Pathogens.

A long-standing question in immunity is how the host detects pathogens. Since many microbes are also beneficial for the host, accurate discrimination between non-pathogens and pathogens is important. Traditionally, the microbe-associated molecular patterns (MAMPs) are thought to induce the innate immune response via the Toll-like receptor signaling. Since many pathogenic as well as nonpathogenic microbes share the same MAMPs, this model is insufficient to explain why immunity is initiated only against pathogenic bacteria and not against the others. An alternative model is the so-called damage-associated molecular pattern (DAMP) hypothesis. In this model, the host immune cells detects the DAMP signals such as the uric acid or high-mobility group box 1 (HMGB1) released by infected cells and triggers innate immune response via the Toll-like receptor signaling. However, whether this is a bonafide response to the pathogen or the pathological response of the host is not yet clear. Another celebrated theory on how host detects pathogens is effector triggered immunity (ETI). First described in plants, the ETI theory suggests that the host detects virulence effector proteins from the pathogens directly or via effects on the host cellular homeostasis and responds to it by inducing beneficial innate immune responses. While host “resistance” proteins that directly detect microbial effectors are found in plants, there is no evidence for such proteins in animals in the literature. In animals, recent studies provide evidence that the bacterial effectors are recognized indirectly because of their effects on cellular homeostasis. Studies from worms, flies, and mammalian cell culture have found that the host cells detects and responds to deficits in key cellular processes induced by the microbial effectors rather than detecting the microbes themselves. According to these studies, the pathogen-derived virulence factors or effectors or toxins induce decrement in the essential cellular processes such as protein translation or mitochondrial respiration or actomyosin cytoskeleton. The host surveillance pathways detects these changes in essential cellular processes and responds to it by mounting an innate immune response as well as xenobiotic detoxification responses. Since changes in these essential cellular processes are most likely to be caused by microbial virulence factors or toxins in the host’s evolutionary history, an innate immune response to such an insult is a well-calculated response. In this special focus, the authors review recent developments in the effector triggered immunity field. Rajamuthiah and Mylonakis review the recent studies, which provide evidence that the bacterial effectors are recognized indirectly because of the effects on cellular homeostasis. The host employs different strategies to detect pathogens including discuss on how effectors not only trigger immune response but also evade immune response or suppress immunity. Pathogenic bacteria frequently employ type secretory systems to deliver effector proteins to the host. Bacterial toxins are secreted into the immediate environment by pathogenic bacteria using either the type I, type II and type V secretory system while the type III secretion system injects the effector proteins into the host cell cytoplasm. Jayamani and Mylonakis review the various effectors employed by E.coli and their effects on the host cellular processes. In addition, they provide detailed account on how these effectors trigger host immune response. Historically, the ETI was first described in plants. In this special focus, Wu et al. comment on recent developments in how plants deploy the ETI to combat pathogens. Hurley et al. review recent efforts to identify plant proteins involved in ETI using a proteomics approach. Although, initially the ETI was described as a response of plants against pathogenic bacterial effectors, recent studies have shown that plant combat fungal effectors using the same strategy. In this special focus, Chaudhari et al. review how pathogenic fungal effectors and how the plants detect and initiate immune response against them. Pathogenic fungal effectors trigger immune response via modulation of cellular process; also they reprogram the host cells to induce structural changes that aid in the infection. Wang et al. also discusses on how necrotrophic fungal effectors trigger innate ETI. In addition, Wang et al. also provides an account on necrotrophic fungi trigger innate immune response via the classical MAMP as well as DAMP response. Wang et pathways thereby making the host hypersusceptible to the fungal infection. They discuss on how a fungal small RNA that acts as virulence effector to suppress host immune response. The relative contribution of these different pathways as well as the outcomes of the response is described in detail. Many pathogenic bacteria employ type III secretion system (T3SS) to inject effector proteins into the host cells. One of the best-known pathogen that employs T3SS to deliver virulence factors is Yersinia. YopM is one of the virulence factors that are delivered via the T3SS into host cells. Also, there is evidence that YopM could penetrate host cells independent of T3SS. YopM was previously thought to induce cytokine secretion by its interaction with host cell kinases RSK1 and PRK2. Hofling et al., provide evidence that the Yersinia effector protein YopM induce cytokine production independent of its interaction with host cell kinases RSK1 and PRK2. They propose that YopM might induce cytokine production via other unknown cellular components. Human respiratory syncytial virus (hRSV) has developed several strategies to interfere with critical functions of the immune system. Several hRSV proteins can modulate directly the function of either innate or adaptive immune cells. Espinoza et al. review how the hRSV viral effectors dampen the immune system.