Differential outcome of infection with attenuated Salmonella in MyD88-deficient mice is dependent on the route of administration

Jincy M. Issac, Dhanya Sarawathiamma, Mai I. Al-Ketbi, Sheikh Azimullah, Samia M. Al-Ojali, Yassir A. Mohamed, Richard A. Flavell, Maria J. Fernandez-Cabezudo, Basel K. Al-Ramadi

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Activation of the innate immune system is a prerequisite for the induction of adaptive immunity to both infectious and non-infectious agents. TLRs are key components of the innate immune recognition system and detect pathogen-associated molecular patterns. Most TLRs utilize the MyD88 adaptor for their signaling pathways. In the current study, we investigated innate and adaptive immune responses to primary as well as secondary Salmonella infections in MyD88-deficient (MyD88-/-) mice. Using i.p. or oral route of inoculation, we demonstrate that MyD88-/- mice are hypersusceptible to infection by an attenuated, double auxotrophic, mutant of Salmonella enterica serovar Typhimurium (S. typhimurium). This is manifested by 2-3 logs higher bacterial loads in target organs, delayed recruitment of phagocytic cells, and defective production of proinflammatory cytokines in MyD88-/- mice. Despite these deficiencies, MyD88-/- mice developed Salmonella-specific memory Th1 responses and produced elevated serum levels of anti-Salmonella Abs, not only of Th1-driven (IgG2c, IgG3) but also IgG1 and IgG2b isotypes. Curiously, these adaptive responses were insufficient to afford full protection against a secondary challenge with a virulent strain of S. typhimurium. In comparison with the high degree of mortality seen in MyD88-/- mice following i.p. inoculation, oral infections led to the establishment of a state of long-term persistence, characterized by continuous bacterial shedding in animal feces that lasted for more than 6 months, but absence from systemic organs. These findings suggest that the absent expression of MyD88 affects primarily the innate effector arm of the immune system and highlights its critical role in anti-bacterial defense.

Original languageEnglish
Pages (from-to)52-63
Number of pages12
JournalImmunobiology
Volume218
Issue number1
DOIs
Publication statusPublished - Jan 2013

Keywords

  • Bacteria
  • Innate immunity
  • Persistence
  • TLRs

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Hematology

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