immunosuppression at the level of these effectors. Therefore, intravenous high-dose vitamin C could be safe and beneficial choice of treatment in the early stages of COVID-19.
High-dose intravenous
vitamin C treatment for
(a mechanistic approach)
Adnan EROL, MD.
Erol Project Development House for the disorders of energy metabolism
Silivri-Istanbul, Turkey
Key words: Sars-CoV-2; Covid-19; Vitamin-C; GAPDH; Macrophage
COVID-19 pneumonia seems to be a lung injury caused by the hyperactivation immune
effector cells. High-dose vitamin C may result in immunosuppression at the level of these
effectors. Therefore, intravenous high-dose vitamin C could be safe and beneficial choice
of treatment in the early stages of COVID-19.
The two-time Nobel Prize-winning chemist Linus Pauling regarded vitamin C almost
as a panacea; therefore, he claimed that high doses vitamin C could combat a host of illnesses,
including cancer. He further believed that vitamin C would make the flu disappear completely
off the face of the earth.
Coronaviruses (CoVs) are large, enveloped, and positive sense RNA viruses that
infect a broad range of vertebrates and cause disease of medical and veterinary significance.
Human respiratory corona viruses have been known since the 1960s to circulate worldwide
and to cause respiratory infection with rather mild symptoms, suggesting that they are well-
adapted to the human host. However, zoonotic coronaviruses, such as severe acute respiratory
syndrome (SARS) and Middle East respiratory syndrome coronavirus (MERS-CoV), can
cause severe respiratory tract infection with high mortality [1].
Pulmonary pathology during severe coronavirus infection
Primary cell types found in the lower respiratory tract are alveolar epithelial cells and
alveolar macrophages (AMs). AMs are not only susceptible to infections, but also release a
significant amount infectious virus. Pathological examinations of samples obtained from
patients who died of SARS revealed diffuse alveolar damage, accompanied by prominent
hyperplasia of pulmonary epithelial cells and presentation of activated alveolar and interstitial
macrophages. Strikingly, these pulmonary manifestations were usually found after clearance
of viremia and in the absence of other opportunistic infections. Therefore, local inflammatory
responses due to excessive host immune response could result in alveolar damage [2].
In a murine model of SARS infection, fast and robust virus replication accompanied
by a delayed type I IFN (interferon) response. Accordingly, type I IFN expression was barely
detectable in most cell types. Plasmacytoid dendritic cells are a notable exception. They
utilize TLR7 (toll-like receptor-7) to sense viral nucleic acids and can induce robust type I
IFN expression following coronavirus infection. The extremely rapid replication of SARS-
CoV together with the upcoming, but delayed, type I IFN response caused extensive lung
inflammation. This was accompanied by influx of inflammatory monocyte-macrophages,
which are attracted by inflammatory mediators. Furthermore, macrophages themselves
additionally produced high levels of inflammatory mediators through type I IFN stimulation,
resulting in further macrophage influx in a pathological feedback loop. Altogether, massive
accumulation of pathogenic inflammatory macrophages increased the severity of SARS.
Moreover, type I IFN-induced immune dysregulation enforce apoptosis of T cells, which
would normally promote virus clearance, resulting in reduced numbers of virus-specific CD8
and CD4 T cells [1, 3].
Activation of effector immune cells
The rapid kinetics of SARS-CoV replication and relative delay in type I IFN
signaling may promote inflammatory M1 macrophage accumulation suggesting that targeted
antagonism of this pathway would improve outcomes in patients with severe coronavirus
infections [2]. Notably, the 2019 novel coronavirus (COVID-19) behaves more like SARS-
CoV; accordingly it was named as SARS-CoV-2, progressing rapidly with acute respiratory
distress syndrome (ARDS) and septic shock, which were eventually followed by multiple
organ failure due to virus-induced cytokine storm in the body [4].
In response to infection macrophages must react rapidly with a substantial pro-
inflammatory burst to kill microorganisms and to recruit additional immune cells to infection
site. A sharp increase in the rate of glycolysis is closely associated with inflammatory
phenotype in macrophages. Activated macrophages and effector T lymphocytes are shifted to
the high glycolytic rate and high glucose uptake, even under oxygen-rich conditions, which is
called as “Warburg effect”, upon immune activation, similar to cancer cells. Warburg effect is
associated with diverse cellular processes, such as angiogenesis, hypoxia, polarization of
macrophages, and activation of T cells. This phenomenon is intimately linked to several
disorders, including sepsis, autoimmune diseases and cancer [5].
Another interesting aspect of glycolysis induction in activated immune cells is the
role of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). It has
been shown that GAPDH binds to the IFNγ coding mRNA, repressing its translation.
However, GAPDH dissociates from IFNγ mRNA, allowing to its translation, upon glycolysis
activation [6]. In addition, due to the glycolytic pathway stimulation in activated immune
cells, their TCA becomes disrupted. Therefore, an accumulation of certain metabolites,
including succinate, occurs. Succinate, in turn, may increase hypoxia-inducible factor-
dependent activation of target genes, such as IL-1β and GLUT1 [7]. Glucose transporter,
GLUT1, is required for the metabolic reprogramming, activation, and expansion of effector
lymphocytes and M1 macrophages [7, 8].
Interaction between macrophages and alveolar epithelial type II (ATII) cells
Type I IFNs (type I interferons) produced by almost all type of cells play a vital role
in host defense against viral infection and cancer immunosurveillance. In response to viral
products pattern recognition receptors, such as retinoic-acid-inducible gene I (RIG-I)-like
receptors (RLRs) transmit downstream signaling pathway to trigger type I IFN production in
alveolar epithelial cells. Upon sensing cytosolic viral RNAs RLRs undergo conformational
changes, oligomerization, and exposure of the CARD domains to recruit a signaling adaptor
called mitochondrial antiviral-signaling (MAVS) protein. The transmembrane (TM) domain
of MAVS is necessary for its mitochondrial outer membrane localization. Once activated,
MAVS develop a functional prion-like structure at mitochondria, leading to the
phosphorylation of IRF3 and subsequent transcription and type I IFNs [9].
Activated macrophages produce large amounts of lactate, which are exported by
MCT4 [5]. Alveolar epithelial cells import lactate, creating a lactate shuttle between
macrophages and ATII cells, and use it as substrate for mitochondrial oxidative energy (ATP)
production [10]. In ATII cells, Lactate inhibits MAVS mitochondrial localization, RLR-
MAVS association, and MAVS aggregation and downstream signaling activation by binding
to the TM domain of MAVS. Thus, macrophage released lactate may attenuate host innate
immune response through decreasing type I IFN production for viral clearance [9].
Proposed mechanism of action of high-dose vitamin C in immune effector cells
Vitamin C is known as an essential anti-oxidant and enzymatic co-factor for
physiological reactions, such as hormone production, collagen synthesis, and immune
potentiation. Humans are unable to synthesize vitamin C; therefore, they must acquire vitamin
C from dietary sources [11]. Vitamin C is transported across cellular membranes by sodium
vitamin C co-transporter (SVCT). In addition, vitamin C spontaneously oxidizes both
intracellularly and extracellularly to its biologically inactive form, dehydroascorbate (DHA)
[11, 12]. DHA is unstable at physiological pH and, unless it is reduced back to vitamin C by
glutathione (GSH), it may irreversibly be hydrolyzed. Therefore, DHA is reduced to vitamin
C after import at the expense of GSH, thioredoxin, and NADPH (reduced nicotinamide
adenine dinucleotide phosphate). Consequently, reactive oxygen species (ROS) production
increases inside the activated immune cells (similar to cancer cells) due to the reduction of
ROS scavenging systems involving redox couples, such as NADPH/NADP+ and GSH/GSSG
(glutathione disulfide). Therefore, high-dose vitamin C, unlike the general assumption, acts as
a pro-oxidant in a cell type-dependent manner [12].
Sepsis is characterized by systemic inflammation, increased oxidative stress, insulin
resistance, and peripheral hypoxia. Remarkably, severe sepsis resulted in a ~43-fold increase
in GAPDH expression [13]. GAPDH is a redox-sensitive enzyme that can become rate-
limiting when glycolysis upregulated in the setting of Warburg effect, as it is in both cancer
cells [12] and activated immune cells. In addition to oxidizing and inhibiting GAPDH, the
elevated ROS may also lead to the DNA damage and the activation of poly(ADP-ribose)
polymerase (PARP). PARP activation leads to the NAD+ (nicotinamide adenine dinucleotide)
consumption following vitamin C treatment. Significantly, NAD+ is required for the
enzymatic activity of GAPDH as a co-factor; therefore, the decrease in NAD+ further
diminishes GAPDH enzymatic activity. Altogether, high-dose vitamin C-induced GAPDH
inhibition decreases the generation of ATP and pyruvate that induces an energetic crisis
(Figure), ultimately leading to cell death [11, 12]. In other words, GAPDH inhibition may
lead to the loss of activity of immune effector cells and related immunosuppression. These
results provide a mechanistic rationale for exploring the therapeutic use of vitamin C to
prevent inflammatory hyperactivation in myeloid and lymphoid cells.
Intravenous high-dose vitamin C treatment for 2019-nCoV disease
The results of meta-analyses have been demonstrated that intravenous (IV) high-dose
vitamin C treatment has significant benefits in the treatment of sepsis and septic shock. Sepsis
is a life-threatening organ dysfunction syndrome triggered by a disrupting host systemic
inflammatory reaction to the pathogenetic microorganisms and their products. ARDS,
devastating and mostly lethal condition, is also easily developed in patients with systemic
inflammatory response, such as sepsis [14].
Rolipram, a typical phosphodiesterase-4 inhibitor, can inhibit TNFα production in
activated macrophages and restrain acute inflammatory response. Rolipram was suggested as
a novel drug treatment for sepsis and septic shock due to its potent immunosuppressive effects
[15]. By analogy, the beneficial effects of intravenous high-dose vitamin C in sepsis and
septic shock are most likely due to its immunosuppressive effects.
While immune effector cells are dependent on glycolysis for their bioenergetic
functions, lung epithelial cells use mitochondrial oxidative phosphorylation to produce ATP.
Therefore, high-dose vitamin C treatment acts as a prooxidant for immune cells, but as an
antioxidant for lung epithelial cells. Furthermore, vitamin c treatment may protect innate
immunity of ATII through the inhibition of the lactate secretion, produced by the activated
immune cells.
In connection with the prooxidant role of vitamin C, which requires
pharmacological (millimolar) rather than physiological (micromolar) concentrations,
reevaluating the high-dose infusion of vitamin C would be a timely choice for the COVID-19-
related ARDS. Altogether, patients diagnosed with COVID-19 and hospitalized with the
breathing difficulty and abnormal biomarkers seem to be candidate for a short period of high
dose intravenous vitamin C treatment in the early periods of the disease. However, the
concern that may arise with high-dose vitamin c treatment is osmotic cell death of immune
cells, but not apoptosis, which could generate a local inflammation in alveolar medium.
Therefore, IV glucocorticoid treatment must be added to attenuate the possible inflammatory
complications of high-dose vitamin c treatment. Previously experienced and comparably well-
tolerated treatment regimen for high-dose intravenous vitamin C could be the administration
of 50 mg/ per kilogram body weight every 6 hours for 4 days [14] with a glucose restriction.
In addition, hydrocortisone 50 mg IV every 6 hours for 7 days must be added to fight against
therapy-induced inflammation. Vitamin C when used as a parenteral agent in high doses may
act pleiotropically as a prooxidant to attenuate pro-inflammatory mediator expression,
improving alveolar fluid clearance, and to act as an antioxidant to improve epithelial cell
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Vitamin C
Vitamin C
Activated effector Immune cell
Glucose versus DHA
competitive transport from
Vitamin C
Alveolar epithelial cell
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CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival.
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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has long been used as a default reference gene in quantitative mRNA profiling experiments. However, its expression reportedly varies in response to a range of pathophysiological variables (inflammation, oxidative stress, hyperinsulinaemia, hypoxia) which feature prominently in sepsis. We therefore assessed the applicability of using GAPDH as a reference gene for expression studies in sepsis compared to other housekeeping genes (succinate dehydrogenase complex subunit A (SDHA), hypoxanthine phosphoribosyltransferase (HPRT)-1). Severe sepsis resulted in a 42.4-fold increase in median GAPDH expression (P < 0.001), whereas median HPRT expression was raised more modestly (2.9-fold; P < 0.001), and there was no significant difference in SDHA expression between sepsis and control patients. HPRT was identified by NormFinder to be the most stably expressed single gene. In order to assess the impact of this variability on data interpretation, interleukin (IL)-10 expression was normalised separately to GAPDH and to the geometric mean of HPRT and SDHA. In the former case, there was no significant difference in IL-10 expression between controls and septic patients, whilst in the latter, a significant 8.5-fold increase in median IL-10 expression was noted (P < 0.001). GAPDH is thus an unreliable housekeeping gene for normalising gene expression in sepsis which should be replaced by alternative, validated reference genes.
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Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.
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Severe acute respiratory syndrome (SARS), which is caused by a novel coronavirus (CoV), is a highly communicable disease with the lungs as the major pathological target. Although SARS likely stems from overexuberant host inflammatory responses, the exact mechanism leading to the detrimental outcome in patients remains unknown. Pulmonary macrophages (Mphi), airway epithelium, and dendritic cells (DC) are key cellular elements of the host innate defenses against respiratory infections. While pulmonary Mphi are situated at the luminal epithelial surface, DC reside abundantly underneath the epithelium. Such strategic locations of these cells within the airways make it relevant to investigate their likely impact on SARS pathogenesis subsequent to their interaction with infected lung epithelial cells. To study this, we established highly polarized human lung epithelial Calu-3 cells by using the Transwell culture system. Here we report that supernatants harvested from the apical and basolateral domains of infected Calu-3 cells are potent in modulating the intrinsic functions of Mphi and DC, respectively. They prompted the production of cytokines by both Mphi and DC and selectively induced CD40 and CD86 expression only on DC. However, they compromised the abilities of the DC and Mphi in priming naïve T cells and phagocytosis, respectively. We also identified interleukin-6 (IL-6) and IL-8 as key SARS-CoV-induced epithelial cytokines capable of inhibiting the T-cell-priming ability of DC. Taken together, our results provide insights into the molecular and cellular bases of the host antiviral innate immunity within the lungs that eventually lead to an exacerbated inflammatory cascades and severe tissue damage in SARS patients.
In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
Highly pathogenic human respiratory coronaviruses cause acute lethal disease characterized by exuberant inflammatory responses and lung damage. However, the factors leading to lung pathology are not well understood. Using mice infected with SARS (severe acute respiratory syndrome)-CoV, we show that robust virus replication accompanied by delayed type I interferon (IFN-I) signaling orchestrates inflammatory responses and lung immunopathology with diminished survival. IFN-I remains detectable until after virus titers peak, but early IFN-I administration ameliorates immunopathology. This delayed IFN-I signaling promotes the accumulation of pathogenic inflammatory monocyte-macrophages (IMMs), resulting in elevated lung cytokine/chemokine levels, vascular leakage, and impaired virus-specific T cell responses. Genetic ablation of the IFN-αβ receptor (IFNAR) or IMM depletion protects mice from lethal infection, without affecting viral load. These results demonstrate that IFN-I and IMM promote lethal SARS-CoV infection and identify IFN-I and IMMs as potential therapeutic targets in patients infected with pathogenic coronavirus and perhaps other respiratory viruses.
More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impairs tumor growth in Apc/KrasG12D mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.