title: MyD88 deficiency leads to decreased NK cell gamma interferon production and T cell recruitment during Chlamydia muridarum genital tract infection, but a predominant Th1 response and enhanced monocytic inflammation are associated with infection resolution.
abstract: We have previously shown that MyD88 knockout (KO) mice exhibit delayed clearance of Chlamydia muridarum genital infection compared to wild-type (WT) mice. A blunted Th1 response and ineffective suppression of the Th2 response were also observed in MyD88 KO mice. The goal of the present study was to investigate specific mechanisms whereby absence of MyD88 leads to these effects and address the compensatory mechanisms in the genital tract that ultimately clear infection in the absence of MyD88. It was observed that NK cells recruited to the genital tract in MyD88 KO mice failed to produce gamma interferon (IFN-γ) mRNA and protein. This defect was associated with decreased local production of interleukin-17 (IL-17), IL-18, and tumor necrosis factor alpha (TNF-α) but normal levels of IL-12p70. Additionally, recruitment of CD4 T cells to the genital tract was reduced in MyD88 KO mice compared to that in WT mice. Although chronic infection in MyD88 KO mice resulted in oviduct pathology comparable to that of WT mice, increased histiocytic inflammation was observed in the uterine horns. This was associated with increased CCL2 levels and recruitment of macrophages as a potential compensatory mechanism. Further deletion of TLR4-TRIF signaling in MyD88 KO mice, using TLR4/MyD88 double-KO mice, did not further compromise host defense against chlamydiae, suggesting that compensatory mechanisms are Toll-like receptor (TLR) independent. Despite some polarization toward a Th2 response, a Th1 response remained predominant in the absence of MyD88, and it provided equivalent protection against a secondary infection as observed in WT mice.
authors.affiliation: Department of Pediatrics, Arkansas Children's Hospital and University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202, USA.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Nagarajan
authors.forename: James
authors.initials: J
authors.lastname: Sikes
authors.forename: Daniel
authors.initials: D
authors.lastname: Prantner
authors.forename: Charles W
authors.initials: CW
authors.lastname: Andrews
authors.forename: Lauren
authors.initials: L
authors.lastname: Frazer
authors.forename: Anna
authors.initials: A
authors.lastname: Goodwin
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Snowden
authors.forename: Toni
authors.initials: T
authors.lastname: Darville
mesh_terms: D000818:Animals; D002690:Chlamydia Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D023502:Chlamydia muridarum; D005187:Fallopian Tubes / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D018417:Th1 Cells / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014599:Uterus / Q000473:pathology; D014627:Vaginitis / Q000382:microbiology
chemical_list: D007378:Interleukins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma