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1.
EMBO J ; 40(20): e106765, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34510494

RESUMO

The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans and transmitted the virus to ACE2-positive cells. Notably, human primary nasal cells were infected by SARS-CoV-2, and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.


Assuntos
COVID-19/transmissão , Proteoglicanas de Heparan Sulfato/metabolismo , Heparina de Baixo Peso Molecular/farmacologia , SARS-CoV-2/patogenicidade , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/metabolismo , Anticorpos Neutralizantes/farmacologia , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno , Humanos , Membrana Mucosa/citologia , Membrana Mucosa/virologia , SARS-CoV-2/metabolismo , Sindecana-1/metabolismo , Sindecana-4/metabolismo , Células Vero
2.
Vet Microbiol ; 260: 109182, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34315003

RESUMO

Immunosuppression can increase the susceptibility of chickens to other disease-causing pathogens and interfere with the efficacy of vaccination against those pathogens. Chicken anaemia virus (CAV) and infectious bursal disease virus (IBDV) are common causes of immunosuppression in chickens. Immunosuppression was induced by experimental infection with either CAV or IBDV to assess the effect of immunosuppression on the efficacy of vaccination with Mycoplasma gallisepticum strain ts-304 against infection with virulent M. gallisepticum, a common bacterial pathogen of chickens worldwide. Birds were experimentally infected with either CAV or IBDV at 1 week of age, before vaccination and challenge with M. gallisepticum to examine the effect of immunosuppression at the time of vaccination, or at 6 weeks of age, after vaccination against M. gallisepticum but before challenge with virulent M. gallisepticum, to investigate the effect of immunosuppression at the time of challenge. All birds were vaccinated with a single dose of the ts-304 vaccine at 3 weeks of age and experimentally challenged with the virulent M. gallisepticum strain Ap3AS at 8 weeks of age. In immunosuppressed chickens there was a reduction in protection offered by the ts-304 vaccine at two weeks after challenge, as measured by tracheal mucosal thicknesses, serum antibody levels against M. gallisepticum, air sac lesion scores and virulent M. gallisepticum load in the trachea. Immunosuppressed birds with detectable serum antibodies against M. gallisepticum were less likely to have tracheal lesions. This study has shown that immunosuppression caused by infection with CAV or IBDV can interfere with vaccination against mycoplasmosis in chickens.


Assuntos
Infecções por Birnaviridae/veterinária , Vírus da Anemia da Galinha/imunologia , Galinhas/imunologia , Infecções por Circoviridae/veterinária , Vírus da Doença Infecciosa da Bursa/imunologia , Infecções por Mycoplasma/veterinária , Mycoplasma gallisepticum/imunologia , Doenças das Aves Domésticas/prevenção & controle , Sacos Aéreos/virologia , Animais , Infecções por Birnaviridae/prevenção & controle , Infecções por Birnaviridae/virologia , Vírus da Anemia da Galinha/patogenicidade , Galinhas/microbiologia , Infecções por Circoviridae/prevenção & controle , Infecções por Circoviridae/virologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunossupressão/veterinária , Vírus da Doença Infecciosa da Bursa/patogenicidade , Membrana Mucosa/virologia , Infecções por Mycoplasma/microbiologia , Infecções por Mycoplasma/prevenção & controle , Mycoplasma gallisepticum/patogenicidade , Doenças das Aves Domésticas/microbiologia , Traqueia/virologia
3.
Front Immunol ; 12: 625649, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093520

RESUMO

Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.


Assuntos
Colo do Útero/virologia , Proteínas do Sistema Complemento/imunologia , Perfilação da Expressão Gênica , Infecções por HIV/virologia , HIV-1/patogenicidade , Membrana Mucosa/virologia , Proteoma , Proteômica , Transcriptoma , Colo do Útero/imunologia , Colo do Útero/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Feminino , Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV-1/crescimento & desenvolvimento , HIV-1/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Fatores de Tempo , Técnicas de Cultura de Tecidos , Internalização do Vírus , Replicação Viral
4.
PLoS Pathog ; 17(6): e1009632, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34061907

RESUMO

Human immunodeficiency virus (HIV) vaccines have not been successful in clinical trials. Dimeric IgA (dIgA) in the form of secretory IgA is the most abundant antibody class in mucosal tissues, making dIgA a prime candidate for potential HIV vaccines. We coupled Positron Emission Tomography (PET) imaging and fluorescent microscopy of 64Cu-labeled, photoactivatable-GFP HIV (PA-GFP-BaL) and fluorescently labeled dIgA to determine how dIgA antibodies influence virus interaction with mucosal barriers and viral penetration in colorectal tissue. Our results show that HIV virions rapidly disseminate throughout the colon two hours after exposure. The presence of dIgA resulted in an increase in virions and penetration depth in the transverse colon. Moreover, virions were found in the mesenteric lymph nodes two hours after viral exposure, and the presence of dIgA led to an increase in virions in mesenteric lymph nodes. Taken together, these technologies enable in vivo and in situ visualization of antibody-virus interactions and detailed investigations of early events in HIV infection.


Assuntos
Colo/virologia , Anticorpos Anti-HIV , Infecções por HIV , Imunoglobulina A Secretora , Membrana Mucosa/virologia , Animais , Macaca mulatta , Membrana Mucosa/imunologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Reto
5.
Am J Respir Cell Mol Biol ; 65(5): 513-520, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34166603

RESUMO

Smoking and human immunodeficiency virus 1 (HIV-1) infection are risk factors for chronic obstructive pulmonary disease (COPD), which is among the most common comorbid conditions in people living with HIV-1. HIV-1 infection leads to persistent expansion of CD8+ T cells, and CD8+ T cell-mediated inflammation has been implicated in COPD pathogenesis. In this study, we investigated the effects of HIV-1 infection and smoking on T-cell dynamics in patients at risk of COPD. BAL fluid, endobronchial brushings, and blood from HIV-1 infected and uninfected nonsmokers and smokers were analyzed by flow cytometry, and lungs were imaged by computed tomography. Chemokines were measured in BAL fluid, and CD8+ T-cell chemotaxis in the presence of cigarette smoke extract was assessed in vitro. HIV-1 infection increased CD8+ T cells in the BAL fluid, but this increase was abrogated by smoking. Smokers had reduced BAL fluid concentrations of the T cell-recruiting chemokines CXCL10 and CCL5, and cigarette smoke extract inhibited CXCL10 and CCL5 production by macrophages and CD8+ T-cell transmigration in vitro. In contrast to the T cells in BAL fluid, CD8+ T cells in endobronchial brushings were increased in HIV-1-infected smokers, which was driven by an accumulation of effector memory T cells in the airway mucosa and an increase in tissue-resident memory T cells. Mucosal CD8+ T-cell numbers inversely correlated with lung aeration, suggesting an association with inflammation and remodeling. HIV-1 infection and smoking lead to retention of CD8+ T cells within the airway mucosa.


Assuntos
Linfócitos T CD8-Positivos/patologia , Infecções por HIV/patologia , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologia , Fumar/efeitos adversos , Adulto , Líquido da Lavagem Broncoalveolar , Linfócitos T CD8-Positivos/virologia , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Quimiotaxia , Feminino , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Membrana Mucosa/virologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/virologia , Fatores de Risco , Tomografia Computadorizada por Raios X , Carga Viral
6.
J Clin Invest ; 131(16)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34166231

RESUMO

BackgroundVRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry.MethodsHealthy, HIV-1-uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4-13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants.ResultsMedian VRC01 levels were quantifiable in serum (96.2 µg/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo HIV-1Bal26 challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); HIV-1Du422.1 infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). HIV-1Bal26 infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003).ConclusionIntravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy.FundingNational Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Anti-HIV/administração & dosagem , Infecções por HIV/prevenção & controle , HIV-1/imunologia , HIV-1/patogenicidade , Reto/imunologia , Vagina/imunologia , Adulto , Anticorpos Monoclonais/farmacocinética , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Técnicas In Vitro , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/imunologia , Membrana Mucosa/virologia , Reto/virologia , Vagina/virologia , Adulto Jovem
7.
BMC Infect Dis ; 21(1): 422, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952203

RESUMO

BACKGROUND: HPV and C.trachomatis are the most prevalent, viral and bacterial STI worldwide. Both commonly have an asymptomatic development and can evolve into a persistent infection which, added to coinfections, may be important cofactors for the oncogenic transformation. OBJECTIVE: Evaluate the prevalence of oral and genital HPV and C.trachomatis infection in women with normal and abnormal cervical cytology. STUDY DESIGN: The cross-sectional study included 200 swabs, 100 oral and 100 cervical from 50 women with normal and 50 with abnormal cervical cytology. HPV and C.trachomatis infections were detected using PCR with specific primers. RESULTS: HPV DNA was detected in 27% (n = 27/100) of women with normal and abnormal cytology. Out of 100 genital samples we detected HPV DNA in 18% (n = 18/100) and 14% (n = 14/100) out of 100 oral samples. HPV genotypes detected were genotype 6 of low-risk and 16, 31, 52, 58 and 16-31 coinfection of high-risk. C.trachomatis DNA was detected in 49% (n = 49/100) of patients. Out of 100 genital samples we detected C.trachomatis in 35% (n = 35/100) and 31% (n = 31) out of 100 oral samples. There is statistically significant (p < 0.05) between cytology and HPV and C.trachomatis infection but there is no statistically significant between cytology and the other characteristics. CONCLUSIONS: Since the histology of oral mucosa resembles that of the uterine cervix, we can anticipate the presence of HPV and other STI which are detected in different lesions of genital areas and the oral mucosa. Therefore, is important C.trachomatis detection and specific treatment in asymptomatic women because this infection may increase the risk of HPV persistence and coinfection induces a pro-inflammatory environment that may promote the carcinogenesis.


Assuntos
Alphapapillomavirus/genética , Colo do Útero/virologia , Infecções por Chlamydia/epidemiologia , Doenças da Boca/epidemiologia , Infecções por Papillomavirus/epidemiologia , Adolescente , Adulto , Idoso , Alphapapillomavirus/isolamento & purificação , Alphapapillomavirus/patogenicidade , Argentina/epidemiologia , Colo do Útero/patologia , Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , Coinfecção/epidemiologia , Estudos Transversais , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Doenças da Boca/microbiologia , Doenças da Boca/virologia , Membrana Mucosa/virologia , Reação em Cadeia da Polimerase , Parceiros Sexuais , Adulto Jovem
8.
Immunology ; 164(2): 348-357, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34037988

RESUMO

Granulocytes mediate broad immunoprotection through phagocytosis, extracellular traps, release of cytotoxic granules, antibody effector functions and recruitment of other immune cells against pathogens. However, descriptions of granulocytes in HIV infection and mucosal tissues are limited. Our goal was to characterize granulocyte subsets in systemic, mucosal and lymphoid tissues during lentiviral infection using the rhesus macaque (RM) model. Mononuclear cells from jejunum, colon, cervix, vagina, lymph nodes, spleen, liver and whole blood from experimentally naïve and chronically SHIVsf162p3-infected RM were analysed by microscopy and polychromatic flow cytometry. Granulocytes were identified using phenotypes designed specifically for RM: eosinophils-CD45+  CD66+  CD49d+ ; neutrophils-CD45+  CD66+  CD14+ ; and basophils-CD45+  CD123+  FcRε+ . Nuclear visualization with DAPI staining and surface marker images by ImageStream (cytometry/microscopy) further confirmed granulocytic phenotypes. Flow cytometric data showed that all RM granulocytes expressed CD32 (FcRγII) but did not express CD16 (FcRγIII). Additionally, constitutive expression of CD64 (FcRγI) on neutrophils and FcRε on basophils indicates the differential expression of Fc receptors on granulocyte subsets. Granulocytic subsets in naïve whole blood ranged from 25·4% to 81·5% neutrophils, 0·59% to 13·3% eosinophils and 0·059% to 1·8% basophils. Interestingly, elevated frequencies of circulating neutrophils, colorectal neutrophils and colorectal eosinophils were all observed in chronic lentiviral disease. Conversely, circulating basophils, jejunal eosinophils, vaginal neutrophils and vaginal eosinophils of SHIVsf162p3-infected RM declined in frequency. Overall, our data suggest modulation of granulocytes in chronic lentiviral infection, most notably in the gastrointestinal mucosae where a significant inflammation and disruption occurs in lentivirus-induced disease. Furthermore, granulocytes may migrate to inflamed tissues during infection and could serve as targets of immunotherapeutic intervention.


Assuntos
Granulócitos/imunologia , Infecções por Lentivirus/imunologia , Macaca mulatta/imunologia , Membrana Mucosa/imunologia , Animais , Basófilos/imunologia , Basófilos/virologia , Eosinófilos/imunologia , Eosinófilos/virologia , Citometria de Fluxo/métodos , Granulócitos/virologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Contagem de Leucócitos/métodos , Membrana Mucosa/virologia , Neutrófilos/imunologia , Neutrófilos/virologia , Receptores de IgG/imunologia
9.
Elife ; 102021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34047696

RESUMO

Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/ß receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection.


Assuntos
Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Imunidade nas Mucosas , Interferon Tipo I/metabolismo , Interleucina-18/metabolismo , Membrana Mucosa/virologia , Ativação de Neutrófilo , Neutrófilos/virologia , Vagina/virologia , Animais , Anticorpos/farmacologia , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Herpes Genital/imunologia , Herpes Genital/metabolismo , Herpes Genital/prevenção & controle , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/imunologia , Interações Hospedeiro-Patógeno , Imunidade nas Mucosas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/inervação , Membrana Mucosa/metabolismo , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Vagina/efeitos dos fármacos , Vagina/imunologia , Vagina/metabolismo , Células Vero
10.
Ann Clin Lab Sci ; 51(1): 124-130, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33653791

RESUMO

EBV positive mucocutaneous ulcer (EBVMCU) is a newly recognized clinicopathologic entity in the 2017 World Health Organization (WHO) classification. Patients frequently present with an isolated ulcerative lesion in mucosal and cutaneous sites with immunosuppression as the main risk factor. The disease typically follows an indolent clinical course. Herein we describe a series of three patients diagnosed with EBVMCU. Histopathologic examination of these cases shows ulceration in mucosal or cutaneous surface with a substantial number of large atypical transformed cells in the background of dense polymorphous infiltrates. One patient regressed spontaneously with no treatment, one patient needed Rutiximab, and one patient had persistent EBVMCU process with possible transformation to large B cell lymphoma. The aim of the present case series is to highlight the pathologic, diagnostic and clinical features of patients with EBVMCU.


Assuntos
Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/patologia , Úlcera/metabolismo , Adulto , Idoso , Humanos , Imunossupressores/farmacologia , Linfoma Difuso de Grandes Células B/complicações , Transtornos Linfoproliferativos/etiologia , Masculino , Membrana Mucosa/metabolismo , Membrana Mucosa/virologia , Lesões Pré-Cancerosas , Dermatopatias/complicações , Úlcera/virologia
11.
J Immunol Methods ; 491: 112995, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33582148

RESUMO

Human immunodeficiency virus (HIV) remains a significant public health issue. In recent years, passive immunization with broadly neutralizing antibodies (bNabs) is being considered as a potentially efficacious approach for fighting HIV. One candidate that holds great promise is represented by the CD4-binding site targeted bNab capable of neutralizing over 90% of circulating HIV strains, VRC01. VRC01 along with its variants and clonal relatives - VRC01-LS and VRC07-523LS are currently being evaluated as vaccines in a number of clinical trials for HIV treatment and prevention. While mucosal areas of the body serve as major ports of HIV entry, reliable quantification of bNabs for pharmacokinetic and bioavailability analyses has been challenging due to low antibody concentrations in these samples. We developed an immunoassay on the Singulex platform which enables ultra-sensitive quantification of VRC01, VRC07, VRC01-LS and VRC07-523LS with a greater than 4-log linear dynamic range (LDR) and less than 120 pg/mL lower limit of quantitation (LLOQ). We implemented this assay to quantify VRC01 levels in rectal, cervical and oral mucosal samples in two passive immunization studies conducted with VRC01 - VRC 601 and VRC 602. Our assay was able to successfully quantify VRC01 levels in mucosal samples from all dosage groups (5 - -40 mg/kg) in these trials. VRC01 levels in a significant proportion of these samples (37% in oral and 25% in rectal mucosa) were below the lower limits of quantitation of other traditional immunoassays used for VRC01 quantification. We also measured VRC01 levels in sera from these trials and found that VRC01 measurements made using our assay exhibited excellent correlation (r2 = 0.9509) with measurements made previously using Enzyme-linked immunosorbent assay (ELISA). Our assay provides a reliable, sensitive and accurate method for quantification of clinically relevant bNabs and will help delineate antibody infiltration and bioavailability characteristics in complex biological matrices (CBM) such as mucosal tissues. This will in turn help determine clinical antibody threshold concentrations required to mediate protection against HIV acquisition and serve to inform dosing regimens and clinical trial design for future efficacy trials with these bNabs.


Assuntos
Anticorpos Anti-HIV/análise , HIV-1/imunologia , Membrana Mucosa/virologia , Anticorpos Amplamente Neutralizantes/análise , Colo do Útero/virologia , Feminino , Humanos , Imunoensaio , Mucosa Intestinal/virologia , Limite de Detecção , Mucosa Bucal/virologia
12.
FASEB J ; 35(2): e21282, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33484474

RESUMO

Cellular viral reservoirs are rapidly established in tissues upon HIV-1/SIV infection, which persist throughout viral infection, even under long-term antiretroviral therapy (ART). Specific integrins are involved in the homing of cells to gut-associated lymphoid tissues (GALT) and inflamed tissues, which may promote the seeding and dissemination of HIV-1/SIV to these tissue sites. In this study, we investigated the efficacy of prophylactic integrin blockade (α4ß7 antibody or α4ß7/α4ß1 dual antagonist TR-14035) on viral infection, as well as dissemination and seeding of viral reservoirs in systemic and lymphoid compartments post-SIV inoculation. The results showed that blockade of α4ß7/α4ß1 did not decrease viral infection, replication, or reduce viral reservoir size in tissues of rhesus macaques after SIV infection, as indicated by equivalent levels of plasma viremia and cell-associated SIV RNA/DNA to controls. Surprisingly, TR-14035 administration in acute SIV infection resulted in consistently higher viremia and more rapid disease progression. These findings suggest that integrin blockade alone fails to effectively control viral infection, replication, dissemination, and reservoir establishment in HIV-1/SIV infection. The use of integrin blockade for prevention or/and therapeutic strategies requires further investigation.


Assuntos
Anticorpos Neutralizantes/uso terapêutico , Integrinas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Animais , Anticorpos Neutralizantes/imunologia , Integrinas/imunologia , Tecido Linfoide/virologia , Macaca mulatta , Membrana Mucosa/metabolismo , Membrana Mucosa/virologia , Fenilalanina/uso terapêutico , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/patogenicidade , Vírus da Imunodeficiência Símia/fisiologia , Replicação Viral
13.
Int J Mol Sci ; 22(3)2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33494358

RESUMO

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in 2010. EBVMCU is a unifocal mucosal or cutaneous ulcer that often occurs after local trauma in patients with immunosuppression; the patients generally have a good prognosis. It is histologically characterized by proliferating EBV-positive atypical B cells accompanied by ulcers. On the basis of conventional pathologic criteria, EBVMCU may be misdiagnosed as EBV-positive diffuse large B-cell lymphoma or other lymphomas. However, its prognosis differs from that of EBV-associated lymphomas, in that patients with EBVMCU frequently show spontaneous regression or complete remission without chemotherapy. Therefore, EBVMCU is now recognized as a low-grade malignancy or a pseudo-malignant lesion. Avoiding unnecessary chemotherapy by distinguishing EBVMCU from other EBV-associated lymphomas will reduce the burden and unnecessary harm on patients. On the basis of these facts, EBVMCU was first described as a new clinicopathological entity by the World Health Organization in 2017. In this review, we discuss the clinicopathological characteristics of previously reported EBVMCU cases, while focusing on up-to-date clinical, pathological, and genetic aspects.


Assuntos
Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/fisiologia , Úlcera/etiologia , Úlcera/metabolismo , Animais , Biomarcadores , Biópsia , Infecções por Vírus Epstein-Barr/virologia , Humanos , Imuno-Histoquímica , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia , Membrana Mucosa/virologia , Fenótipo , Úlcera Cutânea/etiologia , Úlcera Cutânea/metabolismo , Úlcera Cutânea/patologia , Úlcera/patologia
14.
J Virol ; 95(3)2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33177204

RESUMO

Exposure of the genital mucosa to a genetically diverse viral swarm from the donor HIV-1 can result in breakthrough and systemic infection by a single transmitted/founder (TF) virus in the recipient. The highly diverse HIV-1 envelope (Env) in this inoculating viral swarm may have a critical role in transmission and subsequent immune response. Thus, chronic (Envchronic) and acute (Envacute) Env chimeric HIV-1 were tested using multivirus competition assays in human mucosal penile and cervical tissues. Viral competition analysis revealed that Envchronic viruses resided and replicated mainly in the tissue, while Envacute viruses penetrated the human tissue and established infection of CD4+ T cells more efficiently. Analysis of the replication fitness, as tested in peripheral blood mononuclear cells (PBMCs), showed similar replication fitness of Envacute and Envchronic viruses, which did not correlate with transmission fitness in penile tissue. Further, we observed that chimeric Env viruses with higher replication in genital mucosal tissue (chronic Env viruses) had higher binding affinity to C-type lectins. Data presented herein suggest that the inoculating HIV-1 may be sequestered in the genital mucosal tissue (represented by chronic Env HIV-1) but that a single HIV-1 clone (e.g., acute Env HIV-1) can escape this trapped replication for systemic infection.IMPORTANCE During heterosexual HIV-1 transmission, a genetic bottleneck occurs in the newly infected individual as the virus passes from the mucosa, leading to systemic infection with a single transmitted HIV-1 clone in the recipient. This bottleneck in the recipient has just been described (K. Klein et al., PLoS Pathog 14:e1006754, https://doi.org/10.1371/journal.ppat.1006754), and the mechanisms involved in this selection process have not been elucidated. However, understanding mucosal restriction is of the utmost importance for understanding dynamics of infections and for designing focused vaccines. Using our human penile and cervical mucosal tissue models for mixed HIV infections, we provide evidence that HIV-1 from acute/early infection, compared to that from chronic infection, can more efficiently traverse the mucosal epithelium and be transmitted to T cells, suggesting higher transmission fitness. This study focused on the role of the HIV-1 envelope in transmission and provides strong evidence that HIV transmission may involve breaking the mucosal lectin trap.


Assuntos
Colo do Útero/virologia , Infecções por HIV/transmissão , HIV-1/genética , Leucócitos Mononucleares/virologia , Membrana Mucosa/virologia , Pênis/virologia , Proteínas Virais/genética , Feminino , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , RNA Viral/análise , RNA Viral/genética
15.
J Med Virol ; 93(3): 1443-1448, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32880993

RESUMO

Our study intended to longitudinally explore the prediction effect of immunoglobulin A (IgA) on pulmonary exudation progression in COVID-19 patients. The serum IgA was tested with chemiluminescence method. Autoregressive moving average model was used to extrapolate the IgA levels before hospital admission. The positive rate of IgA and IgG in our cohort was 97% and 79.0%, respectively. In this study, the IgA levels peaks within 10-15 days after admission, while the IgG levels peaks at admission. We found that the time difference between their peaks was about 10 days. Viral RNA detection results showed that the positive rate in sputum and feces were the highest. Blood gas analysis showed that deterioration of hypoxia with the enlargement of pulmonary exudation area. And alveolar-arterial oxygen difference and oxygenation index were correlated with IgA and IgG. The results of biopsy showed that the epithelium of lung was exfoliated and the mucosa was edematous. In severe COVID-19 patients, the combination of IgA and IgG can predict the progress of pulmonary lesions and is closely related to hypoxemia and both also play an important defense role in invasion and destruction of bronchial and alveolar epithelium by SARS-CoV-2.


Assuntos
COVID-19/patologia , COVID-19/virologia , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Escarro/virologia , Idoso , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/virologia , Anticorpos Antivirais/sangue , Brônquios/metabolismo , Brônquios/virologia , COVID-19/sangue , COVID-19/metabolismo , Feminino , Humanos , Hipóxia/sangue , Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/metabolismo , Membrana Mucosa/virologia , Oxigênio/metabolismo , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/virologia , RNA Viral/genética , SARS-CoV-2/genética
16.
Oral Dis ; 26 Suppl 1: 40-46, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32862547

RESUMO

Oral and genital mucosal epithelia are multistratified epithelial barriers with well-developed tight and adherens junctions. These barriers serve as the first line of defense against many pathogens, including human immunodeficiency virus (HIV). HIV interaction with the surface of mucosal epithelial cells, however, may activate transforming growth factor-beta (TGF-ß) and mitogen-activated protein kinase signaling pathways. When activated, these pathways may lead to the disruption of epithelial junctions and epithelial-mesenchymal transition (EMT). HIV-induced impairment of the mucosal barrier may facilitate the spread of pathogenic viral, bacterial, fungal, and other infectious agents. HIV-induced EMT promotes highly motile/migratory cells. In oral and genital mucosa, if EMT occurs within a human papillomavirus (HPV)-infected premalignant or malignant cell environment, the HPV-associated neoplastic process could be accelerated by promoting viral invasion of malignant cells. HIV also internalizes into oral and genital mucosal epithelial cells. The majority (90%) of internalized virions do not cross the epithelium, but are retained in endosomal compartments for several days. These sequestered virions are infectious. Upon interaction with activated peripheral blood mononuclear cells and CD4+ T lymphocytes, epithelial cells containing the virus can be transferred. The induction of HIV-1 release and the cell-to-cell spread of virus from epithelial cells to lymphocytes is mediated by interaction of lymphocyte receptor function-associated antigen-1 with the epithelial cell receptor intercellular adhesion molecule-1. Thus, mucosal epithelial cells may serve as a transient reservoir for HIV, which could play a critical role in viral transmission.


Assuntos
Transição Epitelial-Mesenquimal , Infecções por HIV , HIV , Membrana Mucosa , Células Epiteliais , Genitália , HIV/patogenicidade , Humanos , Leucócitos Mononucleares , Membrana Mucosa/virologia , Vírion
17.
mSphere ; 5(4)2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669468

RESUMO

The beta human papillomaviruses (HPVs) are subdivided into 5 species (beta-1 to beta-5), and they were first identified in the skin. However, the beta-3 species appears to be more highly represented in the mucosal epithelia than in the skin. Functional studies have also highlighted that beta-3 HPV49 shares some functional similarities with mucosal high-risk (HR) HPV16. Here, we describe the characterization of the in vitro transforming properties of the entire beta-3 species, which includes three additional HPV types: HPV75, HPV76, and HPV115. HPV49, HPV75, and HPV76 E6 and E7 (E6/E7), but not HPV115 E6 and E7, efficiently inactivate the p53 and pRb pathways and immortalize or extend the life span of human foreskin keratinocytes (HFKs). As observed for HR HPV16, cell cycle deregulation mediated by beta-3 HPV E6/E7 expression leads to p16INK4a accumulation, whereas no p16INK4a was detected in beta-2 HPV38 E6/E7 HFKs. As shown for HPV49 E6, HPV75 and HPV76 E6s degrade p53 by an E6AP/proteasome-mediated mechanism. Comparative analysis of cellular gene expression patterns of HFKs containing E6 and E7 from HR HPV16, beta-3 HPV types, and beta-2 HPV38 further highlights the functional similarities of HR HPV16 and beta-3 HPV49, HPV75, and HPV76. The expression profiles of these four HPV HFKs show some similarities and diverge substantially from those of beta-3 HPV115 E6/E7 and beta-2 HPV38 E6/E7 HFKs. In summary, our data show that beta-3 HPV types share some mechanisms with HR HPV types and pave the way for additional studies aiming to evaluate their potential role in human pathologies.IMPORTANCE Human papillomaviruses are currently classified in different genera. Mucosal HPVs belonging to the alpha genus have been clearly associated with carcinogenesis of the mucosal epithelium at different sites. Beta HPV types have been classified as cutaneous. Although findings indicate that some beta HPVs from species 1 and 2 play a role, together with UV irradiation, in skin cancer, very little is known about the transforming properties of most of the beta HPVs. This report shows the transforming activity of E6 and E7 from beta-3 HPV types. Moreover, it highlights that beta-3 HPVs share some biological properties more extensively with mucosal high-risk HPV16 than with beta-2 HPV38. This report provides new paradigms for a better understanding of the biology of the different HPV types and their possible association with lesions at mucosal and/or cutaneous epithelia.


Assuntos
Alphapapillomavirus/genética , Alphapapillomavirus/patogenicidade , Células Epiteliais/virologia , Membrana Mucosa/virologia , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Alphapapillomavirus/classificação , Animais , Células Cultivadas , Papillomavirus Humano 16/genética , Humanos , Queratinócitos/virologia , Masculino , Camundongos , Membrana Mucosa/citologia , Células NIH 3T3 , Pele/virologia
18.
Exp Biol Med (Maywood) ; 245(12): 997-998, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32551877

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, in part due to the highly infectious nature of the disease. Because SARS-CoV-2 is new, much is unknown regarding mechanisms of transmission, and such information is urgently needed. Here, based on previous findings from related human betacoronaviruses, it is suggested that one possible route of transmission may be via infectious sweat. It is suggested that research be conducted in order to determine whether sweat in SARS-CoV-2 infected individuals harbors virus in quantities that can infect others. Findings could be used for formulations of mitigation strategies and empirically based public health messaging.


Assuntos
Infecções por Coronavirus/transmissão , Pneumonia Viral/transmissão , Suor/virologia , Enzima de Conversão de Angiotensina 2 , Betacoronavirus/patogenicidade , COVID-19 , Infecções por Coronavirus/etiologia , Interações Hospedeiro-Patógeno , Humanos , Membrana Mucosa/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/etiologia , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/transmissão , Sudorese/fisiologia
19.
Eur J Dermatol ; 30(2): 111-118, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32538355

RESUMO

BACKGROUND: The detection rate of human papillomavirus (HPV) in Bowen's disease (BD) varies greatly. OBJECTIVES: To detect HPV DNA in BD samples using next-generation sequencing (NGS) and compare HPV detection rates between pelvic and non-pelvic BD. MATERIALS AND METHODS: We evaluated 99 patients with BD in our institution. DNA was extracted from formalin-fixed and paraffin embedded (FFPE) tissue blocks. The presence of HPV DNA material was detected using special kit-based NGS technology. Clinical characteristics and HPV detection rates were then compared between pelvic and non-pelvic BD samples. RESULTS: HPV was detected in 26 (26.3%) BD samples. A total of 10 types of α-HPV was detected: HPV 16, 53, 31, 58, 66, 26, 27, 57, 45, and 72. The most common HPV type was 16 (12.1%). Only two types (27 and 57) were frequently classified as cutaneous type, and the rest were mucosal types. The HPV detection rate was significantly higher in pelvic BD (45.2%) compared to non-pelvic BD (17.6%). CONCLUSION: The present study suggests that sexually transmitted mucosal α-HPV plays a significant role in the pathogenesis of BD, especially in the pelvic region.


Assuntos
Alphapapillomavirus/isolamento & purificação , Doença de Bowen/virologia , DNA Viral/isolamento & purificação , Infecções por Papillomavirus/virologia , Doenças Virais Sexualmente Transmissíveis/virologia , Pele/virologia , Parede Abdominal/patologia , Parede Abdominal/virologia , Idoso , Idoso de 80 Anos ou mais , Alphapapillomavirus/genética , Biópsia , Doença de Bowen/etiologia , Nádegas , DNA Viral/genética , Feminino , Genótipo , Técnicas de Genotipagem , Virilha/patologia , Virilha/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/patologia , Membrana Mucosa/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Estudos Retrospectivos , Doenças Virais Sexualmente Transmissíveis/complicações , Pele/patologia , Coxa da Perna/patologia , Coxa da Perna/virologia
20.
Pathology ; 52(4): 478-482, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32354659

RESUMO

Multiplex polymerase chain reaction (PCR) testing has revolutionised microbiological practice but also increased the number of positive results of uncertain significance. This phenomenon has been seen in the increasing detection of cytomegalovirus (CMV) in mucocutaneous swabs for herpesviruses, the microbiological significance of which is a priori unclear. The aim of our study was to determine if an incidental finding of a positive CMV result represented CMV disease, if it facilitated a timely diagnosis of CMV disease or whether there were any deleterious outcomes. We performed a retrospective review of patients with an incidentally positive PCR result for CMV on external and mucosal swabs, including medical comorbidities and presence of immunosuppression, subsequent investigations, whether a diagnosis of CMV disease was made, and treatment. CMV detection was infrequent, detected in 158 (3.4%) of 4626 herpes multiplex PCR tests performed. The majority (60.4%) of patients were immunocompromised, and amongst these patients a positive swab represented a new diagnosis or already known CMV disease in 14%. In seven patients (5%), all of whom were immunocompromised, the positive CMV PCR on a swab led to further investigation and subsequent diagnosis and treatment of CMV disease. Whilst not recommended for diagnosis of CMV disease, if CMV is detected on a mucocutaneous swab in an immunocompromised patient, further assessment and investigation for CMV disease should be undertaken.


Assuntos
Infecções por Citomegalovirus/epidemiologia , Achados Incidentais , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/virologia , Reação em Cadeia da Polimerase Multiplex , Estudos Retrospectivos , Pele/virologia , Adulto Jovem
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