HIV and HCV Activate the Inflammasome in Monocytes and Macrophages via Endosomal Toll-Like Receptors without Induction of Type 1 Interferon
| العنوان: | HIV and HCV Activate the Inflammasome in Monocytes and Macrophages via Endosomal Toll-Like Receptors without Induction of Type 1 Interferon |
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| المؤلفون: | Rachel Latanich, Drew M. Pardoll, rd Robert W. Buckheit, Andrea L. Cox, Jeffrey Quinn, Matthew E. Winter, Michael A. Chattergoon, Joel N. Blankson |
| المصدر: | PLoS Pathogens PLoS Pathogens, Vol 10, Iss 5, p e1004082 (2014) |
| بيانات النشر: | Public Library of Science, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Viral Diseases, Gastroenterology and hepatology, Inflammasomes, HIV Infections, Hepacivirus, Clinical immunology, Monocytes, Hepatitis, White Blood Cells, Immunodeficiency Viruses, Interferon, Animal Cells, Biology (General), Immune Response, Cells, Cultured, Innate Immune System, Toll-Like Receptors, Interleukin, virus diseases, Inflammasome, Hep G2 Cells, HIV immunopathogenesis, Hepatitis C, Endocytosis, 3. Good health, Viral Persistence and Latency, Infectious hepatitis, Infectious Diseases, Medical Microbiology, Viral Pathogens, Interferon Type I, Cytokines, medicine.symptom, Cellular Types, medicine.drug, Research Article, QH301-705.5, Immunology, Inflammation, Endosomes, Biology, Microbiology, Virology, Genetics, medicine, Humans, Molecular Biology, Microbial Pathogens, Liver diseases, Medicine and health sciences, Innate immune system, Blood Cells, Biology and life sciences, Macrophages, HIV, TLR7, Cell Biology, RC581-607, TLR8, Molecular Development, Virus Internalization, Immune System, TLR3, HIV-1, Parasitology, Immunologic diseases. Allergy, Developmental Biology |
| الوصف: | Innate immune sensing of viral infection results in type I interferon (IFN) production and inflammasome activation. Type I IFNs, primarily IFN-α and IFN-β, are produced by all cell types upon virus infection and promote an antiviral state in surrounding cells by inducing the expression of IFN-stimulated genes. Type I IFN production is mediated by Toll-like receptor (TLR) 3 in HCV infected hepatocytes. Type I IFNs are also produced by plasmacytoid dendritic cells (pDC) after sensing of HIV and HCV through TLR7 in the absence of productive pDC infection. Inflammasomes are multi-protein cytosolic complexes that integrate several pathogen-triggered signaling cascades ultimately leading to caspase-1 activation and generation pro-inflammatory cytokines including interleukin (IL)-18 and IL-1β. Here, we demonstrate that HIV and HCV activate the inflammasome, but not Type I IFN production, in monocytes and macrophages in an infection-independent process that requires clathrin-mediated endocytosis and recognition of the virus by distinct endosomal TLRs. Knockdown of each endosomal TLR in primary monocytes by RNA interference reveals that inflammasome activation in these cells results from HIV sensing by TLR8 and HCV recognition by TLR7. Despite its critical role in type I IFN production by pDCs stimulated with HIV, TLR7 is not required for inflammasome activation by HIV. Similarly, HCV activation of the inflammasome in monocytes does not require TLR3 or its downstream signaling adaptor TICAM-1, while this pathway leads to type I IFN in infected hepatocytes. Monocytes and macrophages do not produce type I IFN upon TLR8 or TLR7 sensing of HIV or HCV, respectively. These findings reveal a novel infection-independent mechanism for chronic viral induction of key anti-viral programs and demonstrate distinct TLR utilization by different cell types for activation of the type I IFN vs. inflammasome pathways of inflammation. Author Summary Pathogens are detected by the immune system in multiple ways that initiate responses to control infection. Two systems of first line defense against viruses are 1) the production of Type I interferons and 2) production of the cytokines IL-1β and IL-18 by the inflammasome. Type I interferons promote an antiviral state in the infected host. Inflammasome cytokines induce inflammation, modulate adaptive immune responses, and have direct antiviral effects. While both are produced in response to the chronic human viral infections HIV and HCV, we demonstrate here that inflammasome activation does not require cell infection and that the mechanisms for viral sensing as well as cell types in which sensing occurs are distinct between the two viruses and between the type I interferon vs. inflammasome systems. The relative amount of sensing via these different mechanisms may affect the balance between antiviral and inflammatory responses to chronic infection. |
| اللغة: | English |
| تدمد: | 1553-7374 1553-7366 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::91280c862eeb35810da4d2cf65dc450c http://europepmc.org/articles/PMC4006909 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....91280c862eeb35810da4d2cf65dc450c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537374 15537366 |
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