PMID- 28222752 OWN - NLM STAT- MEDLINE DCOM- 20170823 LR - 20181113 IS - 1743-422X (Electronic) IS - 1743-422X (Linking) VI - 14 IP - 1 DP - 2017 Feb 21 TI - Dendritic cells, macrophages, NK and CD8(+) T lymphocytes play pivotal roles in controlling HSV-1 in the trigeminal ganglia by producing IL1-beta, iNOS and granzyme B. PG - 37 LID - 10.1186/s12985-017-0692-x [doi] LID - 37 AB - BACKGROUND: Herpes simplex virus type 1 (HSV-1) cause not only mild symptoms but also blindness and encephalitis. It was previously shown that the immune response against HSV-1 occurs mainly in the trigeminal ganglia (TG) and that Toll-like receptors 2 and 9 (TLR2/9) are important in mediating this response. It was also demonstrated that iNOS (nitric oxide synthase) and interleukin 1 beta (IL-1beta) play an essential role in the defense against HSV-1 infection. Importantly, the present work aimed to identify the primary cells responsible for iNOS and IL-1beta production and search for other important molecules and cells that might or might not depend on TLR2/9 receptors to mediate the immune response against HSV-1. METHODS: C57BL/6 (wild type, WT) and TLR2/9(-/-) mice were infected by the intranasal route with HSV-1 (1 x 10(6) p.f.u.). Cells were obtained from the TG and spleen tissues and the profile of immune cells was determined by flow cytometry in infected and mock infected WT and knockout mice. The percentage of cells producing iNOS, IL-1beta, granzyme B and perforin was also determined by flow cytometry. Chemokine monocyte chemoattractant protein-1 (MCP1) was measured by Cytometric Bead Array (CBA) in the TG, spleen and lung. Expression of type I interferons (IFNs), interleukins (IL) 5 and 10, IL-1beta and granzyme B were quantified by real time PCR. RESULTS: The results indicate that dendritic cells (DCs) and monocytes/macrophages (Mo/Mvarphi) were the main sources of IL-1beta and iNOS, respectively, which, together with type I IFNs, were essential for the immune response against HSV-1. Additionally, we showed that granzyme B produced by CD8(+) T and NK lymphocytes and MCP-1 were also important for this immune response. Moreover, our data indicate that the robust production of MCP-1 and granzyme B is either TLR-independent or down regulated by TLRs and occurs in the TG of TLR2/9(-/-) infected mice. CONCLUSION: Taken together, our data provide strong evidence that the responses mediated by DCs, Mo/Mvarphi, NK and CD8(+) T lymphocytes through IL-1beta, iNOS and granzyme B production, respectively, together with the production of type I IFN early in the infection, are crucial to host defense against HSV-1. FAU - Lucinda, Natalia AU - Lucinda N AD - Imunologia de Doencas Virais, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Fiocruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, MG, Brazil. FAU - Figueiredo, Maria Marta AU - Figueiredo MM AD - Imunologia de Doencas Virais, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Fiocruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, MG, Brazil. FAU - Pessoa, Natalia Lima AU - Pessoa NL AD - Imunologia de Doencas Virais, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Fiocruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, MG, Brazil. FAU - Santos, Beatriz Senra Alvares da Silva AU - Santos BS AD - Imunologia de Doencas Virais, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Fiocruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, MG, Brazil. FAU - Lima, Graciela Kunrath AU - Lima GK AD - Escola de Veterinaria, Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, Belo Horizonte, 31270-901, MG, Brazil. FAU - Freitas, Arthur Molinari AU - Freitas AM AD - Imunologia de Doencas Virais, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Fiocruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, MG, Brazil. FAU - Machado, Alexandre Magalhaes Vieira AU - Machado AM AD - Imunologia de Doencas Virais, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Fiocruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, MG, Brazil. FAU - Kroon, Erna Geessien AU - Kroon EG AD - Laboratorio de Virus, Departamento de Microbiologia, Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, Belo Horizonte, 31270-901, MG, Brazil. FAU - Antonelli, Lis Ribeiro do Valle AU - Antonelli LR AD - Biologia e Imunologia Parasitaria, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Fiocruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, MG, Brazil. FAU - Campos, Marco Antonio AU - Campos MA AUID- ORCID: 0000-0003-4683-0176 AD - Imunologia de Doencas Virais, Centro de Pesquisas Rene Rachou, Fundacao Oswaldo Cruz, Fiocruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, MG, Brazil. marcoasc@cpqrr.fiocruz.br. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170221 PL - England TA - Virol J JT - Virology journal JID - 101231645 RN - 0 (Interferon Type I) RN - 0 (Interleukin-1beta) RN - 0 (Tlr2 protein, mouse) RN - 0 (Tlr9 protein, mouse) RN - 0 (Toll-Like Receptor 2) RN - 0 (Toll-Like Receptor 9) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 1.14.13.39 (Nos2 protein, mouse) RN - EC 3.4.21.- (Granzymes) RN - EC 3.4.21.- (Gzmb protein, mouse) SB - IM MH - Animals MH - CD8-Positive T-Lymphocytes/*immunology MH - Dendritic Cells/*immunology MH - Flow Cytometry MH - Granzymes/metabolism MH - Herpesvirus 1, Human/*immunology MH - Humans MH - Interferon Type I/metabolism MH - Interleukin-1beta/metabolism MH - Killer Cells, Natural/*immunology MH - Macrophages/*immunology MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nitric Oxide Synthase Type II/metabolism MH - Toll-Like Receptor 2/deficiency/metabolism MH - Toll-Like Receptor 9/deficiency/metabolism MH - Trigeminal Ganglion/*immunology/*virology PMC - PMC5320739 OTO - NOTNLM OT - CD8+ T lymphocytes OT - Dendritic cells OT - Encephalitis OT - Herpes simplex virus 1 OT - Innate immunity OT - Macrophages OT - Murine model OT - Neuropathogenesis OT - TLRs EDAT- 2017/02/23 06:00 MHDA- 2017/08/24 06:00 PMCR- 2017/02/21 CRDT- 2017/02/23 06:00 PHST- 2016/12/06 00:00 [received] PHST- 2017/01/18 00:00 [accepted] PHST- 2017/02/23 06:00 [entrez] PHST- 2017/02/23 06:00 [pubmed] PHST- 2017/08/24 06:00 [medline] PHST- 2017/02/21 00:00 [pmc-release] AID - 10.1186/s12985-017-0692-x [pii] AID - 692 [pii] AID - 10.1186/s12985-017-0692-x [doi] PST - epublish SO - Virol J. 2017 Feb 21;14(1):37. doi: 10.1186/s12985-017-0692-x.