Modulation of innate immune signaling by a <i>Coxiella burnetii</i> eukaryotic-like effector protein.

Abstract

The Q fever agent <i>Coxiella burnetii</i> uses a defect in organelle trafficking/intracellular multiplication (Dot/Icm) type 4b secretion system (T4SS) to silence the host innate immune response during infection. By investigating <i>C. burnetii</i> effector proteins containing eukaryotic-like domains, here we identify NopA (nucleolar protein A), which displays four regulator of chromosome condensation (RCC) repeats, homologous to those found in the eukaryotic Ras-related nuclear protein (Ran) guanine nucleotide exchange factor (GEF) RCC1. Accordingly, NopA is found associated with the chromatin nuclear fraction of cells and uses the RCC-like domain to interact with Ran. Interestingly, NopA triggers an accumulation of Ran-GTP, which accumulates at nucleoli of transfected or infected cells, thus perturbing the nuclear import of transcription factors of the innate immune signaling pathway. Accordingly, qRT-PCR analysis on a panel of cytokines shows that cells exposed to the <i>C. burnetii nopA</i>::Tn or a Dot/Icm-defective <i>dotA</i>::Tn mutant strain present a functional innate immune response, as opposed to cells exposed to wild-type <i>C. burnetii</i> or the corresponding <i>nopA</i> complemented strain. Thus, NopA is an important regulator of the innate immune response allowing <i>Coxiella</i> to behave as a stealth pathogen.