Abstract
The innate immune system senses pathogens by pattern recognition receptors in different cell compartments. In the endosome, bacteria are generally recognized by TLRs; facultative intracellular bacteria such as Listeria, however, can escape the endosome. Once in the cytosol, they become accessible to cytosolic pattern recognition receptors, which recognize components of the bacterial cell wall, metabolites or bacterial nucleic acids and initiate an immune response in the host cell. Current knowledge has been focused on the type I IFN response to Listeria DNA or Listeria-derived second messenger c-di-AMP via the signaling adaptor STING. Our study focused on the recognition of Listeria RNA in the cytosol. With the aid of a novel labeling technique, we have been able to visualize immediate cytosolic delivery of Listeria RNA upon infection. Infection with Listeria as well as transfection of bacterial RNA induced a type-I-IFN response in human monocytes, epithelial cells or hepatocytes. However, in contrast to monocytes, the type-I-IFN response of epithelial cells and hepatocytes was not triggered by bacterial DNA, indicating a STING-independent Listeria recognition pathway. RIG-I and MAVS knock-down resulted in abolishment of the IFN response in epithelial cells, but the IFN response in monocytic cells remained unaffected. By contrast, knockdown of STING in monocytic cells reduced cytosolic Listeria-mediated type-I-IFN induction. Our results show that detection of Listeria RNA by RIG-I represents a non-redundant cytosolic immunorecognition pathway in non-immune cells lacking a functional STING dependent signaling pathway.
Highlights
Multicellular organisms evolved efficient host-defense mechanisms to sense invading pathogens such as bacteria and viruses in order to block their replication and spread
Using RNAi we revealed that RIG-I is crucial for L. monocytogenes-induced type I IFN and CXCL10 induction in cell types, such as non-immune cells, without a functional STINGdependent immune response, as indicated by the absence of a direct sensing mechanism for cytosolic DNA
PBMCs were preincubated with chloroquine to block endosomal Toll-like receptors (TLRs) (TLR7, TLR8 and TLR9) and were transfected with bacterial DNA or bacterial RNA extracted from the indicated bacteria (Fig. 1A)
Summary
Multicellular organisms evolved efficient host-defense mechanisms to sense invading pathogens such as bacteria and viruses in order to block their replication and spread. The pathogenicity of foreign genetic material is either recognized through its location, specific structural features or modification of nucleic acids. Two independent studies described a TLR9-independent pathway of cytosolic recognition of double stranded DNA leading to type I IFN induction [13,14]. All studies agree on the fact that the mitochondrial adaptor protein STING ( known as MITA) downstream of the putative DNA receptor is essential for sensing cytosolic DNA [16,17]. A recent study by Sun et al identified Cyclic GMP-AMP Synthase (cGAS) as the so far most convincing DNA recognizing candidate receptor [18]. Upon recognition of DNA, cGAS synthesize the second messenger Cyclic GMP-AMP (cGAMP) which activates STING [18,19]
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