Interferons: Tug of War Between Bacteria and Their Host

Abstract

Type I and III interferons (IFNs) are archetypally antiviral cytokines that are induced in response to recognition of foreign material by pattern recognition receptors (PRRs). Though their roles in anti-viral immunity are well established, recent evidence suggests that they are also crucial mediators of inflammatory processes during bacterial infections. Type I and III IFNs restrict bacterial infection in vitro and in some in vivo contexts. IFNs mainly function through the induction of hundreds of IFN-stimulated genes (ISGs). These include PRRs and regulators of antimicrobial signaling pathways. Other ISGs directly restrict bacterial invasion or multiplication within host cells. As they regulate a diverse range of anti-bacterial host responses, IFNs are an attractive virulence target for bacterial pathogens. This review will discuss the current understanding of the bacterial effectors that manipulate the different stages of the host IFN response: IFN induction, downstream signaling pathways, and target ISGs.

Keywords: bacterial effectors; host-pathogen interactions; immunity; interferon-stimulated genes; interferons; janus kinase signal transducer and activator of transcription signaling; microbial pathogenesis.

Figure 1

Modulation of types I and III interferon responses by bacterial effectors. In many different cell types, the recognition of bacterial PAMPs by PRRs leads to the production of type I and III IFNs (left side). Type I and III IFNs bind their respective receptors initiating signaling pathways which trigger the expression of ISGs (right side). Bacteria have evolved effectors that either inhibit (depicted in red) or stimulate (depicted in green) type I and III IFN responses. Yersinia pseudotuberculosis YopJ effector interferes with the MAP kinase activator TAK1. When internalized in endosomes, Listeria monocytogenes secretes PgdA which modifies its peptidoglycan, hiding it from the host lysozyme. Listeria monocytogenes also secretes Zea which binds RIG-I and potentiates the production of IFNs. The Legionella pneumophila protein SdhA blocks RIG-I and MDA5 cytosolic PRRs preventing them to interact with MAVS. The Shigella flexneri protease IpaJ interferes with STING translocation to the ERGIC while IpaH4.5 inhibits TBK1 kinase. Similarly, Chlamydia trachomatis CpoS effector affects STING migration. EPEC, through the secretion of NleD inhibits RNase L which counteracts the protective effects of type I IFN on epithelial barriers. Additionally, some bacteria perturb type I and III IFN signaling. L. monocytogenes LntA and S. flexneri OspF effectors enter the cell nucleus and potentiate ISGs transcription. LntA sequesters BAHD1, a negative regulator of ISGs transcription therefore stimulating ISGs expression. OspF interacts with HP1γ preventing its phosphorylation, which promotes ISGs expression. C. trachomatis TepP effector inhibits CRK, a component and regulators of type I and III IFN signaling, stimulating ISGs transcription. Finally, S. flexneri IpaH9.8 and OspC3 as well as L. pneumophila SdhA effectors inhibit inflammasome components; GBP1, caspase-4, and AIM2 respectively. PRRs, pattern recognition receptors; PAMPs, pathogen-associated molecular patterns; TLR, Toll like receptor; STING, stimulator of interferon genes; ER, endoplasmic reticulum; ERGIC, ER-Golgi intermediate compartments; IRF, interferon regulatory factor; RIG-I, retinoic acid-inducible gene-I; MDA5, melanoma differentiation-associated protein 5; MAVS, mitochondria-antiviral signaling protein; TAK1, TGFbeta activated kinase 1; TYK2, tyrosine kinase 2; JAK1, Janus kinase 1; STAT, signal transducer and activator of transcription; ISGF3, interferon-stimulated gene factor 3; MAPK, mitogen-activated protein kinase; GBP, guanylate-binding protein; AIM2, absent in melanoma-2; LPS, lipopolysaccharide; ISG, interferon stimulated gene; IFNAR, IFNα receptor; IFNLR,IFNλ receptor. Figure 1 was created with Biorender.com.