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Trivedi, V.S.;  Magnusen, A.F.;  Rani, R.;  Marsili, L.;  Slavotinek, A.M.;  Prows, D.R.;  Hopkin, R.J.;  Mckay, M.A.;  Pandey, M.K. Complement–Sphingolipid System in COVID-19 and Gaucher Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/36640 (accessed on 02 July 2024).
Trivedi VS,  Magnusen AF,  Rani R,  Marsili L,  Slavotinek AM,  Prows DR, et al. Complement–Sphingolipid System in COVID-19 and Gaucher Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/36640. Accessed July 02, 2024.
Trivedi, Vyoma Snehal, Albert Frank Magnusen, Reena Rani, Luca Marsili, Anne Michele Slavotinek, Daniel Ray Prows, Robert James Hopkin, Mary Ashley Mckay, Manoj Kumar Pandey. "Complement–Sphingolipid System in COVID-19 and Gaucher Diseases" Encyclopedia, https://encyclopedia.pub/entry/36640 (accessed July 02, 2024).
Trivedi, V.S.,  Magnusen, A.F.,  Rani, R.,  Marsili, L.,  Slavotinek, A.M.,  Prows, D.R.,  Hopkin, R.J.,  Mckay, M.A., & Pandey, M.K. (2022, November 25). Complement–Sphingolipid System in COVID-19 and Gaucher Diseases. In Encyclopedia. https://encyclopedia.pub/entry/36640
Trivedi, Vyoma Snehal, et al. "Complement–Sphingolipid System in COVID-19 and Gaucher Diseases." Encyclopedia. Web. 25 November, 2022.
Complement–Sphingolipid System in COVID-19 and Gaucher Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/ijms232214340

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-induced disease (COVID-19) and Gaucher disease (GD) exhibit upregulation of complement 5a (C5a) and its C5aR1 receptor, and excess synthesis of glycosphingolipids that lead to increased infiltration and activation of innate and adaptive immune cells, resulting in massive generation of pro-inflammatory cytokines, chemokines and growth factors. This C5a–C5aR1–glycosphingolipid pathway- induced pro-inflammatory environment causes the tissue damage in COVID-19 and GD. Strikingly, pharmaceutically targeting the C5a–C5aR1 axis or the glycosphingolipid synthesis pathway led to a reduction in glycosphingolipid synthesis and innate and adaptive immune inflammation, and protection from the tissue destruction in both COVID-19 and GD. 

lipid viral infection rare-genetic disease innate and adaptive immunity inflammation

1. Introduction

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-induced Disease (COVID-19) displays complement activation products (Table 1) and excess formation of sphingolipids [1][2][3][4]. Additionally, SARS-CoV-2 triggers infiltration and activation of several classes of innate and adaptive immune cells, as well as the abnormal production of pro-inflammatory cytokines, chemokines, and growth factors in COVID-19 (Table 1 and Table 2). Such SARS-CoV-2-induced immune inflammation affects multiple organs (i.e., lung, liver, spleen, cardiovascular system, and brain) and causes the development of moderate (e.g., high fever, shortness of breath, loss of taste and/or smell, sore throat, nausea, and vomiting) to severe (e.g., pneumonia, bronchitis, respiratory failure, lung damage and death) symptoms of COVID-19 [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23].
Table 1. Immune cells and their effector inflammatory mediators in COVID-19.
Coronavirus Immune Cell
Involvement		 Source Changes in
Complement
Products, Cytokines
and Chemokines		 References
SARS-CoV-2 Leucocytes, PMNs
PCs
Endothelial cells		 Blood
Sera
Lungs		 C5a +++
C5aR1 +++
MAC +++		 [24][25][26][27][28]
SARS-CoV-2 Type-II pneumocytes Pulmonary cells
Platelets		 Blood
Sera
Lungs		 C1q P+++
C3b-regulatory factor H (FH) P+++
C3 P+++		 [26][29][30][31]
SARS-CoV-2 Type-II pneumocytes PBMCs Blood
Sera
Lung		 C3a P+++
C3aR P +++
C3b-CD46 P+++		 [26][31][32][33][34]
SARS-CoV-2 PBMCs Blood
Sera		 sC5b-9 P+++ [27][35][36][37]
SARS-2 Respiratory specimen cells
Alveolar cells		 Blood
Sera
Lung		 C4d P+++ [35][38]
SARS-CoV-2 Respiratory
specimen cells		 Blood
Sera		 C3bBbP P+++ [35]
SARS-CoV-2 Respiratory
specimen cells		 Blood
Sera		 C3bc P+++ [35]
SARS-CoV-2 PBMCs
Glomeruli
Cardiac Microthrombi
and Alveolar cells		 Blood Sera
Lung
Heart
Kidney		 C5b-C9 P+++ [36][37][38][39][40]
SARS-CoV-2 Pulmonary cells Lung C1r P+++ [29]
SARS-CoV-1 Pulmonary cells Lung iC3b P+++ [31]
SARS-CoV-1 Pulmonary cells Lung C3c P++ [31]
SARS-CoV-1 Pulmonary cells Lung C3dg P+++ [31]
MERS MOs/Mɸs
T cells
mDCs
pDCs
PMNs		 Liver
SPL
Lung
Kidney
Heart
Serum		 IL12 M+++
IL8 M+++
TNFα M+++
IL-6 M&P+++
IFNλ M+++
CXCL10 M&P+++
CCL2 M+++
CCL3 M+++
CCL5 M+++
IFNα M+ & P+++
IFNβ M+ & P+++		 [41][42][43][44][45][46][47]
SARS-CoV-1 Mos
Mɸs
DCs
Cord blood cells		 Lung
Blood		 IFNβ M+
IFNα M+
TNFα M+++
IFNλ M+++
IL8 M+++
TNFα M+++
IL6 M+++
CCL2 M+++
CCL3 M+++
CCL5 M+++
CXCL10 M+		 [42][48][49][50]
SARS-CoV-2 MOs
Mɸs		 Blood IL6 P+++
IL8 P+++
IL10 P+++
TNFα P+++		 [51]
SARS-CoV-2 CD8+ cells
NK+ cells		 PBMCs IL2 P+
TNFα P+
IFNγ P+++
Granzyme B P+++		 [52][53]
SARS-CoV-2 CD8+ cells
CD4+ cells		 Liver
Lung
Heart		 Cytokines NR [53]
SARS-CoV-2 PMNs Lung Cytokines NR [54]
MERS CD4+ T cells
CD8+ T cells		 Lymph Nodes
Spleen
Tonsils
PBMCs		 Caspase-3 P+++ [55]
SARS-CoV-1 CD4+ cells
CD8+ cells
CD45RO+ and
CD27+ cells		 PBMCs IL2 P++
TNFα P++
IFNγ P+++
IL4 PNS
CXCL10 PNS		 [56][57]
SARS-CoV-2 CD4+ T cells
CD8+ T cells
Regulatory T cells		 PBMCs CCR6 P+++
Perforin P+++
IL6 P+++
IL2 M+++
IL7 M+++		 [51][58][59][60][61][62][63]
MERS Epithelial cells Lung IL1β M+++
IL6 M+++
IL8 M+++
IFNα M+
CCL2 M+
CXCL10 M+		 [64][65]
SARS-CoV-1 Epithelial cells Lung TNFα M+++
IFNβ M+++
CXCL10 M+++		 [64]
COVID-19 (Coronavirus disease 2019), MERS-CoV (Middle East Respiratory Syndrome Coronavirus), SARS-CoV-1 (Severe Acute Respiratory Syndrome Coronavirus-1), SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2), AECs (Airway epithelial cells), Mɸs (Macrophages), DCs (Dendritic cells), PMNs (Polymorphonuclear cells), NK (Natural Killer cells), IFN (interferon), α (alpha), β (beta), γ(gamma), λ (lambda), IL (interleukin), TNF (tumor necrosis factor), CCL (Chemokine (C-C motif) ligand), CXCL (Chemokine (C-X-C motif) ligand), PBMCs (Peripheral Blood Mononuclear Cells), PCs (Pulmonary Cells), MAC (Membrane Attack Complex; MAC), C3a (Complement 3a), C3b (Complement 3b), C3aR (Complement 3a Receptor), C5a (Complement 5a), C5aR1 (C5a Receptor 1), sC5b-9 (soluble C5b-9; MAC); C4d (Complement 4d). C3bBbP (complement 3 b bound protease fragment), C3bc (Complement 3 bc), P (Protein expression level), M (mRNA expression level) + (low), ++ (moderate), and +++ (high), NS (not significant).
Increased levels of complement activation products have been linked to innate and adaptive immune cell activation and increased production of pro-inflammatory cytokines, chemokines, and growth factors in GD (Table 3). The excess tissue and cellular accumulation of glucosylceramides (GCs) and their subsequent roles in the induction of innate and adaptive immune inflammation significantly affect visceral organs (e.g., liver, spleen, lung, bone, and kidney) and the central nervous system (CNS), causing the development of GD manifestations characterized by anemia, thrombocytopenia, hypergammaglobulinemia, splenomegaly, hepatomegaly, respiratory distress, skeletal weakness, loss of neurons, and death [66][67][68][69][70][71][72][73][74][75][76].

2. COVID-19

COVID-19 is caused by infection with SARS-CoV-2, a member of the family of betacoronaviruses that also includes the SARS-CoV-1 and Middle East Respiratory Syndrome-CoV (MERS-CoV) [77][78]. SARS-CoV-2 is a large, enveloped, single-stranded positive-sense RNA virus with a genome size of about 30 kb. The 5′ end of the SARS-CoV-2 genome encodes two polyproteins termed PP1a and PP1ab, which are mutually called replicases. These polyproteins are classified with 16 non-structural proteins, including RNA-dependent RNA polymerase (RDRP), 3-chymotrypsin-like protease (3CLP), and papain-like protease (PLP). The 3′ end of the SARS-CoV-2 genome encodes four essential structural proteins: spike (S; essential for the viral entry into host cells), envelope (E; responsible for viral membrane twist and binding to the nucleocapsid), membrane (M; bind to the viral RNA genome and guarantee the conservation of the RNA in the shape of the beads-on-a-string) and the nucleocapsid (N; required for viral replication and pathogenesis of the disease). The 3′ end also encodes non-structural proteins, including PLP, 3CLP, RDRP, helicase, and the collection of accessory proteins, which affect the host-specific immune reactions [79][80][81]. The S protein is critical for the infectivity of SARS-CoV-2 and is cut by a host protease into the S1 and S2 subunits. The S1 subunit binds to angiotensin converting enzyme-2 (ACE2), which acts as a protease to cleave angiotensin II and also counteracts the effect of angiotensin II [82][83]. ACE2 is the cellular receptor for SARS-CoV-2 and is widely expressed in blood vessels, tongue, lung, adipose tissue, adrenal gland, heart, esophagus, lung, muscle, ovary [22][84][85][86] and eye tissues (i.e., conjunctiva, choroid, vascular endothelium, and nerves) [87][88][89][90][91].
The S2 subunit is activated by transmembrane protease serine-2 (TMPRSS2) associated with the host surface. These combined actions result in host-viral membrane fusion and SARS-CoV-2 entry into the host cells [92][93]. The viral RNA genome is released into the host cell cytoplasm, where it first uses the host translational machinery for the formation of the viral structural and accessory proteins [79][93]. The newly synthesized structural and accessory proteins are transferred through the endoplasmic reticulum and Golgi bodies followed by assembly of new virions in the growing Golgi vesicles [81]. Finally, similar to the MERS-CoV and SARS-CoV-1, the mature SARS-CoV-2 virions are exocytosed from the host cell into the surrounding environment to repeat the infection cycle. Infection results in activation of innate and adaptive immune cells and a massive generation of several pro-inflammatory mediators (Table 1 and Table 2) that instigate moderate to severe disease symptoms of COVID-19 [14][15][16][17][18][19][20][21][22][23]. The SARS-CoV-2-induced development of COVID-19 disease has been reported in people with immunocompromised and morbid conditions, such as sepsis, acute cardiac injury, heart failure, and multi-organ (e.g., liver, spleen, kidney, and brain) disease [94]. Epidemiological studies related to COVID-19 have found that males are slightly more prone to infection as compared to females, but both sexes experience severe forms of COVID-19 and death. Persons > 60 years old or with chronic diseases, such as type 2 diabetes and essential hypertension, were at higher risk for SARS-CoV-2-induced systemic inflammation leading to a severe form of COVID-19 [95][96][97].
Table 2. Coronavirus-induced production of circulatory cytokines.
Coronavirus Source Cytokines Chemokines Growth Factors References
MERS Sera IFNα P+++
IL6 P+++
IL8 P+++		 CCL5 P+++
CXCL10 P+++		   [45][47][98]
SARS-CoV-1 Sera IFNα P+++
IFNγ P+++
IL1 P+++
IL2 P+++
IL6 P+++
IL8 P+++
IL10 P+
IL12 P+++		 CCL2 P+++
CXCL9 P+++
CXCL10 P+++		 TGFβ P+++ [98][99][100][101][102][103][104][105][106][107][108][109]
SARS-CoV-2 Sera IFNγ P+++
TNFα P+++
IL1b P+++
IL1RA P+++
IL2 P++
IL2R P++
IL4 P++
IL5 P++
IL6 P+++
IL7 P+++
IL8 P+++
IL9 P+++
IL10 NS
IL12 P+++		 CCL2 P+
CCL3 P+
CXCL10 P+		 G-CSF P+++
GMCSF P+++
VEGF P+++
FGF P+++
PDGF P+++		 [57][59][62][98][110][111][112][113][114]
SARS-CoV-2 Sera   CCL2 P+++   [109][114]
SARS-CoV-2 Sera   CCL3 NS   [109]
SARS-CoV-2 Sera   CXCL8 P+++   [114]
SARS-CoV-2 Sera   CXCL10 P++   [109][114]
MERS-CoV (Middle East Respiratory Syndrome Coronavirus), SARS-CoV-1 (Severe Acute Respiratory Syndrome Coronavirus-1), SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2), IFN (interferon), IL (interleukin), TNF (tumor necrosis factor), CCL (C-C motif ligand), CXCL (C-X-C motif ligand), TGF (transforming growth factor), GCSF (granulocyte colony stimulating factor), GMCSF (granulocyte-Mɸ colony stimulating factor), VEGF (vascular endothelial cell growth factor), FGF (fibroblast growth factor), PDGF (platelet-derived growth factor), α (alpha), β (beta), γ (gamma), λ (lambda), P (Protein expression level), M (mRNA expression level): + (low), ++ (moderate), and +++ (high), NS (not significant).
Table 3. Immune cells involvement in GD.
  Mouse Model of GD GD Patients
Immune Cells Tissue Recruitment References Immune Cells References
MOs Blood +++ [115] Blood - [116][117]
Mɸs Blood +++, Liver +++,
Spleen +++, Lung +++		 [66][115][118][119] Lymph node +++ [120]
mDCs Blood +++, Liver +++,
Spleen +++, Lung +++		 [66][115][118][119] Blood - [116][117][121][122]
pDCs     Blood - [116][117][121]
PMNs Blood +++, Liver +++,
Spleen +++, Bone Marrow +++		 [66][115]    
CD4 + TCells Liver +++, Spleen +++, Lung +++ [66][118][119] Blood +++ [121][122]
CD8 + T Cells Thymus +++,
Spleen +++		 [118][119] Blood +++ [122][123]
NK Cells     Blood - [121][123]
MOs (Monocytes), Mɸs (Macrophages), mDCs (myeloid dendritic cells), pDCs (plasmacytoid dendritic cells), PMNs (Polymorphonuclear cells), NK (Natural killer cells), Increased (+++) and decreased (-) tissue recruitment.

3. Gaucher Disease

GD is a classic example of a lysosomal storage disease and has a worldwide incidence of approximately 1/40,000 to 1/60,000 [124]. GD is classified into Types 1, 2, and 3, which are all caused by pathogenic variants in GBA1 (in human)/Gba1 (in mouse) that lead to the functional disruption of the encoded lysosomal enzyme, acid β-glucosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase, EC 4.2.1.25; GCase) and to excess tissue accumulation of glucosylceramides (GC) [23]. Type 1 GD mainly affects the liver, spleen, lung, bone, and kidney [125][126]. A significant proportion of patients with Type 1 GD also have CNS manifestations characterized by the mild brain inflammation [66][67][127][128][129]. Type 2 and Type 3 GD are the neuronopathic forms of GD (nGD), which are characterized by severe and chronic brain inflammation that leads to the loss of neurons and early death (e.g., <2 years in patients with Type 2 nGD and 10–40 years in patients with Type 3 nGD) [129][130][131][132][133][134][135][136][137][138][139][140][141][142]. The main neurological symptoms of Type 2 and 3 nGDs are characterized by selective degeneration of the cerebellar dentate nucleus and the dentato-rubro-thalamic pathway, generalized epilepsy and seizures, horizontal saccadic eye movements, ataxia, spasticity, oculomotor abnormalities, hypertonia of the neck muscles, extreme arching of the neck, bulbar signs, limb rigidity, occasional choreoathetoid movements, and progressive dementia [143][144][145][146][147][148][149][150][151][152][153][154][155][156]. Enzyme replacement therapy (e.g., imiglucerase, velaglucerase, or taliglucerase) and substrate reduction therapy (e.g., eliglustat and miglustat) are available to treat many of the visceral aspects of GD but have no impact on the CNS disease and are of limited benefit in the management of immune inflammation and disease complications in multiple organs such as the bones, lungs, and lymph nodes [70][157][158][159]. The development of alternative therapies, i.e., gene, substrate reduction, and enzyme replacement therapies, has been hampered by limitations in understanding disease pathogenesis, inability of therapies to fully cross the blood-brain barrier, and toxicity concerns due to procedural risks [126][160][161][162][163].

4. Complement Activation in COVID-19 and Gaucher Disease

The complement system comprises a group of liquid and cell membrane-associated proteins, which are mainly produced in the liver. However, certain brain cells, such as microglial cells, astrocytes, and neurons, are also involved in the direct synthesis of complement proteins [164][165][166]. Complement activation is a complex process, which largely occurs by the classical, alternative, and lectin pathways [167]. The classical pathway is activated by ligation of the IgG and/or IgM immune complexes (ICs) to their corresponding receptors and/or C1q on the cell surface. The alternative pathway is activated by binding of spontaneously activated C3 protein (C3b fragment) to host and non-host cell surfaces [168][169]. The lectin pathway is activated by the binding of the mannan-binding lectin (MBL) to mannose-containing carbohydrates or related ficolins to certain carbohydrates or acetylated structures [165][170][171]. Each of the complement activation pathways follows a series of reactions generating common key components known as C3 and C5 [172]. The downstream cleavage of C3 by the C3 convertases causes the formation of C3a and C3b [172]. Similarly, the downstream cleavage of C5 by the C5 convertases causes the formation of C5a and C5b [172]. C3a binds the C3aR receptor, and C5a binds C5aR1 and C5aR2 receptors [172]. C3b is a major opsonin that induces the tagging and phagocytic uptake of pathogens, and C5b initiates the terminal complement pathway, resulting in the formation of the membrane attack complex (MAC) composed of C5b, C6, C7, C8 and multiple C9 molecules [35][172][173][174][175]. Several activated components of the complement system are essential for controlling cellular and metabolic functions in both visceral organs and the CNS [176][177][178][179][180]. However, the abnormal activation and production of complement components such as C3, C3b, iC3b, CR3, C5, C5a, and MAC/C5b-9 can contribute to visceral and CNS tissue damage in several diseases including, but not limited to, allergic diseases, cardiovascular diseases, age-related macular degeneration, systemic lupus erythematosus, traumatic brain injury, stroke, neuromyelitis optica spectrum disorders, and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer’s disease and Huntington disease [181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199].
Complement activation has been observed in H5N1 and H1N1 influenza virus infections [200]. The sera and lung tissues of the MERS-CoV-infected, hDPP4-transgenic (hDPP4-Tg) mouse model showed complement activation and increased production of C5a and C5b-9, as well as increased viral replication [201][202]. Furthermore, targeting C5aR with anti-C5aR antibody treatment in the MERS-CoV-infected hDPP4-Tg mouse model decreased viral replication and damage to lung and spleen tissue [201][202]. The lung of the mouse-adapted SARS-CoV animal model has also demonstrated complement activation and higher virus replication [31]. To investigate whether SARS-CoV triggered complement activation in the mouse model, C3-/- and background matched control wildtype (WT) mice were infected with SARS-CoV-2 and their lung tissues analyzed for immune inflammation. The data showed that C3-/- mice infected with SARS-CoV-2 were protected against the development of respiratory dysfunction and lung damage when compared to WT mice [31].
SARS-CoV-2 infected primary human airway epithelial cells also caused complement activation and increased production of C3a [203]. C3aR and C5aR targeting in cellular models also showed protection from lung tissue damage [203]. Lung and skin tissues and sera from patients with severe COVID-19 have shown increased complement activation and massive generation of C5a, C5b-C9, and C5aR1 in blood and pulmonary myeloid cells [176]. Studies have shown that SARS-CoV-2 induced hyperinflammation is linked to the development of acute respiratory distress syndrome (ARDS), systemic clotting, and a variety of cutaneous manifestations in patients with COVID-19 [204][205][206][207][208][209][210][211]. Strikingly, administration of C3 (AMY101) or C5 (eculizumab) targeting drugs have shown marked reduction in the SARS-CoV-2-induced development of severe disease symptoms and lung damage in COVID-19 patients [204][205][206]. These data suggest that complement activation and the resultant activation of the C5a–C5aR1 axis is critical for propagating the disease complications in patients with COVID-19.
Investigations into the mechanisms by which complement activation occurs in COVID-19 revealed (1) the receptor-binding domain of the spike protein of SARS-CoV-2 binds to specific IgG/IgM antibodies, (2) heparan sulfate binds to the spike protein of SARS-CoV-2, and (3) recognition of the spike and nucleocapsid proteins of SARS-CoV-2 by lectin pathway components subsequently triggers complement activation by the classical, alternative, and lectin pathways [32][35][212][213][214]. Mouse IgGs (IgG1, IgG2a/c, IgG2b, and IgG3) and their matching receptors (e.g., FcγRI, FcγRIIb, FcγRIII and FcγRIV) differ from the human IgGs (e.g., IgG1, IgG2, IgG3, and IgG 4) and their receptors (e.g., FcγRI, FcγRIIa, FcγRIIc, FcγRIIIa, FcγRIIb, and FcγRIIIb) [215]. Human or mouse FcγRI binds only to the monomeric IgG, but all the other FcγRs in the mouse (e.g., FcγRIIb, FcγRIII and FcγRIV) and human (e.g., FcγRIIa, FcγRIIb, FcγRIIIa and FcγRIIIb) can bind to IgG-ICs [215][216]. SARS-CoV-2 infection can result in the sustained development of memory B cells and long-lived bone marrow plasma B cells [217][218][219] and the production of IgG, IgM, and IgA antibodies to S, the RBD of S, and N proteins. The SARS-CoV-2-specific IgA/IgM antibodies are present only for a short period of time, whereas the SARS-CoV-2-specific IgG antibodies persist for long periods of time, thereby providing protection against SARS-CoV-2 in patients with COVID-19 [220][221].
The crosslinking of IgG2a/IgG2b ICs to the FcγRIII/FcγRIV in mice and IgG1 IC crosslinking to the activating FcγR in humans cause optimal complement activation and C5a formation [23][222][223][224][225][226][227][228]. Analysis of IgG and their receptors revealed higher expression of the activating FcγR receptors [229] and increased production of SARS-CoV-2-specific IgG antibodies (IgG1 > IgG2 > IgG3) in patients with COVID-19 [23][221][230]. These findings suggest that the IgG isotypes developing in COVID-19 contribute to complement activation. Researchers and others have reported higher levels of complement activation products (e.g., C1q, C3, C4b C5a, C3aR, C5aR1, and C-type lectins) in mouse models and patients with GD. Studies on the Gba1 mutant mouse model, specimens from Type 1 GD patients, and induced pluripotent stem cell (iPSC)-derived Mɸs and lymph nodes from Type 2 and type 3 nGD patients have shown that activation of complement and the C5a–C5aR1 axis leads to tissue inflammation and organ failure in GD [120]. Further, researchers and others have shown that genetic deficiency of C5aR1 or pharmaceutical targeting to block this receptor in mouse models of GD and in human cell models resulted in marked reduction of immune inflammation and tissue damage (e.g., lung, liver, and spleen) [228][231]. Increased production of autoantibodies specific to GC, IgG2a/c and IgG2b are seen in the Gba19V/- mutant mouse model of GD. Also, high levels of GC-specific IgG1 autoantibodies and lower levels of IgG2 and IgG3 autoantibodies have been observed in GD patients [228]. Similarly, experimental mouse models of GD and GD patients have shown elevated levels of mouse/human specific FcγRIII and FcγRIV [228][232][233]. C1q-binding to IgG-IC drives a series of events resulting in the proteolytic cleavage of C4, C2, and C3 and eventually of C5 into C5a and C5b. Further, C5a can be generated locally in immune cells through an FcγR-dependent mechanism involving LAT phosphorylation and production of a C5-cleaving protease [182][222][223][224][225][226][227][234][235][236]. Researchers have observed that massive GC accumulation drives the production of GC-specific IgG2a/c and IgG2b-ICs in Gba19V/- mice, as well as IgG1 and IgG3 ICs in GD patients to initiate complement activation through the classical pathway [228]. These findings suggest common involvement of complement activation and C5a–C5aR1 axis-mediated tissue inflammation in GD and COVID-19. Therefore, targeting complement at the level of the C5a–C5aR1 axis could control SARS-CoV-2-induced tissue inflammation in COVID-19 in addition to GD patients with COVID-19.

5. Complement Activation Is Linked to the Increased Synthesis of Glucosylceramide Synthase Enzymes and Excess Production of Sphingolipids in COVID-19 and GD

Several studies have shown that in vivo and ex vivo stimulation of immune cells with immune complexes (e.g., IgG and IgM ICs) and complement activation products (e.g., C3, C3a, C3b, and C5a) can cause excess secretion of lysosomal enzymes. Sphingolipids are ubiquitous components of the plasma membrane of eukaryotic cells and are essential for controlling cell proliferation, survival, and death [4][237]. However, prolonged overabundance of sphingolipids is detrimental, as seen in several lysosomal storage disorders such as GD, Fabry disease, Tay-Sachs disease, Sandhoff disease, Krabbe disease, and Niemann–Pick disease [238]. GC is an important sphingolipid, representing the backbone of more than 450 structurally different glycosphingolipids. Activation of GCS, the enzyme that places a glucosyl moiety onto ceramide, is the first pathway-committed step in the production of more complex GSLs, such as lactosylceramide and gangliosides [239].
Increased formation of GSLs such as GM2-ganglioside and lactosylceramide, have been observed upon infection by Zika virus and hepatitis C virus, respectively [240][241]. Human cytomegalovirus infection also causes an excess formation of ceramide and GM2-ganglioside [242]. Dengue virus causes the increased production of ceramide and sphingomyelin [243]. Influenza virus infection has also demonstrated increased synthesis of GC and sphingomyelin [244][245]. Conversely, suppression of the biosynthesis of cellular GSLs results in the inhibition of maturation of influenza virus particles in vitro [246][247]. It was recently suggested that GSLs support SARS-CoV-2 replication and infection [248][249]. Elevated levels of 3-ketosphinganine (16-0, 18-0, 18-1, and 20-0), sphinganine, sphingosine, dihydrosphingosine, ceramides, dihydroceramides, sphinganine-1-phosphate (S1P), GA1, and GM3 have been observed in SARS-CoV-2 infection in vitro and in vivo in experimental mouse and human cells models as well as in the sera/plasma of COVID-19 patients [1][2][3][4]. Furthermore, drugs targeting GCS inhibited the replication of SARS-CoV-2 [250].
Pathogenic variants in GBA1/Gba1 and the resultant deficiency of acid-β glucosidase drive massive increases of GCs: 18-0, 20-0, 22-1, 22- 0, 24-1, and 24-0 in tissues (e.g., lung, liver, spleen, and brain) from mouse models and human patients with type 1, 2 and 3 GD [66][67][115][128][132][133][134][228][251][252][253][254][255][256][257]. Genetic deficiency or pharmaceutical targeting of C5aR1 in mouse models and human cellular models of GD (e.g., macrophages, and dendritic cells), showed marked reduction in the generation of GCS and GCs (e.g.,16-0, 18-0, 20-0, 22-1, 22- 0, 24-1, and 24-0) [228][231]. Importantly, studies have shown that a majority of GD patients treated with substrate reduction and/or enzyme replacement therapies and experienced SARS-CoV-2 infection only developed mild symptoms of COVID-19 and survived. These findings suggest that the C5a–C5aR1-induced excess sphingolipid production propagates the disease in COVID-19 and GD. Thus, targeting the C5a–C5aR1 axis-mediated overproduction of GC could control SARS-CoV-2 replication and prevent development of severe disease in patients with COVID-19 and GD patients with COVID-19.

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Vyoma Snehal Trivedi
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Albert Frank Magnusen
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Reena Rani
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Luca Marsili
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Anne Michele Slavotinek
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Daniel Ray Prows
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Robert James Hopkin
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Mary Ashley McKay
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Manoj Kumar Pandey
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Entry Collection: COVID-19
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Update Date: 29 Nov 2022
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