The p47 GTPases Iigp2 and Irgb10 Regulate Innate Immunity and Inflammation to Murine Chlamydia psittaci Infection

Abstract

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-γ-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.

Inefficiency of C3H/HeN Mice to Control Chlamydial Lung Infection Correlates with Downregulation of Neutrophil Activation During the Late Stage of Infection

“…Our previous studies combined with other studies have shown that B6 mice consistently have less pathogen burden or disease compared with C3H mice in models of acute genital tract, respiratory, and systemic infections (18)(19)(20). These studies demonstrated that differences in the innate immunity mainly featured by neutrophil infiltration determine susceptibility to Chlamydia in inbred mice.…”

Genetic Control of Survival and Weight Loss during Pneumonic Burkholderia pseudomallei (Bp) Infection

“…It has been established through published genome wide studies that susceptibility to major infectious diseases in humans may be associated with common polymorphisms [47,48]. These findings include a correlation between human leukocyte antigen (HLA) polymorphisms and the type and/or intensity of the immune response that develops in response to a Bp infection [49].…”

“…Interval mapping tests for the presence of QTLs across the entire genome and summarizes the strength of linkage as a likelihood ratio statistic (LRS) [84,103]. We used a permutation test to establish empirical significance criteria at a genome-wide p value of .05 [100]. The original data sets can be obtained at www.…”

“…Furthermore, an additional advantage to identifying QTLs are the insights gained into the development and physiology of complex traits on a molecular level [96]. QTL mapping has been used to successfully identify genomic regions underlying a variety of human diseases such as chlamydial infections [100], Influenza [73] and alcoholism [101].…”

“…These findings are not surprising in light of findings that genetic factors play a key role in susceptibility to a wide range of other infectious diseases. Published findings have identified host genetic factors that are critical for variable susceptibility to intracellular parasites [115], viruses [116][117][118][119][120], and both intracellular [74,100,121] and extracellular [122] bacterial pathogens. Moreover, recent genome-wide studies have established novel associations between common polymorphisms and susceptibility to several infectious diseases that are responsible for significant morbidity and/or mortality in humans [73,100,123,124].…”