SARS-CoV-2 Causes Transcriptional Alterations Of Endocrine-Specific Genes Leading To A Variety Of Endocrine Issue

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Disturbing findings from a study conducted by Italian researchers reveal that the SARS-CoV-2 coronavirus causes transcriptional alterations of endocrine-specific genes leading to a variety of endocrine issues as result of many of these genes being dysregulated while some are upregulated or downregulated compared to normal healthy settings.

The study findings were published on a preprint server and are currently being peer reviewed.
https://www.researchsquare.com/article/rs-2259682/v1

COVID-19 is a pulmonary and systemic disease. Though the rates of hospitalization and death have been decreasing due to vaccination and improved therapies in addition to the progressive selection of less pathogenic virus variants [41–43], the involvement of extrapulmonary organs remains a long-term threat. Among post-acute sequelae, endocrine and metabolic disorders are relatively common [44].

In spite of an increasing number of studies reporting altered blood hormones and metabolites both in the acute phase and afterwards [30, 45, 46], transcriptional alterations in endocrine organs have been barely investigated.

By comparing mRNA transcript levels of genes expressed in endocrine organs of COVID-19 cases vs. controls, two major findings emerge:

a) virus-containing tissues of five different organs show upregulation of ISGs. WAT represents an exception since transcripts of ISGs are activated both in virus-positive and in virus-negative COVID-19 cases;

b) deregulated transcription of endocrine-specific genes is strictly organ-specific (Fig. 8).

Consistent with our previous studies [5–7], activation of ISGs genes is constantly observed in endocrine tissues infected by SARS-CoV-2. It is known that production of type I IFNs can be elicited in almost every cell type. Similarly, IFN receptors (IFNARs) are expressed on almost all cells, allowing them to acquire an antiviral state [47].

However, in the present study activated type I IFN responses were observed in WAT even in the absence of virus in the tissue. However, non-viral stimuli such as xenogeneic or autologous nucleic acids, activation of STING [48], autocrine signaling of IFNs that upregulates IRF7 may account for IFN activation [47].

More importantly, strong upregulation of leptin transcription has been detected in WAT of severe COVID-19 cases, independently of virus presence in the tissue. Leptin, in addition to its hormonal effects, activates lymphoid cells to produce pro-inflammatory cytokines [49], and high levels of leptin are associated with severe COVID-19 [50].

Leptin levels are also elevated in obesity, which is a major risk factor for severe COVID-19 [51]. The results show that, even after adjusting for BMI, leptin transcript levels remain considerably higher in WAT of COVID-19 cases compared to controls, showing that virus infection and/or inflammatory stimuli may induce leptin transcription.

Similarly to WAT, adrenal specimens infected by SARS-CoV-2 show a substantial upregulation of HSD3B2, CYP17A1 and CYP11B1. These genes encode for enzymes that convert steroids to adrenal hormones. While the first two act in the synthesis of a wide range of steroids, CYP11B1 is specifically involved in the conversion of progesterone to cortisol [52–54].

Upregulated transcription of the above genes seems not to support a primary insufficiency of adrenals in COVID-19.

An apparently controversial scenario was detected in ovaries containing SARS-CoV-2. In fact, infected ovaries exhibited downregulation of crystallin gamma D (CRYGD) and upregulation of the 5-hydroxytryptamine (serotonin) receptor 1A (HTR1A) gene. Crystallin gamma D has a very similar sequence and structure to that of crystallin beta, but it is monomeric [55].

While there are no clear attributed functions of gamma-crystallin in ovaries, beta-crystallin does influence female fertility by regulating apoptosis in granulosa cells and follicular atresia [55]. Hence, downregulation of CRYGD may be consistent with alterations of the menstrual cycle observed in women recovering from COVID-19 [37].

In addition, the enhanced expression of serotonin receptor 1A is in line with decreased serotonin serum levels observed in severe COVID-19 cases [56]. Similar to what found in humans, in mice the Zika virus also targets the ovaries inducing a type I IFN response that is associated with disordered steroidogenesis [57].

In thyroid, alterations of gene transcription were selectively observed when SARS-CoV-2 was present in the tissue. Changes affected factors associated with thyroid dysfunction [58]. Transcription of ZNF804B and FOXE1 was downregulated; ZNF804B is possibly associated with antiviral defense [59], while FOXE1 promotes the expression of multiple thyroid-specific genes, including those encoding for thyroglobulin, thyroid peroxidase, thyroid dual oxidase 2, pendrin and other transporters [60–63].

TSHR gene was also downregulated. Since serum TSH levels are generally low in mild to severe forms of COVID-19 [64], low levels of the TSH receptor indicate a possible impairment of the HPT axis. In a scenario of suppressed function, the enhanced expression of thyroid peroxidase may appear not justified.

However, non-endocrine regulatory mechanisms may be operative during microbial stress responses [65, 66]. Indeed, thyroid peroxidase is a major autoantigen in thyroid autoimmunity and a key player against oxidative stress [67].

Finally, the exocrine and endocrine pancreatic tissue deserves a separate discussion. First, in COVID-19 cases, the pancreas is the only tissue for which alterations of gene transcription are seen in the absence of activated IFN responses and independently of the viral presence in the tissue.

Second, the expression of pancreatic lipase-related protein 1 (PNLIPRP1) was enhanced. Differently from its paralogs (pancreatic triacylglycerol lipase and PNLIPRP2), PNLIPRP1 lacks lipolytic activity and also inhibits pancreatic lipase [68]; thus, enhancement of a lipase inhibitor may be part of a defensive response.

In addition, suppression of lipid catabolism may be linked to a switch of infected cells to glycolytic metabolism [69]. Third, and more important, the results show the downregulation of two beta cell genes that code for insulin (INS) and islet amyloid polypeptide (IAPP). Both hormones are crucial in the regulation of blood glucose levels, and are frequently downregulated in diabetes.

The findings support a potential failure of beta cells in COVID-19 and reminds that stress associated with a reduction of intracellular proinsulin may activate inflammatory pathways in beta-cells [70]. Unexpectedly, somatostatin (SST) mRNA transcripts were downregulated only in virus-negative pancreas specimens.

Somatostatin is produced by pancreatic delta cells and regulates pituitary growth hormone, thyroid stimulating hormone, and most hormones of the gastrointestinal tract [71]. Contextualization of somatostatin downregulation in COVID-19 needs further attention.

Our study has some limitations. First, the sample size per group in each investigated endocrine organ is relatively small, though more than a hundred tissues were analyzed. Second, the significance level was set at FDR = 0.25, a way to identify significant features in relatively small size groups.

On the other hand, important sources of variation such as age, sex and BMI have also been considered in the analyses. Finally, only a few genes highly specific for each organ were evaluated. Their functional relevance, however, does indicate alterations of interest for translational medicine.

In conclusion, transcriptional alterations in endocrine organs of individuals who died because of COVID-19 are tissue-specific. In most organs, significant changes were observed only when the SARS-CoV-2 genome was present in tissue. While infected ovary and thyroid showed downregulation of tissue-specific genes, in adrenals transcription of endocrine genes was enhanced, possibly as part of the stress response. Notably, in beta cells hormone genes were suppressed independently of the presence of virus in the tissue.

This is reminiscent of type 1 diabetes where beta cell functions are inhibited in an inflammatory context ([66]). Also in WAT, the enhanced transcription of functional genes is independent of virus presence in tissue and may be linked to the inflammatory context.

Our findings provide evidence that endocrine dysfunction may arise in COVID-19, especially when the virus invades endocrine organs. Clinicians should be aware that endocrine manifestations in the acute phase of COVID-19 and in the post-COVID syndrome may derive from transcriptional changes of endocrine-specific genes.

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