TLR9 is required for MAPK/NF-kB activation but does not cooperate with TLR2 or TLR6 to induce host resistance to brucella abortus

Marco Túlio Gomes, Priscila Carneiro Campos, Guilherme de Sousa Pereira, Daniella Castanheira Bartholomeu, Gary Splitter, Sergio Costa Oliveira

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Brucella abortus is a Gram-negative intracellular bacterial pathogen that causes a zoonosis of worldwide occurrence, leading to undulant fever in humans and abortion in domestic animals. B. abortus is recognized by several pattern-recognition receptors triggering pathways during the host innate immune response. Therefore, here, we determined the cooperative role of TLR9 with TLR2 or TLR6 receptors in sensing Brucella. Furthermore, we deciphered the host innate immune response against B. abortus or its DNA, emphasizing the role of TLR9-MAPK/ NF-kB signaling pathways in the production of proinflammatory cytokines. TLR9 is required for the initial host control of B. abortus, but this TLR was dispensable after 6 wk of infection. The susceptibility of TLR9−/−-infected animals to Brucella paralleled with lower levels of IFN-γ produced by mouse splenocytes stimulated with this pathogen compared with wild-type cells. However, no apparent cooperative interplay was observed between TLR2-TLR9 or TLR6-TLR9 receptors to control infection. Moreover, B. abortus or its DNA induced activation of MAPK/NF-kB pathways and production of IL-12 and TNF-α by macrophages partially dependent on TLR9 but completely dependent on MyD88. In addition, B. abortusderived CpG oligonucleotides required TLR9 to promote IL-12 and TNF-α production bymacrophages. By confocal microscopy, we demonstrated that TLR9 redistributed and colocalized with lysosomal-associated membrane protein-1 upon Brucella infection. Thus, B. abortus induced TLR9 traffic, leading to cell signaling activation and IL-12 and TNF-α production. Although TLR9 recognized Brucella CpG motifs, our results suggest a new pathway of B. abortus DNA-activating macrophages independent of TLR9.

Original languageEnglish (US)
Pages (from-to)771-780
Number of pages10
JournalJournal of Leukocyte Biology
Volume99
Issue number5
DOIs
StatePublished - May 2016
Externally publishedYes

Keywords

  • Bacterial DNA
  • Cell signaling
  • Cytokine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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