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The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system.

Initial studies found increased severity of coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in patients with diabetes mellitus. Furthermore, COVID-19 might also predispose infected individuals to hyperglycaemia. Interacting with other risk factors, hyperglycaemia might modulate immune and inflammatory responses, thus predisposing patients to severe COVID-19 and possible lethal outcomes. Angiotensin-converting enzyme 2 (ACE2), which is part of the renin-angiotensin-aldosterone system (RAAS), is the main entry receptor for SARS-CoV-2; although dipeptidyl peptidase 4 (DPP4) might also act as a binding target. Preliminary data, however, do not suggest a notable effect of glucose-lowering DPP4 inhibitors on SARS-CoV-2 susceptibility. Owing to their pharmacological characteristics, sodium-glucose cotransporter 2 (SGLT2) inhibitors might cause adverse effects in patients with COVID-19 and so cannot be recommended. Currently, insulin should be the main approach to the control of acute glycaemia. Most available evidence does not distinguish between the major types of diabetes mellitus and is related to type 2 diabetes mellitus owing to its high prevalence. However, some limited evidence is now available on type 1 diabetes mellitus and COVID-19. Most of these conclusions are preliminary, and further investigation of the optimal management in patients with diabetes mellitus is warranted.

/pdf/covid-19-and-diabetes-mellitus-from-pathophysiology-to-5e450o1b49.pdf

COVID-19 and diabetes mellitus: from pathophysiology to clinical management.

After the 1918 flu pandemic, the world is again facing a similar situation. However, the advancement in medical science has made it possible to identify that the novel infectious agent is from the coronavirus family. Rapid genome sequencing by various groups helped in identifying the structure and function of the virus, its immunogenicity in diverse populations, and potential preventive measures. Coronavirus attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. Viral components like spike and nucleocapsid proteins trigger an immune response in the host to eliminate the virus. These viral antigens can be either recognized by the B cells or presented by MHC complexes to the T cells, resulting in antibody production, increased cytokine secretion, and cytolytic activity in the acute phase of infection. Genetic polymorphism in MHC enables it to present some of the T cell epitopes very well over the other MHC alleles. The association of MHC alleles and its downregulated expression has been correlated with disease severity against influenza and coronaviruses. Studies have reported that infected individuals can, after recovery, induce strong protective responses by generating a memory T-cell pool against SARS-CoV and MERS-CoV. These memory T cells were not persistent in the long term and, upon reactivation, caused local damage due to cross-reactivity. So far, the reports suggest that SARS-CoV-2, which is highly contagious, shows related symptoms in three different stages and develops an exhaustive T-cell pool at higher loads of viral infection. As there are no specific treatments available for this novel coronavirus, numerous small molecular drugs that are being used for the treatment of diseases like SARS, MERS, HIV, ebola, malaria, and tuberculosis are being given to COVID-19 patients, and clinical trials for many such drugs have already begun. A classical immunotherapy of convalescent plasma transfusion from recovered patients has also been initiated for the neutralization of viremia in terminally ill COVID-19 patients. Due to the limitations of plasma transfusion, researchers are now focusing on developing neutralizing antibodies against virus particles along with immuno-modulation of cytokines like IL-6, Type I interferons (IFNs), and TNF-α that could help in combating the infection. This review highlights the similarities of the coronaviruses that caused SARS and MERS to the novel SARS-CoV-2 in relation to their pathogenicity and immunogenicity and also focuses on various treatment strategies that could be employed for curing COVID-19.

/pdf/overview-of-immune-response-during-sars-cov-2-infection-1mscglun7r.pdf

Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past.

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease. Here, the authors characterize tissue-level SARS-CoV-2 infection and pathogenesis in transgenic mice expressing human angiotensin converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18-hACE2) and show that infection induces lethality, making the K18-hACE2 model suitable for vaccine and therapeutic evaluation.

/pdf/lethality-of-sars-cov-2-infection-in-k18-human-angiotensin-16kwj0r7no.pdf

Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice.

SARS-COV-2 is a pathogenic agent belonging to the coronavirus family, responsible for the current global world pandemic. Angiotensin-converting enzyme 2 (ACE-2) is the receptor for cellular entry of SARS-CoV-2. ACE-2 is a type I transmembrane metallo-carboxypeptidase involved in the Renin-Angiotensin pathway. By analyzing two independent databases, ACE-2 was identified in several human tissues including the thyroid. Although some cases of COVID-19-related subacute thyroiditis were recently described, direct proof for the expression of the ACE-2 mRNA in thyroid cells is still lacking. Aim of the present study was to investigate by RT-PCR whether the mRNA encoding for ACE-2 is present in human thyroid cells. RT-PCR was performed on in vitro ex vivo study on thyroid tissue samples (15 patients undergoing thyroidectomy for benign thyroid nodules) and primary thyroid cell cultures. The ACE-2 mRNA was detected in all surgical thyroid tissue samples (n = 15). Compared with two reporter genes (GAPDH: 0.052 ± 0.0026 Cycles−1; β-actin: 0.044 ± 0.0025 Cycles−1; ACE-2: 0.035 ± 0.0024 Cycles−1), the mean level of transcript expression for ACE-2 mRNA was abundant. The expression of ACE-2 mRNA in follicular cells was confirmed by analyzing primary cultures of thyroid cells, which expressed the ACE-2 mRNA at levels similar to tissues. The results of the present study demonstrate that the mRNA encoding for the ACE-2 receptor is expressed in thyroid follicular cells, making them a potential target for SARS-COV-2 entry. Future clinical studies in patients with COVID-19 will be required for increase our understanding of the thyroid repercussions of SARS-CoV-2 infection.

/pdf/detection-of-sars-cov-2-receptor-ace-2-mrna-in-thyroid-cells-2lsj9vlxn0.pdf

Detection of SARS-COV-2 receptor ACE-2 mRNA in thyroid cells: a clue for COVID-19-related subacute thyroiditis

The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved.

Per- and polyfluoroalkyl substances (PFAS) represent a group of synthetic compounds widely used in industry plants due to their low grade of degradation, surfactant properties, thermic and flame resistance. These characteristics are useful for the industrial production, however they are also potentially dangerous for human health and for the environment. PFAS are persistent pollutants accumulating in waters and soil and recoverable in foods due to their release by food packaging. Humans are daily exposed to PFAS because these compounds are ubiquitous and, when assimilated, they are difficult to be eliminated, persisting for years both in humans and animals. Due to their persistence and potential danger to health, some old generation PFAS have been replaced by newly synthesized PFAS with the aim to use alternative compounds presumably safer for humans and the environment. Yet, the environmental pollution with PFAS remains a matter of concern worldwide and led to large-scale epidemiological studies both on plants' workers and on exposed people in the general population. In this context, strong concern emerged concerning the potential adverse effects of PFAS on the thyroid gland. Thyroid hormones play a critical role in the regulation of metabolism, and thyroid function is related to cardiovascular disease, fertility, and fetal neurodevelopment. In vitro, ex vivo data, and epidemiological studies suggested that PFASs may disrupt the thyroid hormone system in humans, with possible negative repercussions on the outcome of pregnancy and fetal-child development. However, data on the thyroid disrupting effect of PFAS remain controversial, as well as their impact on human health in different ages of life. Aim of the present paper is to review recent data on the effects of old and new generation PFAS on thyroid homeostasis. To this purpose we collected information from in vitro studies, animal models, and in vivo data on exposed workers, general population, and pregnant women.

/pdf/thyroid-disrupting-effects-of-old-and-new-generation-pfas-4dpdnybfo5.pdf

Thyroid Disrupting Effects of Old and New Generation PFAS.

Subacute thyroiditis (SAT) is a thyroid disease of viral or post-viral origin. Whether SAT represents a complication of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still unclear. Our aim was to systematically review the literature to 1) explore the size of the literature about SAT in COVID-19 and 2) evaluate the clinical characteristics of SAT. PubMed/MEDLINE, Embase, and Scopus were searched until April 20, 2021. Original papers, case reports, and case series reporting SAT in COVID-19 patients were included. Authors and their country, journal, year of publication, COVID-19 and SAT clinical presentation, thyroid function, therapy, and follow-up data were extracted. Nineteen papers (17 case reports and 2 case series) were included, describing 27 patients, 74.1% females, aged 18 to 69 years. COVID-19 was diagnosed by nasopharyngeal swab in 66.7% cases and required hospitalization in 11.1%. In 83.3% cases, SAT occurred after COVID-19. Neck pain was present in 92.6% cases and fever in 74.1%. Median TSH, fT3, and fT4 were 0.01 mU/l, 10.79 pmol/l, and 27.2 pmol/l, respectively. C-reactive-protein and erythrocyte sedimentation rate were elevated in 96% of cases. Typical ultrasonographic characteristics of SAT were observed in 83.3% of cases. Steroids were the most frequent SAT therapy. Complete remission of SAT was recorded in most cases. In conclusion, the size and quality of published data of SAT in COVID-19 patients are poor, with only case reports and case series being available. SAT clinical presentation in COVID-19 patients seems to be similar to what is generally expected.

/pdf/covid-19-associated-subacute-thyroiditis-evidence-based-data-4gwlh7nigo.pdf

Laura Croce

Papers

The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system.

Detection of SARS-COV-2 receptor ACE-2 mRNA in thyroid cells: a clue for COVID-19-related subacute thyroiditis

The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved.

Thyroid Disrupting Effects of Old and New Generation PFAS.

COVID-19-Associated Subacute Thyroiditis: Evidence-Based Data From a Systematic Review.