TLR2 Signaling is Required for the Innate, but Not Adaptive Response to LVS clpB

Roberts, Lydia M.; Ledvina, Hannah E.; Sempowski, Gregory D.; Frelinger, Jeffrey A.

doi:10.3389/fimmu.2014.00426

Cited by 5 publications

(9 citation statements)

References 41 publications

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“…The rescue of the TLR2 defect was surprising. TLR2 has been reported by a variety of groups to be critical in survival of Francisella infection ( 8 , 11 , 12 , 15 , 38 ). This work has been carried out in the Slc11a1 − B6 background.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of Resistance to Francisella Imparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection

Powell

Frelinger

2017

Front. Immunol.

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Natural resistance-associated macrophage protein (NRAMP) encoded by the Slc11a1 gene is a membrane-associated transporter of divalent metal ions. Murine Slc11a1 has two known alleles, a functional Slc11a1Gly169, which is found in DBA2/J, NOD/LtJ, and 129p3/J and related mouse strains, and a non-functional Slc11a1Asp169, that is found in C56Bl/6J (B6) and BALB/cJ mice. B6 mice congenic for Slc11a1Gly169 (B6-Slc11a1G169) are markedly resistant to the intracellular pathogens Salmonella, Leishmania, and Mycobacterium tuberculosis. We examined the host cell response and replication of Francisella in B6-Slc11a1G169 mice. Bone marrow-derived macrophages from either B6-Slc11a1G169 or B6 mice were both effectively invaded by Francisella live vaccine strain (LVS). However, at 16 hours post-infection (hpi), the number of LVS bacteria recovered from B6 macrophages had increased roughly 100-fold, while in B6-Slc11a1G169 mice the number decreased 10-fold. When the mice were challenged intranasally (i.n.) B6 mice lost significant amounts (~15%) of weight, where as B6-Slc11a1G169 mice lost no weight. Three days after infection in B6-Slc11a1G169 mice, we failed to recover viable Francisella from the lungs, livers, or spleens. By contrast, B6 mice had bacterial burdens approaching 1 × 106 CFU/organ in all three organs. To further examine the degree of resistance imparted by Slc11a1Gly169 expression, we challenged mice deficient in TLR2, TLR4, and TLR9, but expressing the functional Slc11a1 (B6-Slc11a1G169Tlr2/4/9−/−). Surprisingly, B6-Slc11a1G169Tlr2/4/9−/− mice had no notable weight loss. Eighty percent of B6-Slc11a1G169Tlr2/4/9−/− mice yielded no detectable Francisella in any organ tested. Additionally, Slc11a1G169 produced little detectable cytokine either in the lung or serum compared to B6 mice. Mice expressing Slc11a1Gly169 survived even high doses (~80 LD50) of LVS inoculation. These data taken together serve to highlight that functional Slc11a1Gly169 can compensate the lack of TLR2/4/9. Thus Slc11a1 is a critical player in murine resistance to pulmonary Francisella infection, but not footpad infection.

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Section: Discussionmentioning

confidence: 99%

“…Spleens, livers, and lungs were homogenized in sterile PBS by using a Biojector (Bioject) as previously described ( 11 ). Tenfold serial dilutions were plated onto chocolate agar.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Resistance to Francisella Imparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection

Powell

Frelinger

2017

Front. Immunol.

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“…Continuing experiments removing the dominant signal, like TLR4 in Salmonella or TLR2 in Francisella , allow for the discovery of possible other immune responses that are manipulated by pathogens [38]. These subdominant signals, while not likely directly involved in pathogenesis and survival, can allow insight into mechanisms of host subversion that might be applicable to other pathogens of interest.…”

Section: Discussionmentioning

confidence: 99%

Distinct innate responses are induced by attenuated Salmonella enterica serovar Typhimurium mutants

Powell

Roberts

Ledvina

et al. 2016

Cellular Immunology

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Upon bacterial infection the host cells generate a wide variety of cytokines. Genetic attenuation of bacterial physiological pathogens can be accomplished not only by disruption of normal bacterial processes, but also by the loss of the ability to redirect the host immune system. We examined nine attenuated Salmonella Typhimurium mutants for their ability to replicate as well as the cytokines produced after infection of Bone Marrow Derived Macrophages (BMDM). Infection of BMDM with attenuated Salmonella mutants led to host cytokine patterns distinct from those that followed WT infection. Surprisingly, each bacterial mutant had a unique cytokine signature. Because some of the mutants induced an IL-10 response not seen in WT, we examined the role of IL-10 on Salmonella replication. Surprisingly, addition of IL-10 before or concurrent with infection restricted growth of WT Salmonella in BMDM. Bacterial attenuation is not a single process and results in attenuated host responses, which result in unique patterns for each attenuated mutants.

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“…We detected specific zymosan induced cytokines which may play an important role for NK cell activation, namely IL-12p70, IL-6, IL-10, and IP-10. While IL-6 and IL-10 are general pro- and anti-inflammatory cytokines (Turner et al, 2014 ) IL-12p70 and IP-10 have been described as inducers of NK cell activation which are at least partially dependent on TLR2 signaling (Lehmann et al, 2001 ; Roberts et al, 2014 ; Liu et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

First Insights in NK—DC Cross-Talk and the Importance of Soluble Factors During Infection With Aspergillus fumigatus

Weiß

Ziegler

Fliesser

et al. 2018

Front. Cell. Infect. Microbiol.

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Invasive aspergillosis (IA) is an infectious disease caused by the fungal pathogen Aspergillus fumigatus that mainly affects immunocompromised hosts. To investigate immune cell cross-talk during infection with A. fumigatus, we co-cultured natural killer (NK) cells and dendritic cells (DC) after stimulation with whole fungal structures, components of the fungal cell wall, fungal lysate or ligands for distinct fungal receptors. Both cell types showed activation after stimulation with fungal components and were able to transfer activation signals to the counterpart not stimulated cell type. Interestingly, DCs recognized a broader spectrum of fungal components and thereby initiated NK cell activation when those did not recognize fungal structures. These experiments highlighted the supportive function of DCs in NK cell activation. Furthermore, we focused on soluble DC mediated NK cell activation and showed that DCs stimulated with the TLR2/Dectin-1 ligand zymosan could maximally stimulate the expression of CD69 on NK cells. Thus, we investigated the influence of both receptors for zymosan, Dectin-1 and TLR2, which are highly expressed on DCs but show only minimal expression on NK cells. Specific focus was laid on the question whether Dectin-1 or TLR2 signaling in DCs is important for the secretion of soluble factors leading to NK cell activation. Our results show that Dectin-1 and TLR2 are negligible for NK cell activation. We conclude that besides Dectin-1 and TLR2 other receptors on DCs are able to compensate for the missing signal.

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TLR2 Signaling is Required for the Innate, but Not Adaptive Response to LVS clpB

Cited by 5 publications

References 41 publications

Efficacy of Resistance to Francisella Imparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection

Efficacy of Resistance to Francisella Imparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection

Distinct innate responses are induced by attenuated Salmonella enterica serovar Typhimurium mutants

First Insights in NK—DC Cross-Talk and the Importance of Soluble Factors During Infection With Aspergillus fumigatus

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