title: Differential outcome of infection with attenuated Salmonella in MyD88-deficient mice is dependent on the route of administration.
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.
authors.affiliation: Department of Medical Microbiology & Immunology, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
authors.forename: Jincy M
authors.initials: JM
authors.lastname: Issac
authors.forename: Dhanya
authors.initials: D
authors.lastname: Sarawathiamma
authors.forename: Mai I
authors.initials: MI
authors.lastname: Al-Ketbi
authors.forename: Sheikh
authors.initials: S
authors.lastname: Azimullah
authors.forename: Samia M
authors.initials: SM
authors.lastname: Al-Ojali
authors.forename: Yassir A
authors.initials: YA
authors.lastname: Mohamed
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Fernandez-Cabezudo
authors.forename: Basel K
authors.initials: BK
authors.lastname: al-Ramadi
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D058491:Bacterial Load / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010586:Phagocytes / Q000276:immunology* / Q000382:microbiology; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology* / Q000382:microbiology
chemical_list: D000907:Antibodies, Bacterial; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88