The p47 GTPases Iigp2 and Irgb10 regulate innate immunity and inflammation to murine Chlamydia psittaci infection.
C57BL/6J mice were 10(5)-fold more resistant to Chlamydia psittaci infection than DBA/2J mice by LD(100) 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-gamma-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.
Miyairi
Isao
I
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Tatireddigari
Venkat R R Arva
VR
Mahdi
Olaimatu S
OS
Rose
Lorne A
LA
Belland
Robert J
RJ
Lu
Lu
L
Williams
Robert W
RW
Byrne
Gerald I
GI
D000818:Animals; D002691:Chlamydophila psittaci / Q000254:growth & development / Q000276:immunology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D007371:Interferon-gamma / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010641:Phenotype; D020543:Proteome / Q000235:genetics; D009956:Psittacosis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control
D020543:Proteome; D007371:Interferon-gamma; D020558:GTP Phosphohydrolases; C101131:Igtp protein, mouse; C522728:Iigp2 protein, mouse; C515445:Irgb10 protein, mouse