Activation and pathogenic manipulation of the sensors of the innate immune system

Abstract

The innate immune system detects the presence of microbes through different families of pattern-recognition receptors (PRRs). PRRs detect pathogens of all origins and trigger signaling events that activate innate and adaptive immunity. These events need to be tightly regulated in order to ensure optimal activation when required, and minimal signaling in the absence of microbial encounters. This regulation is achieved, at least in part, through the precise subcellular positioning of receptors and downstream signaling proteins. Consequently, mislocalization of these proteins inhibits innate immune pathways, and pathogens have evolved to alter host protein localization as a strategy to evade immune detection. This review describes the importance of subcellular localization of various PRR families and their adaptors, and highlights pathogenic immune evasion strategies that operate by altering immune protein localization.

Keywords: Immune evasion; Infection; Inflammasome; Innate immunity; Myddosome; Toll-like receptors.

Fig. 1.

Localization of receptors and adaptors, and their targeting by virulence factors. Pattern recognition receptors are localized at various sub-cellular localizations: Toll-like receptors (TLRs) are at the cell surface and endosomes, RIG-I-like receptors (RLRs), cGAS, and inflammasomes are in the cytosol, IFI16 is in the nucleus. Signaling occurs at membranes: TLR recruit the adaptors TIRAP, MyD88, TRAM and TRIF. RLR signaling occurs via the adaptor MAVS that is localized on mitochondria and peroxisomes. DNA sensors (here shown are cGAS and IFI16) occurs via STING that is localized in the ER at steady state and traffics through the Golgi via the ER-Golgi intermediate compartment (ERGIC). Additional proteins are involved in the trafficking of receptors and adaptors. These include for CD14 that mediates TLR4 internalization, UNC93B that mediates TLR trafficking and 14–3–3ε that contributes to RIG-I migration to mitochondria. Examples of virulence factors are indicated in blue. These alter the subcellular localization of host proteins, either at steady state or following stimulation. Included for example are the type III-secreted Shigella proteins IpaJ and VirA that affect different steps of STING trafficking through the ERGIC. RLR signaling is inhibited by Hepatitis C virus (HCV) NS3/4a that cleaves MAVS or NS3 from Dengue Virus (DenV) that prevents 14–3–3ε mediated RIG-I trafficking to mitochondria. Also included is Salmonella SopB that cleaves lipids necessary for TIRAP localization, or Francisella LPS that is not detected by CD14, a step required for TLR4 endocytosis and function. Finally, Measles virus V protein affects the localization of IFI16 and some inflammasome components, and Coxsackievirus virus 3C protein cleaves TRIF.