Tight Junctions as a Key for Pathogens Invasion in Intestinal Epithelial Cells

Abstract

Tight junctions play a major role in maintaining the integrity and impermeability of the intestinal barrier. As such, they act as an ideal target for pathogens to promote their translocation through the intestinal mucosa and invade their host. Different strategies are used by pathogens, aimed at directly destabilizing the junctional network or modulating the different signaling pathways involved in the modulation of these junctions. After a brief presentation of the organization and modulation of tight junctions, we provide the state of the art of the molecular mechanisms leading to permeability breakdown of the gut barrier as a consequence of tight junctions' attack by pathogens, including bacteria, viruses, fungi, and parasites.

Keywords: enterocytes; gut barrier; intestinal epithelial cells; microorganisms; pathogens; permeability; signaling pathways; tight junction.

Figure 1

Composition of tight junctions in intestinal epithelial cells. Among the over forty proteins involved in the TJ complex, the transmembrane proteins belong mainly to three groups: the claudins family, the Marvel domain-containing proteins (occludin, tricellulin, also known as MarvelD2 and MarvelD3 proteins), and several immunoglobulin superfamily members ((Junctional Adhesion Molecules (JAMs), Coxsackie and Adenovirus Receptor proteins (CAR)) [17]. Other transmembrane proteins such as BVES (blood vessel epicardial substance), the apical polarity determinant Crb3 (Crumbs Cell Polarity Complex Component 3), and angulins colocalize and interact with TJs at the apical level even if not consensually considered to belong to this junctional complex [18]. These proteins relate to a cytoplasmic plaque formed by adaptor and signaling proteins. Adaptor proteins provide a bridge to the cytoskeleton through actin and microtubule tight bonds and include proteins such as zonula occludens proteins (ZO-1/3), cingulin, paracingulin, also known as junction-associated-coiled-coil protein (JACOP), membrane-associated guanylate kinases (MAGI 1–3), Multi-PDZ domain protein 1 (MUPP1), Pals, PATJ, Partitioning defective 3 and 6 proteins (Par3 and 6), Merlin–angiomotin complex. Signaling proteins complete this complex network, including protein kinases (atypical protein kinase C (aPKC), Mitogen-activated protein kinase kinase (MEKK1), complex Cyclin D1/CDK4, Large tumor suppressor kinase 1 (LATS1)), phosphatases (Phosphatase and TENsin homolog (PTEN)), GTPases and their activators (Rap2c, Myosin-IXA, Rho guanine nucleotide exchange factors (PDZGEF1, p114RhoGEF, GEF-H1, ARHGEF11), RICH1, SH3 domain-binding protein 1 (SH3BP1), Tubulin alpha chain (Tuba)), heat shock proteins (Apg-2), and transcriptional and post-transcriptional regulators ((zonula occludens 1-associated nucleic acid binding protein (ZONAB), Symplekin, yes-associated protein 1 (YAP), tafazzin (TAZ)). The last group of proteins localize with the TJ scaffold proteins but move to the nucleus aimed at modulating gene expression. Therefore, they are involved not only in the regulation of the junctional organization and function but also take part in many cells signaling pathways including cellular proliferation, differentiation, and response to many stimuli.

Figure 2

Signaling pathways involved in TJ formation and modulation. This scheme presents a non-exhaustive list of the different signaling pathways involved in the modulation of tight junctions of intestinal epithelial cells. Cytokines (CK). Janus kinase (JAK). Phosphoinositide-3-kinase (PI3K) and Myosin light chain kinase (MLCK) pathways: Phosphoinositide-dependent kinase-1 (PDK1), protein kinase B (Akt1), protein kinase G (PKG), Myosin light chain (MLC), Myosin light chain phosphatase (MLCP), LIM-kinase (LIMK), Ras homolog family member A (RhoA), Rho-associated coiled-coil containing protein kinase (ROCK), Ras-related C3 botulinum toxin substrate 1 (Rac1), Cell division control protein 42 homolog (Cdc42), p21-activated kinase 1 (PAK1), Partitioning defective 6 protein (Par6), Partitioning defective 3 protein (Par3), atypical protein kinase C (aPKC). Growth factor receptor-bound protein 2 (Grb2)/Mitogen-activated protein kinases (MAPK) pathway: Son of sevenless protein (SOS), Ras GTPase (Ras), Rapidly Accelerated Fibrosarcoma kinase (Raf), Mitogen-activated protein kinase kinases (MEKK, MKK), Extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), Apoptosis signal-regulating kinase (Ask). IL-1 pathway: Myeloid differentiation primary response 88 (MYD88), interleukin-1 receptor-associated kinase (IRAK), Mitogen-activated protein kinase kinase kinase 7 (MAP3K7, also known as TAK1), TNF receptor-associated factor 6 (TRAF6), TGF-Beta Activated Kinase (TAB). Zonulin pathway: phospholipase C (PLC), Inositol trisphosphate (IP3), diacyl glycerol (DAG), protein kinase C (PKC), protein kinase A (PKA), Ca²⁺/calmodulin-dependent protein kinase (CamK), Reactive Oxygen Species (ROS), nuclear factor-kappa B (NF-κB), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), I-κB-kinase (IKK), NF-κB Essential Modulator (NEMO), REL Proto-Oncogene, NF-κB Subunit (Rel). Tumor Necrosis Factor (TNF), Eph-like kinase 1 (Elk1), Activator protein 1 (AP-1), myocyte enhancer factor-2 (Mef-2), CCAAT-enhancer-binding protein homologous protein (CHOP).

Figure 3

Role of tight junction interactions in pathogenesis of microorganisms. The compromise of TJ integrity involved different strategies developed by microbial pathogens. Microorganisms or their components directly impact the TJ organization through lytic activity or binding on TJ proteins that interfere on their connection to the TJ complex. Interactions between microbial effectors with IEC receptors lead in the activation of different signaling pathways intimately linked and interacting with each other. As these pathways are involved in many other cellular process (proliferation, oncogenesis, cell cycle, differentiation…), their activation contributes to the host response concomitantly to TJ disruption. Besides, the loss of permeability related to TJ appears as a consequence of a deleterious host response against its aggression though excessive pro-inflammatory cytokine production and endogenous biosynthesis of nitric oxide (NO).