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Mucosal interactions with enteropathogenic bacteria
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Nadine Cerf-Bensussan, Pamela Schnupf, Valérie Gaboriau-Routhiau, Philippe J. Sansonetti
In contrast to the resident bacteria, which mainly remain within the intestinal lumen, enteropathogens can gain access to the basolateral membrane of epithelial cells where TLRs can be more readily activated. Furthermore, pathogens can inject peptidoglycan moieties from the bacterial cell wall and thereby activate cytosolic NOD proteins and their downstream pro-inflammatory signaling cascades. Epithelial PRR activation by pathogens can thus increase the production of microbicidal products and reactive oxygen species, and stimulate the recruitment and activation of host immune cells, notably of phagocytes and DCs, which can in turn initiate adaptive immune responses; all of which are mechanisms that participate in clearing pathogens. As already alluded to, some pathogens can exploit host inflammatory responses to their benefit. Thus, host inflammation induced by Salmonella typhimurium infection results in the elimination of resident bacteria and promotes colonization. During Shigella infection, IL-8 induced via NF-κB and MAP kinase (MAPK) activation of epithelial cells stimulates the recruitment and transmigration of polymorphonuclear leukocytes, which enhances access of Shigella to the basolateral membrane of the epithelium and thereby promotes bacterial dissemination. Or pathogens can subvert the host to respond in an inappropriate manner and to activate the wrong arm of the immune system. Thus, L. monocytogenes infection leads to a potent type 1 interferon response, which functions to protect the host from viral intruders. Listeria does this by releasing a bacterial-specific second messenger, cyclic-di-AMP, during cytosolic growth, which can be sensed by the cytosolic DNA sensor STING (stimulator of interferon genes) (Figure 25.8). STING activation in macrophages leads to type I interferon production, whereby epithelial cells respond by IL-1β and IL-18 production. In the absence of interferon signaling, Listeria virulence is attenuated, indicating the benefit of activating this antiviral pathway for Listeria pathogenesis. It is thought that Listeria benefits from STING activation through a subsequent inhibition of T-cell-mediated immunity (see Figure 25.8).
STINGing the Tumor's immune evasion mechanism
Published in OncoImmunology, 2018
Initially characterized as ubiquitous bacterial secondary messengers, CDN [(cyclic-di-GMP (CDG), cyclic-di-AMP (CDA), and cyclic GMP-AMP (cGAMP)] were shown to constitute a novel class of pathogen associated molecular pattern molecules (PAMP) that activate the TBK1/IRF3/type 1 IFN signaling axis via the cytoplasmic pattern recognition receptor, STING.3,4 The STING signaling pathway has emerged as a central TLR-independent mediator of host innate defense to sensing cytosolic nucleic acids, either through direct binding of exogenous CDN from bacteria, or, shown recently, through synthesis of a structurally distinct CDN produced by a host cyclic GMP-AMP synthetase (cGAS) in response to cytosolic double-stranded DNA (dsDNA).5 We hypothesized that STING agonists, either natural or chemically modified, would provide a completely novel class of molecules to enhance the potency of cancer vaccines.
Novel and emerging innate immune therapeutic targets for pancreatic cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Liang Wang, Imad Shureiqi, John R. Stroehlein, Daoyan Wei
The natural CDNs, such as bis-(3ʹ-5ʹ)-cyclic dimeric guanosine monophosphate (cyclic di-GMP) and bis-(3ʹ-5ʹ)-cyclic dimeric adenosine monophosphate (cyclic di-AMP), were first explored for their anticancer immune potential as direct activators of the STING signaling pathway. Cyclic di-GMP, used as an adjuvant for cancer vaccination, showed improved antitumor effect in melanoma and breast cancer models [9,10]. Intratumoral administration of cyclic di-GMP to glioma-bearing mice enhanced type I IFN response and prolonged mice survival [11]. The intravenous administration of liposome-encapsulated cyclic di-GMP into mice significantly induced type I IFN production and activation of natural killer cells in a lung metastatic melanoma mouse model and resulted in an antitumor effect [12].
Genome-wide bioinformatics analysis of FMN, SAM-I, glmS, TPP, lysine, purine, cobalamin, and SAH riboswitches for their applications as allosteric antibacterial drug targets in human pathogenic bacteria
Published in Expert Opinion on Therapeutic Targets, 2019
Nikolet Pavlova, Robert Penchovsky
The Riboswitches are widely distributed and highly conserved among bacteria and, in the case of the TPP riboswitch, among certain eukaryotes [18]. The discovered riboswitches so far can sense nucleotides (adenine, guanine and 2ʹ-Deoxyguanosine, etc), Ions (Mg2+, Mn2+, and F−), coenzymes (AdoCbl, FMN, SAM, TPP, etc), signaling molecules (cyclic-di-AMP, cyclic-Di-GMP, etc), amino acids (Glycine, Glutamine and Lysine) and other derivatives. The most widely spread riboswitches are these for TPP, FMN, cobalamin, and lysine [19]. This is the main reason we had focused our research on the chosen 8 riboswitches. In fact, the 8th riboswitches discussed in this paper are found in 49 pathogenic bacteria out of 59 known bacterial pathogens. However, we are going to discuss the suitability of another riboswitch as drug targets in other paper. In general, we have found riboswitches in 55 pathogenic bacteria out of 59 that infect humans and lead to the development of serious diseases, in some cases even with lethal effect. Many of these bacteria have a variety of different classes of riboswitches in their genomes. Furthermore, certain riboswitch classes are represented numerous times throughout a single organism’s genome [1]. For instance, we previously found that the cause of anthrax caused by Bacillus anthracis (B. anthracis), is found to have 12 different classes of riboswitches [1]. The third most common pathogen responsible for food poisoning in Great Britain and the USA, Cl. perfringens, is also found to have in 12 classes of riboswitches. For example, 69 genes in B. subtilis appear to be under the control of any one of the eight known riboswitch elements, which corresponds to approximately 2% of the organism’s genome [20].