International Journal of Molecular Sciences

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Open AccessEditorial

Molecular Advances in SARS-CoV-2: A Brief Update on Transmission, Infection, and Pathology Aspects

by João R. Mesquita

Int. J. Mol. Sci. 2022, 23(22), 14250; https://doi.org/10.3390/ijms232214250 - 17 Nov 2022

Viewed by 1140

Abstract

It all started back in late 2019 with a virus making a leap, crossing the barrier of species from an animal reservoir to a human and quickly spreading around the world [...] Full article

(This article belongs to the Special Issue Molecular Advances in SARS-CoV-2 Transmission, Infection and Pathology)

Research

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8 pages, 4657 KiB

Open AccessCommunication

Exploring Mitochondrial Localization of SARS-CoV-2 RNA by Padlock Assay: A Pilot Study in Human Placenta

by Francesca Gabanella, Christian Barbato, Nicoletta Corbi, Marco Fiore, Carla Petrella, Marco de Vincentiis, Antonio Greco, Giampiero Ferraguti, Alessandro Corsi, Massimo Ralli, Irene Pecorella, Cira Di Gioia, Francesco Pecorini, Roberto Brunelli, Claudio Passananti, Antonio Minni and Maria Grazia Di Certo

Int. J. Mol. Sci. 2022, 23(4), 2100; https://doi.org/10.3390/ijms23042100 - 14 Feb 2022

Cited by 14 | Viewed by 2422

Abstract

The ongoing COVID-19 pandemic dictated new priorities in biomedicine research. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is a single-stranded positive-sense RNA virus. In this pilot study, we optimized our padlock assay to visualize genomic and subgenomic regions [...] Read more.

The ongoing COVID-19 pandemic dictated new priorities in biomedicine research. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is a single-stranded positive-sense RNA virus. In this pilot study, we optimized our padlock assay to visualize genomic and subgenomic regions using formalin-fixed paraffin-embedded placental samples obtained from a confirmed case of COVID-19. SARS-CoV-2 RNA was localized in trophoblastic cells. We also checked the presence of the virion by immunolocalization of its glycoprotein spike. In addition, we imaged mitochondria of placental villi keeping in mind that the mitochondrion has been suggested as a potential residence of the SARS-CoV-2 genome. We observed a substantial overlapping of SARS-CoV-2 RNA and mitochondria in trophoblastic cells. This intriguing linkage correlated with an aberrant mitochondrial network. Overall, to the best of our knowledge, this is the first study that provides evidence of colocalization of the SARS-CoV-2 genome and mitochondria in SARS-CoV-2 infected tissue. These findings also support the notion that SARS-CoV-2 infection can reprogram mitochondrial activity in the highly specialized maternal–fetal interface. Full article

(This article belongs to the Special Issue Molecular Advances in SARS-CoV-2 Transmission, Infection and Pathology)

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17 pages, 2392 KiB

Open AccessArticle

COVID-19 and Lung Mast Cells: The Kallikrein–Kinin Activation Pathway

by Seigo Nagashima, Anderson Azevedo Dutra, Mayara Pezzini Arantes, Rafaela Chiuco Zeni, Carolline Konzen Klein, Flávia Centenaro de Oliveira, Giulia Werner Piper, Isadora Drews Brenny, Marcos Roberto Curcio Pereira, Rebecca Benicio Stocco, Ana Paula Camargo Martins, Eduardo Morais de Castro, Caroline Busatta Vaz de Paula, Andréa Novaes Moreno Amaral, Cleber Machado-Souza, Cristina Pellegrino Baena and Lucia Noronha

Int. J. Mol. Sci. 2022, 23(3), 1714; https://doi.org/10.3390/ijms23031714 - 2 Feb 2022

Cited by 19 | Viewed by 3549

Abstract

Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein–kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and [...] Read more.

Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein–kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE⁺ MCs, tryptase⁺ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient. Full article

(This article belongs to the Special Issue Molecular Advances in SARS-CoV-2 Transmission, Infection and Pathology)

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16 pages, 3124 KiB

Open AccessArticle

Molecular Networking for Drug Toxicities Studies: The Case of Hydroxychloroquine in COVID-19 Patients

by Pierre-Jean Ferron, Brendan Le Daré, Julie Bronsard, Clara Steichen, Elodie Babina, Romain Pelletier, Thierry Hauet, Isabelle Morel, Karin Tarte, Florian Reizine, Bruno Clément, Bernard Fromenty and Thomas Gicquel

Int. J. Mol. Sci. 2022, 23(1), 82; https://doi.org/10.3390/ijms23010082 - 22 Dec 2021

Cited by 11 | Viewed by 3562

Abstract

Using drugs to treat COVID-19 symptoms may induce adverse effects and modify patient outcomes. These adverse events may be further aggravated in obese patients, who often present different illnesses such as metabolic-associated fatty liver disease. In Rennes University Hospital, several drug such as [...] Read more.

Using drugs to treat COVID-19 symptoms may induce adverse effects and modify patient outcomes. These adverse events may be further aggravated in obese patients, who often present different illnesses such as metabolic-associated fatty liver disease. In Rennes University Hospital, several drug such as hydroxychloroquine (HCQ) have been used in the clinical trial HARMONICOV to treat COVID-19 patients, including obese patients. The aim of this study is to determine whether HCQ metabolism and hepatotoxicity are worsened in obese patients using an in vivo/in vitro approach. Liquid chromatography high resolution mass spectrometry in combination with untargeted screening and molecular networking were employed to study drug metabolism in vivo (patient’s plasma) and in vitro (HepaRG cells and RPTEC cells). In addition, HepaRG cells model were used to reproduce pathophysiological features of obese patient metabolism, i.e., in the condition of hepatic steatosis. The metabolic signature of HCQ was modified in HepaRG cells cultured under a steatosis condition and a new metabolite was detected (carboxychloroquine). The RPTEC model was found to produce only one metabolite. A higher cytotoxicity of HCQ was observed in HepaRG cells exposed to exogenous fatty acids, while neutral lipid accumulation (steatosis) was further enhanced in these cells. These in vitro data were compared with the biological parameters of 17 COVID-19 patients treated with HCQ included in the HARMONICOV cohort. Overall, our data suggest that steatosis may be a risk factor for altered drug metabolism and possibly toxicity of HCQ. Full article

(This article belongs to the Special Issue Molecular Advances in SARS-CoV-2 Transmission, Infection and Pathology)

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18 pages, 29926 KiB

Open AccessArticle

Untargeted Metabolic Profiling of Extracellular Vesicles of SARS-CoV-2-Infected Patients Shows Presence of Potent Anti-Inflammatory Metabolites

by Faisal A. Alzahrani, Mohammed Razeeth Shait Mohammed, Saleh Alkarim, Esam I. Azhar, Mohammed A. El-Magd, Yousef Hawsawi, Wesam H. Abdulaal, Abdulaziz Yusuf, Abdulaziz Alhatmi, Raed Albiheyri, Burhan Fakhurji, Bassem Kurdi, Tariq A. Madani, Hassan Alguridi, Roaa S. Alosaimi and Mohammad Imran Khan

Int. J. Mol. Sci. 2021, 22(19), 10467; https://doi.org/10.3390/ijms221910467 - 28 Sep 2021

Cited by 19 | Viewed by 4445

Abstract

Extracellular vesicles (EVs) carry important biomolecules, including metabolites, and contribute to the spread and pathogenesis of some viruses. However, to date, limited data are available on EV metabolite content that might play a crucial role during infection with the SARS-CoV-2 virus. Therefore, this [...] Read more.

Extracellular vesicles (EVs) carry important biomolecules, including metabolites, and contribute to the spread and pathogenesis of some viruses. However, to date, limited data are available on EV metabolite content that might play a crucial role during infection with the SARS-CoV-2 virus. Therefore, this study aimed to perform untargeted metabolomics to identify key metabolites and associated pathways that are present in EVs, isolated from the serum of COVID-19 patients. The results showed the presence of antivirals and antibiotics such as Foscarnet, Indinavir, and lymecycline in EVs from patients treated with these drugs. Moreover, increased levels of anti-inflammatory metabolites such as LysoPS, 7-α,25-Dihydroxycholesterol, and 15-d-PGJ2 were detected in EVs from COVID-19 patients when compared with controls. Further, we found decreased levels of metabolites associated with coagulation, such as thromboxane and elaidic acid, in EVs from COVID-19 patients. These findings suggest that EVs not only carry active drug molecules but also anti-inflammatory metabolites, clearly suggesting that exosomes might play a crucial role in negotiating with heightened inflammation during COVID-19 infection. These preliminary results could also pave the way for the identification of novel metabolites that might act as critical regulators of inflammatory pathways during viral infections. Full article

(This article belongs to the Special Issue Molecular Advances in SARS-CoV-2 Transmission, Infection and Pathology)

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20 pages, 54834 KiB

Open AccessArticle

SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues

by Guoshuai Cai, Mulong Du, Yohan Bossé, Helmut Albrecht, Fei Qin, Xizhi Luo, Xiao Michelle Androulakis, Chao Cheng, Mitzi Nagarkatti, Prakash Nagarkatti, David C. Christiani, Michael L. Whitfield, Christopher I. Amos and Feifei Xiao

Int. J. Mol. Sci. 2021, 22(17), 9228; https://doi.org/10.3390/ijms22179228 - 26 Aug 2021

Cited by 18 | Viewed by 4373

Abstract

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper [...] Read more.

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22⁺ or ANXA1⁺ DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19. Full article

(This article belongs to the Special Issue Molecular Advances in SARS-CoV-2 Transmission, Infection and Pathology)

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Review

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18 pages, 5363 KiB

Open AccessReview

SARS-CoV-2 Virus−Host Interaction: Currently Available Structures and Implications of Variant Emergence on Infectivity and Immune Response

by Luís Queirós-Reis, Priscilla Gomes da Silva, José Gonçalves, Andrea Brancale, Marcella Bassetto and João R. Mesquita

Int. J. Mol. Sci. 2021, 22(19), 10836; https://doi.org/10.3390/ijms221910836 - 7 Oct 2021

Cited by 27 | Viewed by 4041

Abstract

Coronavirus disease 19, or COVID-19, is an infection associated with an unprecedented worldwide pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has led to more than 215 million infected people and more than 4.5 million deaths worldwide. SARS-CoV-2 cell [...] Read more.

Coronavirus disease 19, or COVID-19, is an infection associated with an unprecedented worldwide pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has led to more than 215 million infected people and more than 4.5 million deaths worldwide. SARS-CoV-2 cell infection is initiated by a densely glycosylated spike (S) protein, a fusion protein, binding human angiotensin converting enzyme 2 (hACE2), that acts as the functional receptor through the receptor binding domain (RBD). In this article, the interaction of hACE2 with the RBD and how fusion is initiated after recognition are explored, as well as how mutations influence infectivity and immune response. Thus, we focused on all structures available in the Protein Data Bank for the interaction between SARS-CoV-2 S protein and hACE2. Specifically, the Delta variant carries particular mutations associated with increased viral fitness through decreased antibody binding, increased RBD affinity and altered protein dynamics. Combining both existing mutations and mutagenesis studies, new potential SARS-CoV-2 variants, harboring advantageous S protein mutations, may be predicted. These include mutations S13I and W152C, decreasing antibody binding, N460K, increasing RDB affinity, or Q498R, positively affecting both properties. Full article

(This article belongs to the Special Issue Molecular Advances in SARS-CoV-2 Transmission, Infection and Pathology)

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12 pages, 675 KiB

Open AccessReview

Perspective of the Relationship between the Susceptibility to Initial SARS-CoV-2 Infectivity and Optimal Nasal Conditioning of Inhaled Air

by Ranjan Ramasamy

Int. J. Mol. Sci. 2021, 22(15), 7919; https://doi.org/10.3390/ijms22157919 - 24 Jul 2021

Cited by 10 | Viewed by 4657

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as with the influenza virus, has been shown to spread more rapidly during winter. Severe coronavirus disease 2019 (COVID-19), which can follow SARS-CoV-2 infection, disproportionately affects older persons and males as well as people living in [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as with the influenza virus, has been shown to spread more rapidly during winter. Severe coronavirus disease 2019 (COVID-19), which can follow SARS-CoV-2 infection, disproportionately affects older persons and males as well as people living in temperate zone countries with a tropical ancestry. Recent evidence on the importance of adequately warming and humidifying (conditioning) inhaled air in the nasal cavity for reducing SARS-CoV-2 infectivity in the upper respiratory tract (URT) is discussed, with particular reference to: (i) the relevance of air-borne SARS-CoV-2 transmission, (ii) the nasal epithelium as the initial site of SARS-CoV-2 infection, (iii) the roles of type 1 and 3 interferons for preventing viral infection of URT epithelial cells, (iv) weaker innate immune responses to respiratory viral infections in URT epithelial cells at suboptimal temperature and humidity, and (v) early innate immune responses in the URT for limiting and eliminating SARS-CoV-2 infections. The available data are consistent with optimal nasal air conditioning reducing SARS-CoV-2 infectivity of the URT and, as a consequence, severe COVID-19. Further studies on SARS-CoV-2 infection rates and viral loads in the nasal cavity and nasopharynx in relation to inhaled air temperature, humidity, age, gender, and genetic background are needed in this context. Face masks used for reducing air-borne virus transmission can also promote better nasal air conditioning in cold weather. Masks can, thereby, minimise SARS-CoV-2 infectivity and are particularly relevant for protecting more vulnerable persons from severe COVID-19. Full article

(This article belongs to the Special Issue Molecular Advances in SARS-CoV-2 Transmission, Infection and Pathology)

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