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* Department of Pediatrics,
Department of Molecular Sciences, and
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163;
Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105;
¶ LeBonheur Children’s Medical Center, Memphis TN 38163;
|| Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan; and
# Key Laboratory of Nerve Regeneration, Nantong University, Nantong, China
C57BL/6J mice were 105-fold more resistant to Chlamydia psittaci infection than DBA/2J mice by LD100 determinations. Linkage analysis using BXD recombinant inbred strains revealed a single effector locus at a 1.5-Mbp region on chromosome 11 encoding a cluster of three p47 GTPases (Irgb10, Igtp, and Iigp2). Western blots of infected tissue showed that Irgb10 was elevated in resistant mice and one of the two possible Iigp2 protein isoforms was preferentially expressed in susceptible mice. The BXD39 strain, susceptible at Irgb10 and resistant at Iigp2, had an intermediate phenotype implicating the nonredundant role of these p47 GTPases. C57BL/6J and DBA/2J exhibited a difference in IFN-
-dependent chlamydial control, which was reversible by Iigp2 small interfering RNA knockdown. Microarrays of infected peritoneal lavage revealed >10-fold up-regulation of neutrophil-recruiting chemokines in susceptible mice and >100-fold increase in macrophage differentiation genes in resistant mice, indicating that the susceptibility pattern involves the stimulation of different inflammatory cell-recruiting pathways. Massive neutrophil recruitment was seen in susceptible mice by histology and flow cytometry, and neutrophil chemokine receptor (CXCR2) knockout mice on a susceptible background survived a lethal challenge, confirming that neutrophil recruitment was required for susceptibility. Congenic Igtp knockout mice also susceptible at Irgb10 and Iigp2 on a resistant background recruited neutrophils and succumbed to infection. We conclude that Irgb10 and Iigp2 act together to confer differential susceptibility against murine chlamydial infection. Data indicate that these p47 GTPases have cell-autonomous effects that result in vastly different inflammatory stimulations, leading to either recovery or death.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by Public Health Service’s Immunity and Latency Grant AI 19782 from (to G.I.B.), a Children’s Foundation Research Center and LeBonheur Children’s Medical Center Small Grant (to I.M.), and a St. Jude Children’s Research Hospital Fellowship Grant (to I.M.). Support was also provided by National Institutes of Health Grants P20-MH 62009, P20-DA 21131, U01AA13499, U01NR105417, U01CA105417 (to R.W.W.), and U01AA014425 (to L.L.).
2 Address correspondence and reprint requests to Dr. Gerald I. Byrne, Department of Molecular Sciences, University of Tennessee Health Science Center, 858 Madison Avenue, Memphis, TN 38163. E-mail address: gbyrne{at}utmem.edu
3 Abbreviations used in this paper: QTL, quantitative trait loci; IFU, inclusion-forming unit; LOD, likelihood odds ratio; siRNA, small interfering RNA.
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