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1.
Gastroenterology ; 160(3): 925-928.e4, 2021 02.
Article in English | MEDLINE | ID: covidwho-1575253
2.
Rev Med Virol ; 31(6): e2234, 2021 11.
Article in English | MEDLINE | ID: covidwho-1574124

ABSTRACT

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Genetic Predisposition to Disease , Influenza, Human/immunology , Respiratory Syncytial Virus Infections/immunology , Severe Acute Respiratory Syndrome/immunology , Antiviral Agents/therapeutic use , Biological Variation, Individual , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/virology , Gene Expression , Humans , Immunity, Innate , Immunologic Factors/therapeutic use , Influenza, Human/drug therapy , Influenza, Human/genetics , Influenza, Human/virology , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/immunology , Orthomyxoviridae/drug effects , Orthomyxoviridae/immunology , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/drug effects , Respiratory Syncytial Viruses/immunology , SARS Virus/drug effects , SARS Virus/immunology , SARS-CoV-2/classification , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/genetics , Severe Acute Respiratory Syndrome/virology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
3.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-1389454

ABSTRACT

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Data Mining/methods , HIV Infections/epidemiology , HIV Infections/metabolism , Host-Pathogen Interactions/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Anti-Inflammatory Agents/therapeutic use , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Complement System Proteins/genetics , Complement System Proteins/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Databases, Genetic , Gene Expression Regulation , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/immunology , HIV-1/pathogenicity , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Inflammation , Interferons/genetics , Interferons/immunology , Interleukins/genetics , Interleukins/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , SARS-CoV-2 , Signal Transduction , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
4.
Int J Mol Sci ; 22(15)2021 Jul 28.
Article in English | MEDLINE | ID: covidwho-1335097

ABSTRACT

Different mechanisms were proposed as responsible for COVID-19 neurological symptoms but a clear one has not been established yet. In this work we aimed to study SARS-CoV-2 capacity to infect pediatric human cortical neuronal HCN-2 cells, studying the changes in the transcriptomic profile by next generation sequencing. SARS-CoV-2 was able to replicate in HCN-2 cells, that did not express ACE2, confirmed also with Western blot, and TMPRSS2. Looking for pattern recognition receptor expression, we found the deregulation of scavenger receptors, such as SR-B1, and the downregulation of genes encoding for Nod-like receptors. On the other hand, TLR1, TLR4 and TLR6 encoding for Toll-like receptors (TLRs) were upregulated. We also found the upregulation of genes encoding for ERK, JNK, NF-κB and Caspase 8 in our transcriptomic analysis. Regarding the expression of known receptors for viral RNA, only RIG-1 showed an increased expression; downstream RIG-1, the genes encoding for TRAF3, IKKε and IRF3 were downregulated. We also found the upregulation of genes encoding for chemokines and accordingly we found an increase in cytokine/chemokine levels in the medium. According to our results, it is possible to speculate that additionally to ACE2 and TMPRSS2, also other receptors may interact with SARS-CoV-2 proteins and mediate its entry or pathogenesis in pediatric cortical neurons infected with SARS-CoV-2. In particular, TLRs signaling could be crucial for the neurological involvement related to SARS-CoV-2 infection.


Subject(s)
COVID-19/metabolism , Cerebral Cortex/metabolism , Neurons/virology , SARS-CoV-2/pathogenicity , Toll-Like Receptors/metabolism , COVID-19/genetics , COVID-19/immunology , Child , Cytokines/metabolism , Gene Expression Profiling , Gene Expression Regulation , Humans , Neurons/immunology , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Signal Transduction/genetics , Toll-Like Receptors/genetics , Virus Replication
5.
Adv Exp Med Biol ; 1304: 53-71, 2021.
Article in English | MEDLINE | ID: covidwho-1237448

ABSTRACT

Innate immunity is the first defense line of the host against various infectious pathogens, environmental insults, and other stimuli causing cell damages. Upon stimulation, pattern recognition receptors (PRRs) act as sensors to activate innate immune responses, containing NF-κB signaling, IFN response, and inflammasome activation. Toll-like receptors (TLRs), retinoic acid-inducible gene I-like receptors (RLRs), NOD-like receptors (NLRs), and other nucleic acid sensors are involved in innate immune responses. The activation of innate immune responses can facilitate the host to eliminate pathogens and maintain tissue homeostasis. However, the activity of innate immune responses needs to be tightly controlled to ensure the optimal intensity and duration of activation under various contexts. Uncontrolled innate immune responses can lead to various disorders associated with aberrant inflammatory response, including pulmonary diseases such as COPD, asthma, and COVID-19. In this chapter, we will have a broad overview of how innate immune responses function and the regulation and activation of innate immune response at molecular levels as well as their contribution to various pulmonary diseases. A better understanding of such association between innate immune responses and pulmonary diseases may provide potential therapeutic strategies.


Subject(s)
COVID-19 , Humans , Immunity, Innate , Receptors, Pattern Recognition , SARS-CoV-2 , Toll-Like Receptors/genetics
6.
J Med Virol ; 93(4): 2476-2486, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217395

ABSTRACT

The coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has already resulted in a huge setback to mankind in terms of millions of deaths, while the unavailability of an appropriate therapeutic strategy has made the scenario much more severe. Toll-like receptors (TLRs) are crucial mediators and regulators of host immunity and the role of human cell surface TLRs in SARS-CoV-2 induced inflammatory pathogenesis has been demonstrated recently. However, the functional significance of the human intracellular TLRs including TLR3, 7, 8, and 9 is yet unclear. Hitherto, the involvement of these intracellular TLRs in inducing pro-inflammatory responses in COVID-19 has been reported but the identity of the interacting viral RNA molecule(s) and the corresponding TLRs have not been explored. This study hopes to rationalize the comparative binding of the major SARS-CoV-2 mRNAs to the intracellular TLRs, considering the solvent-based force-fields operational in the cytosolic aqueous microenvironment that predominantly drives these interactions. Our in silico study on the binding of all mRNAs with the intracellular TLRs depicts that the mRNA of NSP10, S2, and E proteins of SARS-CoV-2 are possible virus-associated molecular patterns that bind to TLR3, TLR9, and TLR7, respectively, and trigger downstream cascade reactions. Intriguingly, binding of the viral mRNAs resulted in variable degrees of conformational changes in the ligand-binding domain of the TLRs ratifying the activation of the downstream inflammatory signaling cascade. Taken together, the current study is the maiden report to describe the role of TLR3, 7, and 9 in COVID-19 immunobiology and these could serve as useful targets for the conception of a therapeutic strategy against the pandemic.


Subject(s)
COVID-19/virology , RNA, Messenger/genetics , RNA, Viral/metabolism , SARS-CoV-2/metabolism , Toll-Like Receptors/metabolism , Binding Sites , COVID-19/immunology , COVID-19/metabolism , Computer Simulation , Genome, Viral , Humans , Molecular Docking Simulation , Protein Binding , RNA, Messenger/analysis , RNA, Messenger/metabolism , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/genetics , Toll-Like Receptors/chemistry , Toll-Like Receptors/genetics
7.
Platelets ; 32(3): 325-330, 2021 Apr 03.
Article in English | MEDLINE | ID: covidwho-1092288

ABSTRACT

Platelets play an essential role in maintaining vascular integrity after injury. In addition, platelets contribute to the immune response to pathogens. For instance, they express receptors that mediate binding of viruses, and toll-like receptors that activate the cell in response to pathogen-associated molecular patterns. Platelets can be beneficial and/or detrimental during viral infections. They reduce blood-borne viruses by engulfing the free virus and presenting the virus to neutrophils. However, platelets can also enhance inflammation and tissue injury during viral infections. Here, we discuss the roles of platelets in viral infection.


Subject(s)
Blood Platelets/immunology , COVID-19/immunology , Host-Pathogen Interactions/immunology , Neutrophils/immunology , Receptors, Virus/immunology , Viral Proteins/immunology , Viruses/immunology , Animals , Blood Platelets/pathology , Blood Platelets/virology , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cell Communication/genetics , Cell Communication/immunology , Dendritic Cells/immunology , Dendritic Cells/pathology , Dendritic Cells/virology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate , Lymphocytes/immunology , Lymphocytes/pathology , Lymphocytes/virology , Neutrophils/pathology , Neutrophils/virology , Platelet Activation/immunology , Protein Binding , Receptors, Virus/genetics , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Viral Proteins/genetics , Viruses/pathogenicity
8.
J Med Virol ; 93(4): 2476-2486, 2021 04.
Article in English | MEDLINE | ID: covidwho-1028269

ABSTRACT

The coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has already resulted in a huge setback to mankind in terms of millions of deaths, while the unavailability of an appropriate therapeutic strategy has made the scenario much more severe. Toll-like receptors (TLRs) are crucial mediators and regulators of host immunity and the role of human cell surface TLRs in SARS-CoV-2 induced inflammatory pathogenesis has been demonstrated recently. However, the functional significance of the human intracellular TLRs including TLR3, 7, 8, and 9 is yet unclear. Hitherto, the involvement of these intracellular TLRs in inducing pro-inflammatory responses in COVID-19 has been reported but the identity of the interacting viral RNA molecule(s) and the corresponding TLRs have not been explored. This study hopes to rationalize the comparative binding of the major SARS-CoV-2 mRNAs to the intracellular TLRs, considering the solvent-based force-fields operational in the cytosolic aqueous microenvironment that predominantly drives these interactions. Our in silico study on the binding of all mRNAs with the intracellular TLRs depicts that the mRNA of NSP10, S2, and E proteins of SARS-CoV-2 are possible virus-associated molecular patterns that bind to TLR3, TLR9, and TLR7, respectively, and trigger downstream cascade reactions. Intriguingly, binding of the viral mRNAs resulted in variable degrees of conformational changes in the ligand-binding domain of the TLRs ratifying the activation of the downstream inflammatory signaling cascade. Taken together, the current study is the maiden report to describe the role of TLR3, 7, and 9 in COVID-19 immunobiology and these could serve as useful targets for the conception of a therapeutic strategy against the pandemic.


Subject(s)
COVID-19/virology , RNA, Messenger/genetics , RNA, Viral/metabolism , SARS-CoV-2/metabolism , Toll-Like Receptors/metabolism , Binding Sites , COVID-19/immunology , COVID-19/metabolism , Computer Simulation , Genome, Viral , Humans , Molecular Docking Simulation , Protein Binding , RNA, Messenger/analysis , RNA, Messenger/metabolism , RNA, Viral/chemistry , RNA, Viral/genetics , SARS-CoV-2/genetics , Toll-Like Receptors/chemistry , Toll-Like Receptors/genetics
9.
Gastroenterology ; 160(3): 925-928.e4, 2021 02.
Article in English | MEDLINE | ID: covidwho-977281
11.
Virus Res ; 289: 198163, 2020 11.
Article in English | MEDLINE | ID: covidwho-752747

ABSTRACT

BACKGROUND: Susceptibility to severe viral infections was reported to be associated with genetic variants in immune response genes using case reports and GWAS studies. SARS-CoV-2 is an emergent viral disease that caused millions of COVID-19 cases all over the world. Around 15 % of cases are severe and some of them are accompanied by dysregulated immune system and cytokine storm. There is increasing evidence that severe manifestations of COVID-19 might be attributed to human genetic variants in genes related to immune deficiency and or inflammasome activation (cytokine storm). OBJECTIVE: Identify the candidate genes that are likely to aid in explaining severe COVID-19 and provide insights to understand the pathogenesis of severe COVID-19. METHODS: In this article, we systematically reviewed genes related to viral susceptibility that were reported in human genetic studies (Case-reports and GWAS) to understand the role of host viral interactions and to provide insights into the pathogenesis of severe COVID-19. RESULTS: We found 40 genes associated with viral susceptibility and 21 of them were associated with severe SARS-CoV disease and severe COVID-19. Some of those genes were implicated in TLR pathways, others in C-lectin pathways, and others were related to inflammasome activation (cytokine storm). CONCLUSION: This compilation represents a list of candidate genes that are likely to aid in explaining severe COVID-19 which are worthy of inclusion in gene panels and during meta-analysis of different variants in host genetics studies of COVID-19. In addition, we provide several hypotheses for severe COVID-19 and possible therapeutic targets.


Subject(s)
Betacoronavirus , Coronavirus Infections/genetics , Pandemics , Pneumonia, Viral/genetics , Adolescent , Adult , Age Factors , Alleles , COVID-19 , Coronavirus Infections/drug therapy , Genetic Predisposition to Disease , Genome-Wide Association Study , Host-Pathogen Interactions/genetics , Humans , Inflammasomes/genetics , Lectins/genetics , Middle Aged , Models, Genetic , Molecular Targeted Therapy , Mutation , Polymorphism, Single Nucleotide , SARS-CoV-2 , Severe Acute Respiratory Syndrome/genetics , Signal Transduction/genetics , Toll-Like Receptor 3/genetics , Toll-Like Receptors/genetics , Virus Diseases/genetics , Young Adult
12.
Infect Genet Evol ; 85: 104507, 2020 11.
Article in English | MEDLINE | ID: covidwho-731865

ABSTRACT

The COVID-19 pandemic highlighted healthcare disparities in multiple countries. As such morbidity and mortality vary significantly around the globe between populations and ethnic groups. Underlying medical conditions and environmental factors contribute higher incidence in some populations and a genetic predisposition may play a role for severe cases with respiratory failure. Here we investigated whether genetic variation in the key genes for viral entry to host cells-ACE2 and TMPRSS2-and sensing of viral genomic RNAs (i.e., TLR3/7/8) could explain the variation in incidence across diverse ethnic groups. Overall, these genes are under strong selection pressure and have very few nonsynonymous variants in all populations. Genetic determinant for the binding affinity between SARS-CoV-2 and ACE2 does not show significant difference between populations. Non-genetic factors are likely to contribute differential population characteristics affected by COVID-19. Nonetheless, a systematic mutagenesis study on the receptor binding domain of ACE2 is required to understand the difference in host-viral interaction across populations.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Toll-Like Receptors/genetics , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , Humans , Mutagenesis, Site-Directed , Protein Binding , Protein Domains , Selection, Genetic , Serine Endopeptidases/metabolism , Toll-Like Receptor 3/chemistry , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 7/chemistry , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/chemistry , Toll-Like Receptor 8/genetics , Toll-Like Receptor 8/metabolism , Toll-Like Receptors/chemistry , Toll-Like Receptors/metabolism , Virus Internalization
13.
FASEB J ; 34(7): 8787-8795, 2020 07.
Article in English | MEDLINE | ID: covidwho-593467

ABSTRACT

The dynamics, such as transmission, spatial epidemiology, and clinical course of Coronavirus Disease-2019 (COVID-19) have emerged as the most intriguing features and remain incompletely understood. The genetic landscape of an individual in particular, and a population in general seems to play a pivotal role in shaping the above COVID-19 dynamics. Considering the implications of host genes in the entry and replication of SARS-CoV-2 and in mounting the host immune response, it appears that multiple genes might be crucially involved in the above processes. Herein, we propose three potentially important genetic gateways to COVID-19 infection; these could explain at least in part the discrepancies of its spread, severity, and mortality. The variations within Angiotensin-converting enzyme 2 (ACE2) gene might constitute the first genetic gateway, influencing the spatial transmission dynamics of COVID-19. The Human Leukocyte Antigen locus, a master regulator of immunity against infection seems to be crucial in influencing susceptibility and severity of COVID-19 and can be the second genetic gateway. The genes regulating Toll-like receptor and complement pathways and subsequently cytokine storm induced exaggerated inflammatory pathways seem to underlie the severity of COVID-19, and such genes might represent the third genetic gateway. Host-pathogen interaction is a complex event and some additional genes might also contribute to the dynamics of COVID-19. Overall, these three genetic gateways proposed here might be the critical host determinants governing the risk, severity, and outcome of COVID-19. Genetic variations within these gateways could be key in influencing geographical discrepancies of COVID-19.


Subject(s)
Betacoronavirus/physiology , Complement Activation/genetics , Coronavirus Infections/genetics , HLA Antigens/genetics , Host-Pathogen Interactions/genetics , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Receptors, Virus/genetics , Toll-Like Receptors/genetics , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/transmission , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/genetics , Disease Resistance/immunology , Genetic Predisposition to Disease , Genetic Variation , HLA Antigens/immunology , Host-Pathogen Interactions/immunology , Humans , Inflammation , Metagenomics , Mutation, Missense , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/transmission , Prognosis , Quantitative Trait Loci , Receptors, Virus/physiology , Risk , SARS-CoV-2 , Toll-Like Receptors/immunology , Treatment Outcome
14.
Signal Transduct Target Ther ; 5(1): 84, 2020 05 29.
Article in English | MEDLINE | ID: covidwho-437295

ABSTRACT

To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Host-Pathogen Interactions/drug effects , Pandemics , Pneumonia, Viral/drug therapy , Signal Transduction/drug effects , Adaptive Immunity/drug effects , Angiotensin-Converting Enzyme 2 , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Disease Progression , Gastrointestinal Microbiome/immunology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/drug effects , Molecular Targeted Therapy , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction/genetics , Signal Transduction/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
15.
BMC Med Genet ; 21(1): 113, 2020 05 25.
Article in English | MEDLINE | ID: covidwho-361259

ABSTRACT

BACKGROUND: Maternal cytomegalovirus (CMV) infection and/or reactivation in pregnancy is associated with a myriad of adverse infant outcomes. However, the role of host genetic polymorphisms in modulating maternal CMV status is inconclusive. This study investigated the possible association of single nucleotide polymorphisms in toll-like receptor (TLR) and cytokine genes with maternal plasma CMV DNA status in black Zimbabweans. METHODS: In a cross-sectional study, 110 women in late gestation who included 36 CMV infected cases and 74 CMV uninfected, age and HIV status matched controls were enrolled. Twenty single nucleotide polymorphisms in 10 genes which code for proteins involved in immunity against CMV were genotyped using Iplex GOLD SNP genotyping protocol on the Agena MassARRAY® system. Statistical analyses were performed using Stata SE and the 'Genetics' and 'SNPassoc' packages of the statistical package R. RESULTS: The TLR7 rs179008A > T (p < 0.001) polymorphism was associated while the TLR9 rs352139T > C (p = 0.049) polymorphism was on the borderline for association with CMV positive (CMV+) status. In contrast, the interleukin (IL)-6 rs10499563T > C (p < 0.001) and TLR2 rs1816702C > T (p = 0.001) polymorphisms were associated with CMV negative (CMV-) status. Furthermore, allele frequencies of SNPs in TLR2, TLR4, TLR9, TLR7, IL-6, IL-10, IL-28B, IL-1A and interferon AR1 (IFNAR1) genes are being reported here for the first time in a Zimbabwean population. The allele frequencies in the Zimbabwean population are generally comparable to other African populations but different when compared to European and Asian populations. CONCLUSIONS: Toll-like receptor and interleukin genetic polymorphisms influence CMV status in late gestation among black Zimbabweans. This is attributable to possible modulation of immune responses to CMV reactivation in a population previously exposed to CMV infection.


Subject(s)
Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/etiology , Cytomegalovirus , Genetic Variation , Interleukin-6/genetics , Pregnancy Complications, Infectious , Toll-Like Receptors/genetics , Adolescent , Adult , Alleles , Cytomegalovirus/immunology , Disease Susceptibility , Female , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Male , Odds Ratio , Polymorphism, Single Nucleotide , Pregnancy , Toll-Like Receptor 2/genetics , Toll-Like Receptor 7/genetics , Toll-Like Receptor 9/genetics , Young Adult
16.
J Med Virol ; 92(10): 2105-2113, 2020 10.
Article in English | MEDLINE | ID: covidwho-209797

ABSTRACT

Coronavirus disease-2019 (COVID-19) outbreak due to novel coronavirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has come out as a major threat for mankind in recent times. It is continually taking an enormous toll on mankind by means of increasing number of deaths, associated comorbidities, and socioeconomic loss around the globe. Unavailability of chemotherapeutics/vaccine has posed tremendous challenges to scientists and doctors for developing an urgent therapeutic strategy. In this connection, the present in silico study aims to understand the sequence divergence of spike protein (the major infective protein of SARS-CoV-2), its mode of interaction with the angiotensin-converting enzyme-2 receptor (ACE2) receptor of human and related animal hosts/reservoir. Moreover, the involvement of the human Toll-like receptors (TLRs) against the spike protein has also been demonstrated. Our data indicated that the spike glycoprotein of SARS-CoV-2 is phylogenetically close to bat coronavirus and strongly binds with ACE2 receptor protein from both human and bat origin. We have also found that cell surface TLRs, especially TLR4 is most likely to be involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory responses. The present study supported the zoonotic origin of SARS-CoV-2 from a bat and also revealed that TLR4 may have a crucial role in the virus-induced inflammatory consequences associated with COVID-19. Therefore, selective targeting of TLR4-spike protein interaction by designing competitive TLR4-antagonists could pave a new way to treat COVID-19. Finally, this study is expected to improve our understanding on the immunobiology of SARS-CoV-2 and could be useful in adopting spike protein, ACE2, or TLR-guided intervention strategy against COVID-19 shortly.


Subject(s)
Alphacoronavirus/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Receptors, Virus/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Toll-Like Receptors/chemistry , Alphacoronavirus/classification , Alphacoronavirus/metabolism , Alphacoronavirus/pathogenicity , Angiotensin-Converting Enzyme 2/classification , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Binding Sites , COVID-19/immunology , COVID-19/virology , Chiroptera/immunology , Chiroptera/virology , Data Mining , Eutheria/immunology , Eutheria/virology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Models, Molecular , Phylogeny , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Receptors, Virus/classification , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/classification , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics , Toll-Like Receptors/classification , Toll-Like Receptors/genetics , Toll-Like Receptors/metabolism , Viverridae/immunology , Viverridae/virology
17.
Clin Immunol ; 215: 108448, 2020 06.
Article in English | MEDLINE | ID: covidwho-125370

ABSTRACT

The novel coronavirus SARS-CoV2 causes COVID-19, a pandemic threatening millions. As protective immunity does not exist in humans and the virus is capable of escaping innate immune responses, it can proliferate, unhindered, in primarily infected tissues. Subsequent cell death results in the release of virus particles and intracellular components to the extracellular space, which result in immune cell recruitment, the generation of immune complexes and associated damage. Infection of monocytes/macrophages and/or recruitment of uninfected immune cells can result in massive inflammatory responses later in the disease. Uncontrolled production of pro-inflammatory mediators contributes to ARDS and cytokine storm syndrome. Antiviral agents and immune modulating treatments are currently being trialled. Understanding immune evasion strategies of SARS-CoV2 and the resulting delayed massive immune response will result in the identification of biomarkers that predict outcomes as well as phenotype and disease stage specific treatments that will likely include both antiviral and immune modulating agents.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/pathogenicity , Coronavirus Infections/drug therapy , Immunologic Factors/therapeutic use , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2 , Azithromycin/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Cytokines/genetics , Cytokines/immunology , Disease Management , Gene Expression Regulation , Humans , Hydroxychloroquine/therapeutic use , Immune Evasion/genetics , Immune Evasion/immunology , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/genetics , Tumor Necrosis Factor Receptor-Associated Peptides and Proteins/immunology
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