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Immune Responses
Published in Ronald Fayer, Lihua Xiao, Cryptosporidium and Cryptosporidiosis, 2007
Epithelial cells express Toll-like receptors (TLRs), a group of innate molecular sensors of infection that ligate with conserved antigenic structures such as bacterial lipopolysaccharide (TLR4), bacterial cell wall components (TLR2), or DNA (TLR9) (Abreu et al., 2005). Cell signaling via an adaptor molecular that associates with TLRs, MyD88, leads to activation and migration to the cell nucleus of NF-?B, a key transcription factor for a variety of inflammatory molecules. NF-?B has been shown to be activated during C. parvum infection, and a key function for this molecule appears to be to prevent the infected cell undergoing apoptosis (Chen et al., 2001). It was shown that activation of a bile duct epithelial cell line via TLR2 and TLR4 occurs during C. parvum infection. Transfection of the cells with dominantnegative TLR2, TLR4, or MyD88 mutants or treatment of cells with interference RNA to the TLRs inhibited NF-?B activation by the parasite (Chen et al., 2005). MyD88 deficiency in these epithelial cells also increased parasite replication and in another study MyD881 mice had enhanced susceptibility to C. parvum infection (note that the MyD88 deficiency of these animals is not confined to epithelial cells) (Rogers et al., 2006). Treatment of neonatal mice with an oligodeoxynucleotide that is a ligand for TLR9 induced resistance to parasite reproduction (Barrier et al., 2006). Clearly, therefore, TLRs play a role in innate immunity, but the parasite molecules that act as ligands have yet to be identified.
Coxiella burnetii as a Model Organism
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Erin J. van Schaik, Anthony E. Gregory, Gerald F. Audette, James E. Samuel
Pathogens are initially recognized by the innate immune system through pattern-recognition receptors (PRRs) on the surface of host immune cells, which recognize unique pathogen-associated molecular patterns (PAMPs). Bacterial pathogens use one of two strategies to evade the immune system, either by overt or by stealth attacks [35]. C. burnetii is a prime example of a stealth pathogen due to its ability to invade and replicate within macrophages with minimal stimulation of innate immune responses. Many of the mechanisms that C. burnetii uses to evade the innate immune system remain to be determined, but new research is shedding light on several of these strategies. The activation of immune responses is complicated by the fact that most laboratories use the LPS phase II variant (RSA439) since it can be used at BL2, yet this clone is distinct from virulent LPS phase I variants. For clarity in this review, immune evasion strategies will be restricted to a description of responses that occur after stimulation with virulent full-length LPS variants. Many studies have been performed using in vitro culture systems and determined that although C. burnetii is pro-inflammatory, the response is not as robust as against most pathogens. For example C. burnetii stimulates an atypical activation of macrophages after infection to an M2 state that results in lower secretion of several pro-inflammatory cytokines [36]. In addition, low levels of IL-1β are released after C. burnetii infection and recently a T4BSS effector, IcaA, was shown to prevent inflammasome activation, suggesting that C. burnetii inhibits this innate immune response [37, 38]. The most well-defined interactions of C. burnetii with the innate immune system that result in cytokine release are with tolllike receptor (TLR) 2 and TLR4; however, the role of these receptors during infection remains incompletely understood. TLR2 is a surface PRR on immune cells including macrophages that recognize lipoproteins on the surface of Gram-negative and Gram-positive bacteria [39]. Gram-negative bacteria are also recognized through their lipid A structure in LPS by TLR4 on the surface of innate immune cells, particularly dendritic cells (DCs) and macrophages [39]. Both TLR2 and TLR4 can induce an inflammatory response by signaling through MyD88, whereas TLR4 can also cause a type I interferon response through TRIF signaling [39].
Pro-inflammatory responses induced by A. fumigatus and A. versicolor in various human macrophage models
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Elisabeth Øya, Anita Solhaug, Anette K. Bølling, Reidun Øvstebø, Tonje B. Steensen, Anani K.J. Afanou, Jørn A. Holme
In vitro studies with spores/hyphae, extracts, and/or specific components from mold demonstrated that mold and/or their products are recognized by pattern recognition receptors (PRRs), including membrane-bounded toll-like receptors (TLRs), nucleotide-oligomerization domain (NOD)-like receptors (NLRs), C-type lectin receptors (including dectin-1 and mannose receptor (MR)), and protease-activated receptors (PARs) (Becker et al. 2015; Portnoy, Williams, and Barnes 2016). TLR2 and TLR4 are considered to play a crucial role in cellular recognition and response to mold (Mambula et al. 2002; Meier et al. 2003; Netea et al. 2003; Wang et al. 2001). When activated, TLR2/4 trigger a series of signaling cascades, leading to activation of the transcription factor NF-κB, which is subsequently followed by expression of various cytokines and chemokines (Park and Mehrad 2009; Takeda and Akira 2005).