Requirement of UNC93B1 Reveals a Critical Role for TLR7 in Host Resistance to Primary Infection with Trypanosoma Cruzi

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2011 Jul 15

PMID 21753151

Citations 46

Authors

Braulia C Caetano

Bianca B Carmo

Mariane B Melo

Anna Cerny

Sara L dos Santos

Daniella C Bartholomeu

Douglas T Golenbock

Ricardo T Gazzinelli

Affiliations

Soon will be listed here.

Abstract

UNC93B1 associates with TLR3, 7, and 9, mediating their translocation from the endoplasmic reticulum to the endolysosome, thus allowing proper activation by microbial nucleic acids. We found that the triple-deficient 3d mice, which lack functional UNC93B1 as well as functional endosomal TLRs, are highly susceptible to infection with Trypanosoma cruzi. The enhanced parasitemia and mortality in 3d animals were associated with impaired proinflammatory response, including reduced levels of IL-12p40 and IFN-γ. Importantly, the phenotype of 3d mice was intermediary between MyD88(-/-) (highly susceptible) and TLR9(-/-) (moderately susceptible), indicating the involvement of an additional UN93B1-dependent TLR(s) on host resistance to T. cruzi. Hence, our experiments also revealed that TLR7 is a critical innate immune receptor involved in recognition of parasite RNA, induction of IL-12p40 by dendritic cells, and consequent IFN-γ by T lymphocytes. Furthermore, we show that upon T. cruzi infection, triple TLR3/7/9(-/-) mice had similar phenotype than 3d mice. These data imply that the nucleic acid-sensing TLRs are critical determinants of host resistance to primary infection with T. cruzi.

Citing Articles

Quantitative Proteomic Analysis of Macrophages Infected with Reveals Different Responses Dependent on the SLAMF1 Receptor and the Parasite Strain.

Herreros-Cabello A, Del Moral-Salmoral J, Morato E, Marina A, Barrocal B, Fresno M Int J Mol Sci. 2024; 25(13).

PMID: 39000601 PMC: 11242706. DOI: 10.3390/ijms25137493.

The IRAK1/IRF5 axis initiates IL-12 response by dendritic cells and control of Toxoplasma gondii infection.

Pereira M, Ramalho T, Andrade W, Durso D, Souza M, Fitzgerald K Cell Rep. 2024; 43(2):113795.

PMID: 38367238 PMC: 11559090. DOI: 10.1016/j.celrep.2024.113795.

The transcriptome landscape of 3D-cultured placental trophoblasts reveals activation of TLR2 and TLR3/7 in response to low parasite exposure.

Silberstein E, Chung C, Debrabant A Front Microbiol. 2023; 14:1256385.

PMID: 37799608 PMC: 10548471. DOI: 10.3389/fmicb.2023.1256385.

TLR8 escapes X chromosome inactivation in human monocytes and CD4 T cells.

Youness A, Cenac C, Faz-Lopez B, Grunenwald S, Barrat F, Chaumeil J Biol Sex Differ. 2023; 14(1):60.

PMID: 37723501 PMC: 10506212. DOI: 10.1186/s13293-023-00544-5.

A Review on the Immunological Response against .

Macaluso G, Grippi F, Di Bella S, Blanda V, Gucciardi F, Torina A Pathogens. 2023; 12(2).

PMID: 36839554 PMC: 9964664. DOI: 10.3390/pathogens12020282.

References

Baida R, Santos M, Carmo M, Yoshida N, Ferreira D, Ferreira A . Molecular characterization of serine-, alanine-, and proline-rich proteins of Trypanosoma cruzi and their possible role in host cell infection. Infect Immun. 2006; 74(3):1537-46. PMC: 1418663. DOI: 10.1128/IAI.74.3.1537-1546.2006. View

Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S . Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004; 303(5663):1526-9. DOI: 10.1126/science.1093620. View

Melo M, Kasperkovitz P, Cerny A, Konen-Waisman S, Kurt-Jones E, Lien E . UNC93B1 mediates host resistance to infection with Toxoplasma gondii. PLoS Pathog. 2010; 6(8):e1001071. PMC: 2928809. DOI: 10.1371/journal.ppat.1001071. View

Atwood 3rd J, Minning T, Ludolf F, Nuccio A, Weatherly D, Alvarez-Manilla G . Glycoproteomics of Trypanosoma cruzi trypomastigotes using subcellular fractionation, lectin affinity, and stable isotope labeling. J Proteome Res. 2006; 5(12):3376-84. DOI: 10.1021/pr060364b. View

Golgher D, Gazzinelli R . Innate and acquired immunity in the pathogenesis of Chagas disease. Autoimmunity. 2004; 37(5):399-409. DOI: 10.1080/08916930410001713115. View

Rassi Jr A, Rassi A, Marin-Neto J . Chagas disease. Lancet. 2010; 375(9723):1388-402. DOI: 10.1016/S0140-6736(10)60061-X. View

Koga R, Hamano S, Kuwata H, Atarashi K, Ogawa M, Hisaeda H . TLR-dependent induction of IFN-beta mediates host defense against Trypanosoma cruzi. J Immunol. 2006; 177(10):7059-66. DOI: 10.4049/jimmunol.177.10.7059. View

Michailowsky V, Silva N, Rocha C, Vieira L, Lannes-Vieira J, Gazzinelli R . Pivotal role of interleukin-12 and interferon-gamma axis in controlling tissue parasitism and inflammation in the heart and central nervous system during Trypanosoma cruzi infection. Am J Pathol. 2001; 159(5):1723-33. PMC: 3277321. DOI: 10.1016/s0002-9440(10)63019-2. View

OGarra A, Murphy K . From IL-10 to IL-12: how pathogens and their products stimulate APCs to induce T(H)1 development. Nat Immunol. 2009; 10(9):929-32. DOI: 10.1038/ni0909-929. View

10.

Ho L, Ohno T, Oboki K, Kajiwara N, Suto H, Iikura M . IL-33 induces IL-13 production by mouse mast cells independently of IgE-FcepsilonRI signals. J Leukoc Biol. 2007; 82(6):1481-90. DOI: 10.1189/jlb.0407200. View

11.

Campos M, Closel M, Valente E, Cardoso J, Akira S, Alvarez-Leite J . Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J Immunol. 2004; 172(3):1711-8. DOI: 10.4049/jimmunol.172.3.1711. View

12.

Chessler A, Ferreira L, Chang T, Fitzgerald K, Burleigh B . A novel IFN regulatory factor 3-dependent pathway activated by trypanosomes triggers IFN-beta in macrophages and fibroblasts. J Immunol. 2008; 181(11):7917-24. PMC: 2597000. DOI: 10.4049/jimmunol.181.11.7917. View

13.

Paiva C, Lannes-Vieira J, Gattass C . Trypanosoma cruzi: protective response of vaccinated mice is mediated by CD8+ cells, prevents signs of polyclonal T lymphocyte activation, and allows restoration of a resting immune state after challenge. Exp Parasitol. 1999; 91(1):7-19. DOI: 10.1006/expr.1999.4356. View

14.

Abuin G, Freitas-Junior L, Colli W, Alves M, Schenkman S . Expression of trans-sialidase and 85-kDa glycoprotein genes in Trypanosoma cruzi is differentially regulated at the post-transcriptional level by labile protein factors. J Biol Chem. 1999; 274(19):13041-7. DOI: 10.1074/jbc.274.19.13041. View

15.

Mancuso G, Gambuzza M, Midiri A, Biondo C, Papasergi S, Akira S . Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nat Immunol. 2009; 10(6):587-94. DOI: 10.1038/ni.1733. View

16.

Hirschfeld M, Ma Y, Weis J, Vogel S, Weis J . Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol. 2000; 165(2):618-22. DOI: 10.4049/jimmunol.165.2.618. View

17.

Buscaglia C, Campo V, Frasch A, Di Noia J . Trypanosoma cruzi surface mucins: host-dependent coat diversity. Nat Rev Microbiol. 2006; 4(3):229-36. DOI: 10.1038/nrmicro1351. View

18.

Lima M, Lenzi H, Gattass C . Negative tissue parasitism in mice injected with a noninfective clone of Trypanosoma cruzi. Parasitol Res. 1995; 81(1):6-12. DOI: 10.1007/BF00932410. View

19.

Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408(6813):740-5. DOI: 10.1038/35047123. View

20.

Takeuchi O, Akira S . Pattern recognition receptors and inflammation. Cell. 2010; 140(6):805-20. DOI: 10.1016/j.cell.2010.01.022. View