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1.
PLoS Pathog ; 19(5): e1011409, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37200377

RESUMO

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.


Assuntos
COVID-19 , Masculino , Camundongos , Animais , Humanos , COVID-19/metabolismo , Testículo , SARS-CoV-2 , Efeito Espectador , Inflamação/metabolismo , Camundongos Transgênicos
2.
Semin Cancer Biol ; 75: 127-135, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33440245

RESUMO

Extracellular vesicles (EVs) have emerged as important players in all aspects of cancer biology. Their function is mediated by their cargo and surface molecules including proteins, lipids, sugars and nucleic acids. RNA in particular is a key mediator of EV function both in normal and cancer cells. This statement is supported by several lines of evidence. First, cells do not always randomly load RNA in EVs, there seems to be a specific manner in which cells populate their EVs with certain RNA molecules. Moreover, cellular uptake of EV-RNA and the secondary compartmentalization of EV-RNA in recipient cells is widely reported, and these RNAs have an impact on all aspects of cancer growth and the anti-tumoral immune response. Additionally, EV-RNA seems to work through various mechanisms of action, highlighting the intricacies of EVs and their RNA cargo as prominent means of inter-cellular communication.


Assuntos
Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias/patologia , RNA/genética , Animais , Biomarcadores Tumorais/genética , Comunicação Celular , Progressão da Doença , Humanos , Neoplasias/genética , Neoplasias/metabolismo
3.
Immun Inflamm Dis ; 12(8): e1343, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39092750

RESUMO

The involvement of neutrophils in the lungs during the recovery phase of coronavirus disease 2019 (COVID-19) is not well defined mainly due to the limited accessibility of lung tissues from COVID-19 survivors. The lack of an appropriate small animal model has affected the development of effective therapeutic strategies. We here developed a long COVID mouse model to study changes in neutrophil phenotype and association with lung injury. Our data shows persistent neutrophil recruitment and neutrophil extracellular trap formation in the lungs for up to 30 days post-infection which correlates with lung fibrosis and inflammation.


Assuntos
COVID-19 , Modelos Animais de Doenças , Armadilhas Extracelulares , Pulmão , Neutrófilos , SARS-CoV-2 , Animais , Armadilhas Extracelulares/imunologia , COVID-19/imunologia , COVID-19/complicações , Camundongos , Neutrófilos/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Pulmão/patologia , Pulmão/imunologia , Pulmão/virologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/virologia , Lesão Pulmonar/patologia , Lesão Pulmonar/etiologia , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Infiltração de Neutrófilos/imunologia , Humanos , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Fibrose Pulmonar/etiologia
4.
Front Microbiol ; 13: 1062499, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36713156

RESUMO

Sexual transmission of Zika virus (ZIKV) is associated with virus persistence in the testes and shedding in the seminal fluid for months after recovery. We previously demonstrated that ZIKV can establish long-term replication without causing cytotoxicity in human Sertoli cells (SC), responsible for maintaining the immune privileged compartment of seminiferous tubules. Functional gene expression analyses also predicted activation of multiple virus sensing pathways including TLR3, RIG-I, and MDA5. Here, we elucidated which of the RNA virus sensing receptors play a decisive role in restricting ZIKV replication. We show that both poly I:C and IFN-ß treatment induced a robust antiviral state and reduced ZIKV replication significantly, suggesting that virus sensing and antiviral signaling are functional in SC. Silencing of TLR3, 7, and 9 did not affect virus replication kinetics; however, both RIG-I and MDA5 played a synergistic role in inducing an anti-ZIKV response. Further, the impact of SC-specific immunosuppressive pathways that collectively regulate SC function, specifically the TGF-ß superfamily members, TGF-ß, Activin A, and BMP6, on ZIKV replication was investigated. While ZIKV did not modulate the expression of TGF-ß and Activin A, BMP6 signaling was suppressed at later stages of infection. Notably, treatment with BMP6 increased IFN-ß, p-IRF3, and p-STAT1 levels, and expression of key interferon-stimulated genes including MDA5, suggesting that BMP6 enhances antiviral response in SC. Collectively, this study further delineates the key role of the RIG-I-like receptors in sensing ZIKV in SC, and reveals a novel role of BMP6 in modulating innate immune and antiviral response in the testes.

5.
bioRxiv ; 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36172118

RESUMO

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ failure including testicular injury and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury can likely result either from direct virus infection of resident cells or by exposure to systemic inflammatory mediators or virus antigens. We here characterized SARS-CoV-2 infection in different human testicular 2D and 3D models including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not establish a productive infection in any testicular cell types. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma depicted a significant decrease in cell viability and death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 envelope protein, but not Spike or nucleocapsid proteins led to cytopathic effects on testicular cells that was dependent on the TLR2 receptor. A similar trend was observed in the K18h-ACE2 mouse model which revealed gross pathology in the absence of virus replication in the testis. Collectively, data strongly indicates that the testicular injury is not due to direct infection of SARS-CoV-2 but more likely an indirect effect of exposure to systemic inflammation or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.

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