ABSTRACT
A novel coronavirus disease, COVID-19, has created a global pandemic in 2020, posing an enormous challenge to healthcare systems and affected communities. COVID-19 is caused by severe acute respiratory syndrome (SARS)-coronavirus-2 (CoV-2) that manifests as bronchitis, pneumonia, or a severe respiratory illness. SARS-CoV-2 infects human cells via binding a "spike" protein on its surface to angiotensin-converting enzyme 2 (ACE2) within the host. ACE2 is crucial for maintaining tissue homeostasis and negatively regulates the renin-angiotensin-aldosterone system (RAAS) in humans. The RAAS is paramount for normal function in multiple organ systems including the lungs, heart, kidney, and vasculature. Given that SARS-CoV-2 internalizes via ACE2, the resultant disruption in ACE2 expression can lead to altered tissue function and exacerbate chronic diseases. The widespread distribution and expression of ACE2 across multiple organs is critical to our understanding of the varied clinical outcomes of COVID-19. This perspective review based on the current literature was prompted to show how disruption of ACE2 by SARS-CoV-2 can affect different organ systems.
Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Renin-Angiotensin System/physiology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , COVID-19/epidemiology , COVID-19/virology , Host-Pathogen Interactions , Humans , Pandemics , Protein Binding , SARS-CoV-2/physiology , Virus InternalizationABSTRACT
We have developed a transgenic mouse model of Type 1 Diabetes (T1D) in which human GAD65 is expressed in pancreatic ß-cells, and human MHC-II is expressed on antigen presenting cells. Induced GAD65 antigen presentation activates T-cells, which initiates the downstream events leading to diabetes. In our humanized mice, we have shown downregulation of eukaryotic translation initiation factor 5 A (elF5A), expressed only in actively dividing mammalian cells. In-vivo inhibition of elF5A hypusination by deoxyhypusine synthase (DHS) inhibitor "GC7" was studied; DHS inhibitor alters the pathophysiology in our mouse model by catalyzing the crucial hypusination and the rate-limiting step of elF5A activation. In our mouse model, we have shown that inhibition of eIF5A resets the pro-inflammatory bias in the pancreatic microenvironment. There was: (a) reduction of Th1/Th17 response, (b) an increase in Treg numbers, (c) debase in IL17 and IL21 cytokines levels in serum, (d) lowering of anti-GAD65 antibodies, and (e) ablation of the ER stress that improved functionality of the ß-cells, but minimal effect on the cytotoxic CD8 T-cell (CTL) mediated response. Conclusively, immune modulation, in the case of T1D, may help to manipulate inflammatory responses, decreasing disease severity, and may help manage T1D in early stages of disease. Our study also demonstrates that without manipulating the CTLs mediated response extensively, it is difficult to treat T1D.
Subject(s)
Enzyme Inhibitors/chemistry , Glutamate Decarboxylase/genetics , Peptide Initiation Factors/metabolism , RNA-Binding Proteins/metabolism , T-Lymphocytes/metabolism , Animals , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Down-Regulation/drug effects , Endoplasmic Reticulum Stress/drug effects , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Female , Gene Expression Regulation/drug effects , Glutamate Decarboxylase/metabolism , Heptanes/chemistry , Heptanes/metabolism , Heptanes/pharmacology , Humans , Insulin-Secreting Cells/metabolism , Interleukins/blood , Male , Mice , Mice, Transgenic , Oxidoreductases Acting on CH-NH Group Donors/antagonists & inhibitors , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Peptide Initiation Factors/antagonists & inhibitors , Peptide Initiation Factors/genetics , RNA-Binding Proteins/antagonists & inhibitors , RNA-Binding Proteins/genetics , T-Lymphocytes/immunology , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Eukaryotic Translation Initiation Factor 5AABSTRACT
BACKGROUND: Thyroid cancer and thyroid autoimmunity are considered opposite extremes of immune-responses. However, several studies have suggested that thyroid cancer coexists with autoimmune thyroid diseases like Hashimoto Thyroiditis (HT) and Graves disease (GD). We have shown that the risk of developing thyroid cancer is higher in patients with a silent form of autoimmune thyroid disease -Euthyroid Hashimoto Thyroiditis-(EHT). METHODS: We analyzed data from 2633 consecutive patients with GD, HT, EHT and non-Autoimmune Thyroid Disease (Non-AITD) for the presence of Differentiated Thyroid Cancer (DTC). We further investigated the microenvironment, and cellular mechanism of protection from DTC in GD/EHT by ex-vivo aspirating infiltrates from thyroid samples. We also re-constituted in vitro the in-vivo microenvironment to mimic an in-vivo context. We isolated NK cells and differentiated macrophages into M1 and M2 phenotype from healthy human peripheral blood monocytes. RESULTS: DTC was less frequent/aggressive in GD as compared to EHT or Non-AITD. Intra-thyroidal immune-cell profiling revealed differential Natural Killer (NK) cell activity and macrophage polarization in the settings of GD versus EHT. In GD, NK-cells were activated, and macrophages showed M1-like phenotype whereas, in EHT, NK-cells were less active and macrophages displayed M2-like phenotype. Furthermore, in vitro co-cultures of NK-cells with differentiated macrophage subsets revealed that the presence of activated NK (NA) cells favors M1 macrophages, boosts macrophage action and amplifies the innate defense mechanisms. Moreover, co-culture of M2 macrophages with NA, increases the cytotoxicity of NK-cells and favors a pro-inflammatory microenvironment that reverts the anti-inflammatory M2 towards pro-inflammatory M1. CONCLUSION: Surveillance innate immune-cells like Natural Killer (NK) cells and macrophages are complementary to each other in their actions. We discovered here that activated NK-cells in the background of the thyroid autoimmune disease, GD, drive macrophage differentiation to the M1/killer phenotype which in turn is cytotoxic to cancer cells and down regulates the M2/repair phenotype. Understanding the molecular basis of macrophage-NK cell interface in Thyroid Cancer, ETH and GD will open new vistas for immunopathology and therapeutic intervention. Macrophages/innate immunity can be modulated from M2 to M1 phenotype to help treat thyroid cancer as naturally done by GD.
