Toll-Like Receptor 3 Agonist Protection against Experimental<i>Francisella tularensis</i>Respiratory Tract Infection

Pyles, Richard B.; Jezek, G. Eric; Eaves-Pyles, Tonyia

doi:10.1128/iai.00736-09

Cited by 30 publications

(22 citation statements)

References 40 publications

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“…infection (18). Other studies have shown that prior administration of known TLR agonists reduces overall organ burdens and increases survival following subsequent F. tularensis infection (46)(47)(48). However, other properties likely also contribute to the limited systemic replication of the ⌬0831 bacteria, since the Schu S4 ⌬0831 strain also failed to replicate in the spleens and livers of mice when administered systemically via i.p.…”

Section: Discussionmentioning

confidence: 99%

FTT0831c/FTL_0325 Contributes to Francisella tularensis Cell Division, Maintenance of Cell Shape, and Structural Integrity

et al. 2014

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Section: Discussionmentioning

confidence: 99%

FTT0831c/FTL_0325 Contributes to Francisella tularensis Cell Division, Maintenance of Cell Shape, and Structural Integrity

et al. 2014

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“…TLR3 mediates an inflammatory and antiviral response that is damaging for host survival during influenza virus infection (36,52,57). Remarkably, TLR3 has a critical but unexplained role in protection during nonviral infections of the lung, including Haemophilus influenzae (58), Francisella tularensis (59), and Schistosoma mansoni (60) infections. In the complete absence of TLR3, we could not detect any IFN-production after stimulation with poly(I·C), which demonstrates the essential role of TLR3 for the detection of naked dsRNA by AECs.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor Expression and Induction of Type I and Type III Interferons in Primary Airway Epithelial Cells

Ioannidis

McNally

et al. 2013

J Virol

185

173

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E pithelial cells lining the airway represent the first barrier to the entry of respiratory viruses and are their main replication target. In addition to its function as a mechanical barrier and in gas exchange, the airway epithelium plays an important role in pathogen detection and is a source of cytokines and other inflammatory mediators that modulate immunity in the respiratory tract (1-7). Airway epithelial cells (AECs) express Toll-like receptor 1 (TLR1) to , and their activation with TLR agonists has been shown to induce the production of several cytokines, chemokines, and antimicrobial peptides. It is worth noting that the majority of these studies have been done at the mRNA level and using continuous cell lines or nonpolarized primary cells as responders to stimulation. Morphology and differentiation are critical in determining infection and immunity of the airway epithelium. First, AECs cultured under air-liquid interface (ALI) differentiate into ciliated cells that are more resistant to virus infection and mount less exacerbated inflammatory responses (12). Second, mucin is a negative regulator of TLR signaling exclusively expressed on the apical surfaces of differentiated AECs (13). Third, multiple receptors and adhesion molecules have a polarized distribution in AECs, i.e., the alpha/beta interferon (IFN-␣/␤) receptor (IFNAR) is exclusively expressed on the basolateral surface (14). Thus, primary polarized AEC cultures provide a valuable system that is a better representation of the airway epithelial microenvironment in vivo than cell lines (15-17).One of the major downstream products of TLR signaling is the IFN family (18). IFNs are a diverse group of cytokines characterized for inducing antiviral resistance, and there are three types (type I, type II, and type III) based on their biological effects, receptor usage, and structure. Only type I and type III IFNs are directly produced in response to virus infection. Type I IFNs are key immune regulators essential for mounting a robust immune response to many viral infections (19,20). All subtypes of type I IFNs engage the ubiquitously expressed IFNAR and initiate a signaling cascade that leads to the induction of Ͼ300 IFN-stimulated genes (21). Type III IFNs include interleukin-28A (IL-28A), IL-28B, and IL-29 (also known as IFN-1, IFN-2, and IFN-3) (22, 23) and signal through the IFN-receptor (IFNLR) that is composed of an exclusive IFN-R1 chain and a shared IL-10R2 chain (23). Despite the low amino acid homology between type I and type III IFNs, they trigger common signaling pathways and biological activities (24,25). This functional redundancy is contested by the different receptor distributions and by the differential regulation of type I and type III IFN production during infection. Although IFNAR is present in all cells, the expression of IFNLR is limited to epithelial cells (26,27). Type III IFNs are produced at higher levels and during longer times in the lung than type I IFNs during influenza virus infection (28). These differences are likely t...

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“…Modulation of the host’s immune response is an emerging method of combating pathogen resistance (Collier et al, 2013). Host-mediated therapies have been evaluated in the clearance of Salmonella enterica (Ma et al, 2009), Mycobacterium tuberculosis (Guo and Zhao, 2012), Francisella tularensis (Pyles et al, 2010), Escherichia coli (Vuopio-Varkila et al, 1988), as well as fungal (Parameswaran and Segal, 2007) and viral infections (Halperin et al, 2006). In addition, combining host-mediated with pathogen-mediated therapies (such as ampB) have shown synergy in the treatment of CL.…”

Section: Introductionmentioning

confidence: 99%

Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles

Collier

Peine

Gautam

et al. 2016

International Journal of Pharmaceutics

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Leishmaniasis is a disease caused by parasites of Leishmania sp., which effects nearly 12 million people worldwide and is associated with treatment complications due to widespread parasite resistance toward pathogen-directed therapeutics. The current treatments for visceral leishmaniasis (VL), the systemic form of the disease, involve pathogen-mediated drugs and have long treatment regimens, increasing the risk of forming resistant strains. One way to limit emergence of resistant pathogens is through the use of host-mediated therapeutics. The host-mediated therapeutic AR-12, which is FDA IND-approved for cancer treatment, has shown activity against a broad spectrum of intracellular pathogens; however, due to hydrophobicity and toxicity, it is difficult to reach therapeutic doses. We have formulated AR-12 into microparticles (AR-12/MPs) using the novel biodegradable polymer acetalated dextran (Ace-DEX) and used this formulation for the systemic treatment of VL. Treatment with AR-12/MPs significantly reduced liver, spleen, and bone marrow parasite loads in infected mice, while combinatorial therapies with amphotericin B had an even more significant effect. Overall, AR-12/MPs offer a unique, host-mediated therapy that could significantly reduce the emergence of drug resistance in the treatment of VL.

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Toll-Like Receptor 3 Agonist Protection against ExperimentalFrancisella tularensisRespiratory Tract Infection

Cited by 30 publications

References 40 publications

FTT0831c/FTL_0325 Contributes to Francisella tularensis Cell Division, Maintenance of Cell Shape, and Structural Integrity

FTT0831c/FTL_0325 Contributes to Francisella tularensis Cell Division, Maintenance of Cell Shape, and Structural Integrity

Toll-Like Receptor Expression and Induction of Type I and Type III Interferons in Primary Airway Epithelial Cells

Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles

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