The virus-antibody complexes formed during COVID-19 infection, ligate Fc receptors, activate complement, cause inflammation and trigger type III hypersensitivity. I summarize the results for FcR signaling in the activation of CD4+ T cells, platelets, and a likely contribution to brain cells. FcRs engagement by the immune complexes (ICs) triggers thrombosis and neurological disease. Anaphylatoxins C3a, and C5a produced post complement activation by the ICs cause inflammation and cell death. FcR signaling in CD4+ T cells and platelets, overly induce the gene expression of signaling pathways that drive cellular activation and differentiation. Further understanding of these mechanisms is required for understanding the pathology and the development of therapies required to manage long-term symptoms of COVID-19 disease.

• CD4+ T cells, Platelets, Olfactory Receptors, Fc receptors, GPCRs, and Complement

Chauhan AK (2021) Type III hypersensitivity reactants in platelets and CD4+ T cell Activation in COVID-19 Mechanisms for Thrombosis and Brain Blood Clot Formation. J Transl Med Epidemiol 5(1): 1044.

• Immune complexes (ICs) and complement contribute to the blood clot formation in COVID-19.

• Complement activating ICs cause type III hypersensitivity observed in COVID-19 patients.

• Complement opsonized ICs triggers thrombotic events and thrombocytopenia.

• CD4+ T cells that express Fc receptors form aggregates with platelets by engaging ICs.

• FcR signaling in the CD4+ T cells and platelets drives Gprotein coupled receptor protein expression.

• Enhanced expression of olfactory receptor oroteins is observed in CD4+ T cells upon ICs treatment.

• CD32a expressed by platelets contribute to the antibody dependent enhancement of SARS-Cov-1virus in vitro.

COVID-19 infection is now classified as type III hypersensitivity immune reaction, grouped in this category by World Health Organization (1-4). The immune reactants that cause type III hypersensitivity also contribute to the development of autoimmune diseases. A sequel of lingering clinical symptoms persist in the COVID-19 patients, which is now termed as long COVID (5). The COVID-19 infection causes both the cardiovascular and neurological disease (6, 7). Two adenovirus vector-based vaccines have shown the association with blood clot formation. High levels of immune complexes (ICs) are observed in COVID-19 patients, which associate with high rates of virus replication (6). Fcγ- receptors (FcγRs) signaling in many cell types, including brain cells and complement activation contribute to the brain injury (8, 9). FcγRs ligation by ICs on platelets cause COVID-19 vasculitis (2). A recent study identified the platelet activating ICs in COVID-19, which contributed to the vasculopathy (10). COVID-19 patients exhibit a sepsis induced coagulopathy, likely caused by complement anaphylatoxins such as C3a and C5a. Examination of the brain biopsies from COVID-19 patients implicated type III hypersensitivity reaction in this pathology (11). This study would have been further convincing and interesting if the presence of activated complement fragments and neoepitope on polymerized C9 within the immune deposits were also examined. Complement activation products such as C4d and C5b-9 co-deposits with viral spike glycoprotein and these deposits are present in the interalveolar septa in the lungs of COVID-19 patients (12). Activation of classical complement pathway does contribute to the chronic fatigue syndrome, a pathology that show symptoms similar to long COVID-19 symptoms (13).

A prominent role for CD4+ T cell responses in COVID-19 infection and vaccine responses is suggested (14). Enhanced antigen presentation contributes to the generation of effector T cell subsets observed in the viral infections. Even though, the reactants that drive type III hypersensitivity contribute to the development of the effector T lymphocytic populations such as TH1 and Tfh, such events have not been examined in the COVID-19 infections (15, 16). In several studies, we have established the role of type III hypersensitivity immune reactants in the activation and differentiation of naïve human CD4+ T cells, including TH1 and TH17 subset (17-20). Similar results were also reported for other Fc receptors i.e., FcγRIIa and FcµR (21, 22). FcR signaling in the appropriate cytokine milieu generates IL- 21 producing Tfh cells that express Bcl6 and PD1 (16, 23). Tfh subset is important for the development of antibody producing plasma B cells. Two PD1+ populations are observed in the peripheral blood, one of these two populations that express PD1, show binding to ICs, phosphorylate Syk and these cells produce inflammatory cytokines, including IL-21, which support plasma B cell development (20, 23). I have proposed that during immune contraction, FcγR+ cell population (IC bound cells) (Figure. 1) contribute to the longer lasting memory pool of lymphocytes (15, 20, 23). Understanding of how these pathways contribute to the disease pathology in SARS-Cov2 viral infection is important.

Figure 1; Stimulated emission depletion (STED) microscopic images of an activated human CD4+ T cells. Cell stained with IC-Alexa Fluor 488 (green) (A). Stained with ICs-Alexa Fluor 488 (green) and for TLR3-Alexa Fluor 594 (red) (B). Stained with ICs-Alexa Fluor 488 (green) and for TLR8-Alexa Fluor 594 (red) (C). Both membrane and cytosolic staining with ICs is observed. TLR3 and TLR8 show co-staining with ICs.

Various haematological manifestations including blood clot formation are observed during COVID-19 pathology (24). Severe COVID-19 infection show strong local pulmonary thrombotic microangiopathy, direct endothelial cell infection and injury by the virus that affect the coagulopathic response to virus (25). Studies have implicated a role for platelet activation in thrombosis, observed in COVID-19 patients. Up to 30% of COVID-19 patients show thrombotic events. The ICs formed in antigen excess such as in viral infection are not efficiently cleared due to their soluble nature, facilitated by complement opsonization. Such ICs do interact with FcγRIIa expressed by the platelets, which lead to their activation, leading to the formation of clots, and microvascular thrombosis. C5a receptor 1 is a member of GPCR family of protein that is being targeted for COVID-19 therapy (26). Complement pathway is a therapeutic target to treat COVID-19 infection (27). An excellent study recently published show changes in the gene expression pattern from immunological pathways and GPCR signaling in the platelets obtained from SARS-Cov-2 infection (28). These authors reported increased level of cellular aggregates such as platelets-monocytes; platelets- neutrophils; platelets-lymphocytes both CD4 and CD8 T cells. We suggest a role for FcR in cellular aggregation from ICs ligation. Such events would occur in the brain tissue leading to the clot formation, where brain cells express FcγRI, FcγRIIA, and FcγRIIIA (8, 9). Activated platelets show increased phosphorylation of ERK1/2 (extracellular signal-regulated protein kinase); p38 and eukaryotic translational initiation factor elF4E. It is also noted that an increase in mitogen associated protein kinase (MAPK) pathway occur in platelets (28). This pathway is also up-regulated from signaling triggered by ICs opsonized with terminal complement complex (TCC) also referred to as C5b-9. Phosphorylation of ERK1/2 and Akt upon treatment with ICs and C5b-9 is observed (29). C5b-9 formation does occur in COVID-19 patients (30). I will discuss the role of FcR signaling in CD4 T cells observed by us and correlate them with the recent reported results observed in COVID-19 patient platelets.

Contribution of CD4+ T cells to Thrombosis:

Activation and differentiation of the CD4+ T cells often occur in autoimmunity, and this also transpire during COVID-19 infection (15, 20). Studies have shown the presence of differentiated CD4+ T helper cell subsets in the COVID-19 patients (31, 32). Both TH1 and TH17 subsets are present at higher levels in COVID-19 patients (32). A common observation in these reports is the upregulation of IFN-γ producing population (31). Another subset that is often observed in COVID-19 patients is circulating peripheral follicular helper T cells (pTfh), marked by the expression of inducible costimulatory molecule (ICOS), programmed death 1 (PD1), granulocyte-macrophage colony-stimulating factor (GM- CSF) and/or IL-6. One medical hypothesis report implicated pTfh phenotype, along with type III hypersensitivity reactants in COVID-19 pathology (1). It is not certain whether SARS-Cov2 virus infects CD4+ T cells, since these cells have not shown to express ACE-2 receptor or demonstrate the presence of SARS- Cov2 RNA. An argument can be made that this virus can utilize CD32a expressed on activated CD4+ T cells for entry (21). CD4+ T cells will be a dominant contributor to the cytokine storm observed in COVID-19 patients (33). A question that remains to be addressed is whether CD4+ T cells directly contribute to the thrombotic events. Engagement of FcRs on CD4+ T cells by ICs does triggers production of proinflammatory cytokines such as IL-1A, IL-1B, IL-2, IL-6, IL-10, IL-12A, IL-21 and GM-CSF (20). Level of these cytokines as wells as Th17 population is increased in chronic fatigue syndrome, a pathology compared to long COVID symptoms. Increased production of these cytokines is observed in COVID-19 patients. In addition to the cytokine produced by innate cells, additional cytokines secreted by CD4+ T cells will generate high levels of proinflammatory responses, such as those observed in COVID-19 infection. One of these cytokines IL-6 is a therapeutic target for COVID-19 infection treatment. The contribution of FcγRs in CD4+ T cell function has been largely ignored, based on the report from a single group, which was not supported by any experimental data (34). Several groups including ours have confirmed IFN-γ production upon the FcR signaling, including FcγRIIa, FcγRIIIa and FcµR expressed by CD4+ T cells (15, 20-22). The binding of labeled ICs to the activated human CD4+ T cells show presence of FcRs both on the membrane and intracellularly in CD4+ T cells (Figure 1). The ICs formed during COVID-19 infection will be a crucial participant in these observed pathological events. The ligation of ICs to the FcRs on CD4+ T cells will facilitate the formation of cellular aggregates, as those observed in thrombotic clots (Figure 1, controls published in (figure 3) in reference (35). In a mouse model of autoimmune gastritis, germinal centers show aggregation of T and B cells, that is promoted by the binding of ICs to cell surface FcγRs. These aggregates expressed GL-7, a marker for germinal center reaction (Chauhan, A.K. and DiPaolo, R.: unpublished data available upon request). CD4+ T cells from COVID-19 patients should be examined for the expression of FcRs and their potential role in cellular aggregation and antibody dependent enhancement (33, 35).

Another key observation is the upregulation of pattern recognition receptors (PRRs) proteins in the CD4+ T cells, an event that will occur in COVID-19 infection (20, 35). PRR are key proteins that triggers signaling events to counteract the invading pathogens such as viruses. These PRR protein pathways are studied and associated with innate immune responses. The activated human CD4+ T cells express TLR3 and TLR8 both on the cell surface and intracellularly (Figure 1). The RNA transcripts of all three NA-TLRs are upregulated when cosignal in these cells is provided via FcR signaling compared to CD28 (20). A DNA virus, herpes simplex (HSV) becomes ubiquitinated and is degraded by proteasome to release the DNA in macrophages (36). We expect these mechanisms to participate in nucleic acid sensing by CD4+ T cells, since RNA transcripts of ubiqutination pathway and proteasome assembly, i.e., PSMB8 and PSMB9 are upregulated upon FcR signaling (NCBI gene Accession no. GSE127664). A critical role for TLR3 and TLR8 in recognizing viruses by endocytosis via clathrin-dependent endocytosis is suggested (37). Surface expression of TLR3 is observed in mouse CD8+ dendritic cells, marginal zone B cells and fibroblasts (38). We have also shown induced expression at transcript and protein level and the relocation of both TLR3 and TLR8 proteins on human CD4+ T cell surface upon FcR signaling (20, 35). Both TLR3 and TLR8 colocalize with ICs as documented by the staining of these proteins on the cell surface in activated human naïve CD4+ T cells (Figure. 1) (35). FcRs synergize signaling with NA- TLRs in CD4+ T cells, driving the production of IL-17A and IL- 21, similar to that observed in B cells (35). Three key NA-TLRs along with MyD88, HMGB1 are up-regulated via FcR ligation by ICs, a perfect scenario that would occur in COVID-19 patients (35). FcR signaling in CD4+ T cells up-regulates RNA-transcripts from pathways such as antigen presentation, ubiqutination i.e., proteasome assembly, and PDGFA, similar to those observed in COVID-19 platelets (NCBI Accession no. GSE127664) (28). FcRs signaling in human CD4+ T cells upregulate RNA-seq transcripts from GPCR signaling pathway. A 4.9-fold enrichment of 204 genes in the category GOTERM_PBGO:0007186, GPCR proteins signaling pathway at a false detection rate (FDR) of 7.98E-89 and at a p Value of 4.71E-92 is observed (Figure. 3). Similarly, platelets from COVID-19 patients also show increased expression of genes from GPCR signaling pathway.

Immune Complex Activate Platelets by Engaging FcγRIIA

Platelet activating viral-ICs are present in COVID-19 patients, and they possibly drive thrombotic events (10). Platelets in COVID-19 patients demonstrate the presence of mRNA from SARS-Cov2 N1 gene, suggesting the infectivity of these cell types, despite the lack of documented expression of ACE2 receptor (28). SARS-Cov2 mRNA is proposed to interact with TLR7 and stimulate proinflammatory cytokine production (39). In a model of HIV-1 pseudovirions entry in the platelets, it was observed that platelets endocytose viral particles and are activated via TLR signaling (40). Thus, it is important to investigate the participation of NA-TLR signaling in COVID-19 infection. We propose that NA-TLRs expressed both on platelets and CD4+ T cells surface contributes to the enhanced infectivity (35). It is important to assess the TLR3 and TLR8 expression and their cellular location in the activated platelets and CD4+ T cells, post activation with ICs purified from COVID-19 plasma. It is very reasonable to assume that virus containing ICs will simultaneously engage both FcRs and TLRs on platelets, B cells, T cells, neutrophils, and monocytes, a crucial event for thrombosis and coagulopathy (10). IgG-ICs does activate platelets and contribute to the thrombus formation (41). ICs activate classical complement pathway leading to the generation of C5b-9 on cell wall, as well as in the plasma (18). The C5b-9 also activate platelets and induce secretion of Willebrand factor, which cause damage to endothelial cells by inserting into the cell wall (30). Complement deposition on platelets is observed in SLE patients with history of thromboembolism. Sub-lytic C5b- 9 induces signaling pathways and their role in platelet function can-not be ignored. Increased levels of circulating ICs are present in acute stroke observed in Cytomegalovirus (CMV) infection (42). These patients show anti-CMV antibodies in the ICs present during CMV infection. A key observation was the upregulation of Platelet Derived Growth Factor (PDGFA) in the platelets of COVID-19 patients (28). PDGFA is upregulated upon Fc signaling post IC treatment in CD4+ T cells along with PDGF receptor α (NCBI Accession no. GSE127664). G-protein coupled receptors (GPCRs) signaling proteins are also upregulated in the platelets of COVID-19 patients (28). GPCR proteins are part of olfactory receptors (ORs) family, and these proteins regulate sense of smell (43). Loss of sense of smell is a hallmark in COVID-19 patients. These studies suggest an active role for FcR signaling in the platelet function during active viral infection. Recently, brain blood clot formation post vaccination with adenovirus vectors is explained based on anti-PF4-polyanion antibodies mediated platelet activation (44). PF4 released by activated platelets modulate T cell responses. Studies have now also shown a role for platelets in neuroinflammation (45).

Up-regulation of Olfactory Receptor genes by FcR signaling

Olfactory sensory dysfunction occurs in COVID-19 patients. This occurs largely due to the disruption of mechanical contacts between odorants and olfactory receptors (ORs), olfactory neurons, and in the brain. Retrograde transport from nasal epithelium to the brain is impacted by COVID-19 infection (46). ORs show highly conserved region of 40% amino acids that distinguish them from other GPCR proteins. Both B and T lymphocytes as well as other immunological cells coexpress ORs and GPCRs. In addition to autoimmunity, resident CD4+ T cells are present in patients’ samples from Alzheimer, Parkinson, and Stroke. A recent study showed that the meninges show the richest levels of CD4 T cells, > 75% of brain CD4+ T cells that reside in the brain tissue, rather than in the meninges (47). These findings are contrary to the accepted paradigm that the brain is immune privileged. The egress of immune cells from brain tissue is regulated by G-proteins. These cells also produce elevated levels of proinflammatory cytokines. ORs play a central role in cell growth, differentiation and apoptosis. Human aorta and coronary artery express OR10J5 gene. Activation by odorant triggers intracellular Ca2+ influx and phosphorylation of protein kinase B (Akt) (48). OR2AG1 and OR1D2 genes influence the contractibility of human airways smooth muscle cells (48). Both of these genes are prominently overexpressed by the engagement of FcRs by ICs in human CD4+ T cells, compared to cosignaling triggered by CD28 ligation (Figure 2). The members of the OR superfamily proteins are expressed in peripheral CD4+ T cells in mice and they modulate chemokine/ chemokine receptor-induced responses through the production of cGMP (49). It is not clear at this point how the overexpression these ORs genes influence perception of smell and taste. It is thus important to examine the role of ORs expressed by brain CD4+ T cells in COVID-19 infection. Other notable genes upregulated via FcR signaling are neuropeptide Y receptor, neurophililin 3, olfactomedin 2, and oligodendrocyte transcription factor 3.

Limited studies have explored the expression and the role of FcRs signaling in neurological disorders. It is now clear that neuronal cells do express FcRs and these receptors play a role in the brain development (8). ICs contribute to the acute stroke in cytomegalovirus infection and pneumonia (42). Recently, various FcRs are shown to be expressed in the brain of animal models (8, 9). This suggests a need to further examine the impact of cross-linking of virus-antibody complexes with FcRs on neurons and astrocytes. It remains an open question, whether the FcR signaling in the neurons modulate GPCR signaling, which in turn could influence sense of smell during viral infections such as COVID-19. Olfactory receptor activity category GOTERM_MF_ FATGO:0004984, showed 149 genes that are upregulated at FDR of 1.07E-103 and p Value of 7.38E-107 in the CD4+ T cells when treated with ICs compared to anti-CD28 (Figure. 2).

Figure 2: Heat map of 384 OR gene expression in CD4+ T cells in four paired patients. CD4+ T cells activated by treating with ICs and anti-CD28 (For detail see NCBI Accession no GSC 127664). Both categories were first normalized using RNA transcript levels in paired untreated cells. Patient 3 and 4 showed dominant overexpression of OR genes upon ICs treatment

The genes from OR pathway also represent gene from GPCR signaling pathway, confirming the upregulation of GPCR signaling. Correlation between upregulated OR and GPCR is known and is documented by STRING network analysis (Figure. 3).

Figure 3: STRING (11.0) gene network correlation diagram. Genes upregulated by FcγRIIIa cosignaling (triggered via ICs ligation) over CD28 cosignaling (anti-CD28) in human CD4+ T cells. Both categories were normalized for base level expression in untreated cells, before comparison. Genes associated with olfactory receptors (ORs) and GPCR signaling proteins are shown. A total of 204 genes from GO:0007186, G-protein receptor coupled protein signaling pathway at FDR of 7.98E-89, show 4.9-fold enrichment at a P value of 4.71E-92. 148 genes from GO:00070608, sensory perception of smell at FDR of 1.08E-102, 9.27-fold enrichment at a P value of 6.38E-106 was observed. These genes were included in the GPCR group. Red line – indicates the presence of fusion evidence; Purple line – experimental evidence; Yellow line – text-mining evidence; Light blue line – database evidence; Black line – co-expression evidence.

It will be also important to examine the fate/role of GPCR/OR signaling in brain CD4+ T cells during COVID-19 infection.

Long term clinical symptoms are observed in approximately 30% of patients post COVID-19 infection. The pathogenic mechanisms that contribute to the thrombosis and neuropathological disease remains unknown. Long term, COVID-19 patients mimic the pathology of autoimmune disorders. Presence of viral-ICs; complement activation, and elevated levels of proinflammatory cytokines suggest ominous activation of autoimmune responses in COVID-19 pathology. The type III hypersensitivity is a key contributor to the autoimmunity, which is now proposed to occur in COVID-19 patients. The reactants needed for type III hypersensitivity contribute to the proliferation and differentiation of human naïve CD4+ T cells. The effector memory cells generated by type III immune reactants, in immune contraction phase will contribute to the central memory. The ICs formed during infection will activate both platelets and CD4+ T cells. In these cells, gene transcripts from ubiquitination, proteasome assembly and GPCR signaling pathways are upregulated (NCBI GSE127664). In order to design therapies for long COVID, it will be thus important to investigate the role of FcR+ bearing CD4+ T cells in viral pathology. During HIV-1 infection, a population of both CD4+ and CD8+ T cells show binding to labeled ICs, suggesting an increase in FcγR+ T cell subset. Both FcRIIa and FcγRIIIa enhance antigen presentation in CD4+ T cells (20, 21). The overt expression of antibody recognizing FcRs on the major population of the lymphocytes and brain cells will be crucial for understanding blood clot formation. It remains to be seen whether in long COVID-19 patients enhanced autoimmune responses are observed. These responses should also be investigated in children with Kawasaki disease symptoms post COVID-19 infection. Similar concerns remain from the enhanced NA-TLR signaling that would occur upon the inoculation of nucleic acid-based vaccines.

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