Bacteria fighting back: how pathogens target and subvert the host innate immune system

Abstract

The innate immune system has evolved under selective pressure since the radiation of multicellular life approximately 600 million years ago. Because of this long history, innate immune mechanisms found in modern eukaryotic organisms today are highly complex but yet built from common molecular strategies. It is now clear that evolution has selected a conserved set of antimicrobial peptides as well as pattern-recognition receptors (PRRs) that initiate cellular-based signals as a first line of defense against invading pathogens. Conversely, microbial pathogens employ their own strategies in order to evade, inhibit, or otherwise manipulate the innate immune response. Here, we discuss recent discoveries that have changed our view of immune modulatory mechanisms employed by bacterial pathogens, focusing specifically on the initial sites of microbial recognition and extending to host cellular signal transduction, proinflammatory cytokine production, and alteration of protein trafficking and secretion.

Figure 1

Bacterial effectors that target and manipulate the innate immune and inflammatory pathways. Upon LPS stimulation, the TLR4 dimer associates with MD2 and forms a complex with CD14 to signal through the cytoplasmic tails of TLR4. Stimulated TLR4 binds MyD88 and Mal (also TIRAP), which recruits IRAK1/4, TRAF6, and TRICA1 to stimulate inflammatory cell survival pathways (MAPK and NF-κB). Bacterial effector proteins inhibit this process in many different ways. MprF, from Staphylococcus aureus, repels cationic defensin peptides electrostatically. ClpX proteolytically degrades defensin molecules. The M1 protein binds and sequesters the AMP LL-37. YopK shields the Type III translocon from being recognized by host intracellular sensors. Tir, while functioning to maintain intimate contact between A/E pathogens and host, also utilizes ITIM-like motifs to downregulate TLR signaling. OspF possesses phosphothreonine lyase activity, which potently downregulates the MAPK cascade through covalent modification. OspI prevents TRAF6 auto-polyubiquitinylation to reduce NF-κB signaling. YopJ is an acetyl transferase that targets the MAPK pathway and also has activity against TAK1. LF cleaves the amino terminus of MAPKK1/2. AvrA inhibits the JNK pathway through acetyltransferase activity toward MAPKKs. IpaH9.8 targets the NEMO complex for proteasomal degradation. OspG binds to ubiquitinylated E2 enzymes to prevent the eventual ubiquitinylation of IκBα. NleC is a protease that degrades the p65 subunit of NF-κB. NleE modifies TAB2 and TAB3 to regulate NF-κB signaling.

Figure 2

Bacterial effectors that inhibit the GSP to suppress innate immune secretory mechanisms. NleF binds to the transmembrane protein Tmp21 to prevent COPI docking and thereby disrupt retrograde traffic. IpaJ cleaves the N-terminal myristoyl tail from Arf1, thus removing it from the membrane and promoting Golgi destruction. NleA/EspI prevent the uncoating of CopII vesicles, thus inhibiting their fusion during anterograde traffic. EspG disrupts the GSP through its Arf binding and Rab1GAP activities. VirA possesses Rab1GAP activity that acts to disrupt Golgi architecture.