Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
1.
Int J Mol Sci ; 23(6)2022 Mar 17.
Article in English | MEDLINE | ID: covidwho-1760648

ABSTRACT

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus endemic to Africa and the Arabian Peninsula, which causes diseases in humans and livestock. C-type lectin receptors (CLRs) represent a superfamily of pattern recognition receptors that were reported to interact with diverse viruses and contribute to antiviral immune responses but may also act as attachment factors or entry receptors in diverse species. Human DC-SIGN and L-SIGN are known to interact with RVFV and to facilitate viral host cell entry, but the roles of further host and vector CLRs are still unknown. In this study, we present a CLR-Fc fusion protein library to screen RVFV-CLR interaction in a cross-species approach and identified novel murine, ovine, and Aedes aegypti RVFV candidate receptors. Furthermore, cross-species CLR binding studies enabled observations of the differences and similarities in binding preferences of RVFV between mammalian CLR homologues, as well as more distant vector/host CLRs.


Subject(s)
Aedes , Rift Valley Fever , Rift Valley fever virus , Animals , Humans , Lectins, C-Type/genetics , Mammals , Mice , Mosquito Vectors/genetics , Sheep
2.
J Virol ; 96(7): e0199521, 2022 04 13.
Article in English | MEDLINE | ID: covidwho-1745826

ABSTRACT

C-type lectin domain-containing proteins (CTLDcps) shape host responses to pathogens and infectious disease outcomes. Previously, we identified the murine CTLDcp Cd302 as restriction factor, limiting hepatitis C virus (HCV) infection of murine hepatocytes. In this study, we investigated in detail the human orthologue's ability to restrict HCV infection in human liver cells. CD302 overexpression in Huh-7.5 cells potently inhibited infection of diverse HCV chimeras representing seven genotypes. Transcriptional profiling revealed abundant CD302 mRNA expression in human hepatocytes, the natural cellular target of HCV. Knockdown of endogenously expressed CD302 modestly enhanced HCV infection of Huh-7.5 cells and primary human hepatocytes. Functional analysis of naturally occurring CD302 transcript variants and engineered CD302 mutants showed that the C-type lectin-like domain (CTLD) is essential for HCV restriction, whereas the cytoplasmic domain (CPD) is dispensable. Coding single nucleotide polymorphisms occurring in human populations and mapping to different domains of CD302 did not influence the capacity of CD302 to restrict HCV. Assessment of the anti-HCV phenotype at different life cycle stages indicated that CD302 preferentially targets the viral entry step. In contrast to the murine orthologue, overexpression of human CD302 did not modulate downstream expression of nuclear receptor-controlled genes. Ectopic CD302 expression restricted infection of liver tropic hepatitis E virus (HEV), while it did not affect infection rates of two respiratory viruses, including respiratory syncytial virus (RSV) and the alpha coronavirus HVCoV-229E. Together, these findings suggest that CD302 contributes to liver cell-intrinsic defense against HCV and might mediate broader antiviral defenses against additional hepatotropic viruses. IMPORTANCE The liver represents an immunoprivileged organ characterized by enhanced resistance to immune responses. However, the importance of liver cell-endogenous, noncytolytic innate immune responses in pathogen control is not well defined. Although the role of myeloid cell-expressed CTLDcps in host responses to viruses has been characterized in detail, we have little information about their potential functions in the liver and their relevance for immune responses in this organ. Human hepatocytes endogenously express the CTLDcp CD302. Here, we provide evidence that CD302 limits HCV infection of human liver cells, likely by inhibiting a viral cell entry step. We confirm that the dominant liver-expressed transcript variant, as well as naturally occurring coding variants of CD302, maintain the capacity to restrict HCV. We further show that the CTLD of the protein is critical for the anti-HCV activity and that overexpressed CD302 limits HEV infection. Thus, CD302 likely contributes to human liver-intrinsic antiviral defenses.


Subject(s)
Hepacivirus , Hepatitis C , Lectins, C-Type , Receptors, Cell Surface , Antiviral Agents/metabolism , Hepacivirus/physiology , Hepatitis C/immunology , Hepatocytes/immunology , Hepatocytes/virology , Humans , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Virus Replication
3.
Int J Mol Sci ; 22(17)2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1374426

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 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.


Subject(s)
COVID-19/immunology , Cell Adhesion Molecules/genetics , Dendritic Cells/immunology , Gene Expression Regulation/immunology , Lectins, C-Type/genetics , Receptors, Cell Surface/genetics , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/pathology , COVID-19/virology , Cell Adhesion Molecules/metabolism , Datasets as Topic , Dendritic Cells/metabolism , Genome-Wide Association Study , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Lectins, C-Type/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mendelian Randomization Analysis , Nasopharynx/immunology , Nasopharynx/pathology , Nasopharynx/virology , RNA-Seq , Receptors, Cell Surface/metabolism , Severity of Illness Index , Single-Cell Analysis
4.
J Biol Chem ; 297(1): 100847, 2021 07.
Article in English | MEDLINE | ID: covidwho-1246014

ABSTRACT

The zoonotic transmission of highly pathogenic coronaviruses into the human population is a pressing concern highlighted by the ongoing SARS-CoV-2 pandemic. Recent work has helped to illuminate much about the mechanisms of SARS-CoV-2 entry into the cell, which determines host- and tissue-specific tropism, pathogenicity, and zoonotic transmission. Here we discuss current findings on the factors governing SARS-CoV-2 entry. We first reviewed key features of the viral spike protein (S) mediating fusion of the viral envelope and host cell membrane through binding to the SARS-CoV-2 receptor, angiotensin-converting enzyme 2. We then examined the roles of host proteases including transmembrane protease serine 2 and cathepsins in processing S for virus entry and the impact of this processing on endosomal and plasma membrane virus entry routes. We further discussed recent work on several host cofactors that enhance SARS-CoV-2 entry including Neuropilin-1, CD147, phosphatidylserine receptors, heparan sulfate proteoglycans, sialic acids, and C-type lectins. Finally, we discussed two key host restriction factors, i.e., interferon-induced transmembrane proteins and lymphocyte antigen 6 complex locus E, which can disrupt SARS-CoV-2 entry. The features of SARS-CoV-2 are presented in the context of other human coronaviruses, highlighting unique aspects. In addition, we identify the gaps in understanding of SARS-CoV-2 entry that will need to be addressed by future studies.


Subject(s)
COVID-19/metabolism , SARS-CoV-2/physiology , Virus Internalization , Animals , Basigin/genetics , Basigin/metabolism , COVID-19/genetics , COVID-19/virology , Host-Pathogen Interactions , Humans , Lectins, C-Type/genetics , Lectins, C-Type/metabolism , Neuropilin-1/genetics , Neuropilin-1/metabolism , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/genetics
5.
J Infect Dis ; 224(Supplement_6): S631-S641, 2021 Dec 08.
Article in English | MEDLINE | ID: covidwho-1195718

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding receptor ACE2 and the spike protein priming protease TMPRSS2 are coexpressed in human placentae. It is unknown whether their expression is altered in the context of HIV infection and antiretroviral therapy (ART). METHODS: We compared mRNA levels of SARS-CoV-2 cell-entry mediators ACE2, TMPRSS2, and L-SIGN by quantitative polymerase chain reaction in 105 placentae: 45 from pregnant women with HIV (WHIV) on protease inhibitor (PI)-based ART, 17 from WHIV on non-PI-based ART, and 43 from HIV-uninfected women. RESULTS: ACE2 levels were lower, while L-SIGN levels were higher, in placentae from WHIV on PI-based ART compared to those on non-PI-based ART and to HIV-uninfected women. TMPRSS2 levels were similar between groups. Black race was significantly associated with lower expression of ACE2 and higher expression of L-SIGN. ACE2 levels were significantly higher in placentae of female fetuses. CONCLUSIONS: We identified pregnant women of black race and WHIV on PI-based ART to have relatively lower expression of placental ACE2 than those of white race and HIV-uninfected women. This may potentially contribute to altered susceptibility to COVID-19 in these women, favorably by reduced viral entry or detrimentally by loss of ACE2 protection against hyperinflammation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 , Cell Adhesion Molecules/metabolism , HIV Infections/blood , Lectins, C-Type/metabolism , Placenta/metabolism , Receptors, Cell Surface/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Adult , Angiotensin-Converting Enzyme 2/genetics , Antiretroviral Therapy, Highly Active , COVID-19/diagnosis , Case-Control Studies , Cell Adhesion Molecules/genetics , Female , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Humans , Lectins, C-Type/genetics , Pregnancy , RNA, Messenger , Real-Time Polymerase Chain Reaction , Receptors, Cell Surface/genetics
6.
FEBS Open Bio ; 10(11): 2363-2374, 2020 11.
Article in English | MEDLINE | ID: covidwho-792010

ABSTRACT

Comorbidities in COVID-19 patients often worsen clinical conditions and may represent death predictors. Here, the expression of five genes, known to encode coronavirus receptors/interactors (ACE2, TMPRSS2, CLEC4M, DPP4 and TMPRSS11D), was investigated in normal and cancer tissues, and their molecular relationships with clinical comorbidities were investigated. Using expression data from GENT2 databases, we evaluated gene expression in all anatomical districts from 32 normal tissues in 3902 individuals. Functional relationships with body districts were analyzed by chilibot. We performed DisGeNet, genemania and DAVID analyses to identify human diseases associated with these genes. Transcriptomic expression levels were then analyzed in 31 cancer types and healthy controls from approximately 43 000 individuals, using GEPIA2 and GENT2 databases. By performing receiver operating characteristic analysis, the area under the curve (AUC) was used to discriminate healthy from cancer patients. Coronavirus receptors were found to be expressed in several body districts. Moreover, the five genes were found to associate with acute respiratory syndrome, diabetes, cardiovascular diseases and cancer (i.e. the most frequent COVID-19 comorbidities). Their expression levels were found to be significantly altered in cancer types, including colon, kidney, liver, testis, thyroid and skin cancers (P < 0.0001); AUC > 0.80 suggests that TMPRSS2, CLEC4M and DPP4 are relevant markers of kidney, liver, and thyroid cancer, respectively. The five coronavirus receptors are related to all main COVID-19 comorbidities and three show significantly different expression in cancer versus control tissues. Further investigation into their role may help in monitoring other comorbidities, as well as for follow-up of patients who have recovered from SARS-CoV-2 infection.


Subject(s)
COVID-19/prevention & control , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Neoplasms/genetics , SARS-CoV-2/isolation & purification , Angiotensin-Converting Enzyme 2/genetics , COVID-19/epidemiology , COVID-19/virology , Cell Adhesion Molecules/genetics , Comorbidity , Databases, Genetic , Dipeptidyl Peptidase 4/genetics , Epidemics , Female , Genetic Predisposition to Disease/genetics , Humans , Lectins, C-Type/genetics , Male , Membrane Proteins/genetics , Neoplasms/classification , Neoplasms/epidemiology , Receptors, Cell Surface/genetics , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Proteases/genetics
8.
J Infect Dis ; 221(4): 647-659, 2020 02 03.
Article in English | MEDLINE | ID: covidwho-326851

ABSTRACT

BACKGROUND: Human infection with Middle East respiratory syndrome coronavirus (MERS-CoV) poses an ongoing threat to public health worldwide. The studies of MERS patients with severe disease and experimentally infected animals showed that robust viral replication and intensive proinflammatory response in lung tissues contribute to high pathogenicity of MERS-CoV. We sought to identify pattern recognition receptor (PRR) signaling pathway(s) that mediates the inflammatory cascade in human macrophages upon MERS-CoV infection. METHODS: The potential signaling pathways were manipulated individually by pharmacological inhibition, small interfering ribonucleic acid (siRNA) depletion, and antibody blocking. The MERS-CoV-induced proinflammatory response was evaluated by measuring the expression levels of key cytokines and/or chemokines. Reverse transcription-quantitative polymerase chain reaction assay, flow cytometry analysis, and Western blotting were applied to evaluate the activation of related PRRs and engagement of adaptors. RESULTS: MERS-CoV replication significantly upregulated C-type lectin receptor (CLR) macrophage-inducible Ca2+-dependent lectin receptor (Mincle). The role of Mincle for MERS-CoV-triggered cytokine/chemokine induction was established based on the results of antibody blockage, siRNA depletion of Mincle and its adaptor spleen tyrosine kinase (Syk), and Syk pharmacological inhibition. The cytokine and/or chemokine induction was significantly attenuated by siRNA depletion of retinoic acid-inducible-I-like receptors (RLR) or adaptor, indicating that RLR signaling also contributed to MERS-CoV-induced proinflammatory response. CONCLUSIONS: The CLR and RLR pathways are activated and contribute to the proinflammatory response in MERS-CoV-infected macrophages.


Subject(s)
Coronavirus Infections/immunology , DEAD Box Protein 58/metabolism , Lectins, C-Type/metabolism , Macrophages/immunology , Macrophages/virology , Middle East Respiratory Syndrome Coronavirus/metabolism , Animals , CARD Signaling Adaptor Proteins , Chemokines/metabolism , Chlorocebus aethiops , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Cytokines/immunology , Cytokines/metabolism , DEAD Box Protein 58/genetics , Gene Knockdown Techniques , Humans , Lectins, C-Type/genetics , Lung/immunology , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , RNA, Small Interfering/metabolism , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Signal Transduction , Transcriptome , Tretinoin/pharmacology , Vero Cells , Virus Replication
SELECTION OF CITATIONS
SEARCH DETAIL