scholarly journals Pharmacological iron-chelation as an assisted nutritional immunity strategy against Piscirickettsia salmonis infection

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Mario Caruffo ◽  
Dinka Mandakovic ◽  
Madelaine Mejías ◽  
Ignacio Chávez-Báez ◽  
Pablo Salgado ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Host Cells ◽  
Bacterial Disease ◽  
Protective Capacity ◽  
Intracellular Iron ◽  
Piscirickettsia Salmonis

Abstract Salmonid Rickettsial Septicaemia (SRS), caused by Piscirickettsia salmonis, is a severe bacterial disease in the Chilean salmon farming industry. Vaccines and antibiotics are the current strategies to fight SRS; however, the high frequency of new epizootic events confirms the need to develop new strategies to combat this disease. An innovative opportunity is perturbing the host pathways used by the microorganisms to replicate inside host cells through host-directed antimicrobial drugs (HDAD). Iron is a critical nutrient for P. salmonis infection; hence, the use of iron-chelators becomes an excellent alternative to be used as HDAD. The aim of this work was to use the iron chelator Deferiprone (DFP) as HDAD to treat SRS. Here, we describe the protective effect of the iron chelator DFP over P. salmonis infections at non-antibiotic concentrations, in bacterial challenges both in vitro and in vivo. At the cellular level, our results indicate that DFP reduced the intracellular iron content by 33.1% and P. salmonis relative load during bacterial infections by 78%. These findings were recapitulated in fish, where DFP reduced the mortality of rainbow trout challenged with P. salmonis in 34.9% compared to the non-treated group. This is the first report of the protective capacity of an iron chelator against infection in fish, becoming a potential effective host-directed therapy for SRS and other animals against ferrophilic pathogens.

scholarly journals Recent Advances in Iron Chelation and Gallium-Based Therapies for Antibiotic Resistant Bacterial Infections

2021 ◽  
Vol 22 (6) ◽  
pp. 2876
Author(s):  
Víctor Vinuesa ◽  
Michael J. McConnell
Keyword(s):  
Antimicrobial Activity ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Bacterial Species ◽  
Iron Chelation ◽  
Iron Chelator ◽  
In Vivo Studies ◽  
Iron Chelators

Iron is essential for multiple bacterial processes and is thus required for host colonization and infection. The antimicrobial activity of multiple iron chelators and gallium-based therapies against different bacterial species has been characterized in preclinical studies. In this review, we provide a synthesis of studies characterizing the antimicrobial activity of the major classes of iron chelators (hydroxamates, aminocarboxylates and hydroxypyridinones) and gallium compounds. Special emphasis is placed on recent in-vitro and in-vivo studies with the novel iron chelator DIBI. Limitations associated with iron chelation and gallium-based therapies are presented, with emphasis on limitations of preclinical models, lack of understanding regarding mechanisms of action, and potential host toxicity. Collectively, these studies demonstrate potential for iron chelators and gallium to be used as antimicrobial agents, particularly in combination with existing antibiotics. Additional studies are needed in order to characterize the activity of these compounds under physiologic conditions and address potential limitations associated with their clinical use as antimicrobial agents.

Deferiprone Stimulates Aged Dermal Fibroblasts via HIF-1α Modulation

2020 ◽  
Author(s):  
Andrea Pagani ◽  
B Manuela Kirsch ◽  
Ursula Hopfner ◽  
Matthias M Aitzetmueller ◽  
Elizabeth A Brett ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Cell Metabolism ◽  
Hypoxia Inducible Factor ◽  
Survival Rates ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Dermal Fibroblasts ◽  
Topical Formulation

Abstract Background Hypoxia-inducible factor 1α (HIF-1α), a transcription factor responsible for tissue homeostasis and regeneration, presents reduced functionality in advanced age. In addition to absence of oxygen, sequestration of iron also stimulates HIF-1α. Therefore, we analyzed the efficacy of the iron-chelator deferiprone (DFP) at stimulating dermal fibroblasts. Objectives The main objective of this study was to quantify the DFP concentrations capable of stimulating dermal fibroblasts in vitro and to correlate the effective DFP concentrations with the ability of DFP to penetrate the epidermis, reach the dermis, and activate HIF-1α in vivo. Methods We measured cell proliferation, metabolic activity, HIF-1α expression, and lactate dehydrogenase levels of both young and aged fibroblasts after a 24-hour in vitro preconditioning with DFP. In addition, we evaluated cell survival rates and morphology with different cellular stainings. Finally, we performed a transdermal permeation study with a 1% DFP topical formulation to quantify the concentration required to reach the dermis. Results In vitro administration of iron-chelation therapy (156-312.5 µg/mL DFP ) on aged fibroblasts resulted in activation of various antiaging processes. The concentration required to reach the dermis within 24 hours was 1.5% (0.15 mg/mL), which corresponds well with the effective doses of our laboratory analyses. Conclusions The activation of HIF-1α by DFP enhances cell metabolism, proliferation, and survival of fibroblasts while reducing lactate dehydrogenase levels. Modulation of HIF-1α is linked to activation of key regeneration enzymes and proteins, and by proxy, antiaging. Therefore, the antiaging properties of DFP and its satisfactory dermal penetration make it a promising regenerative agent.

Effect of bovine lactoferrin onChlamydia trachomatisinfection and inflammation

2017 ◽  
Vol 95 (1) ◽  
pp. 34-40 ◽  
Author(s):  
Rosa Sessa ◽  
Marisa Di Pietro ◽  
Simone Filardo ◽  
Alessia Bressan ◽  
Luigi Rosa ◽  
...  
Keyword(s):  
Acute Infection ◽  
Host Cells ◽  
Developmental Cycle ◽  
Bovine Lactoferrin ◽  
Bacterial Disease ◽  
Chronic Infections ◽  
Sexually Transmitted ◽  
Obligate Intracellular Pathogen

Chlamydia trachomatis is an obligate, intracellular pathogen responsible for the most common sexually transmitted bacterial disease worldwide, causing acute and chronic infections. The acute infection is susceptible to antibiotics, whereas the chronic one needs prolonged therapies, thus increasing the risk of developing antibiotic resistance. Novel alternative therapies are needed. The intracellular development of C. trachomatis requires essential nutrients, including iron. Iron-chelating drugs inhibit C. trachomatis developmental cycle. Lactoferrin (Lf), a pleiotropic iron binding glycoprotein, could be a promising candidate against C. trachomatis infection. Similarly to the efficacy against other intracellular pathogens, bovine Lf (bLf) could both interfere with C. trachomatis entry into epithelial cells and exert an anti-inflammatory activity. In vitro and in vivo effects of bLf against C. trachomatis infectious and inflammatory process has been investigated. BLf inhibits C. trachomatis entry into host cells when incubated with cell monolayers before or at the moment of the infection and down-regulates IL-6/IL-8 synthesized by infected cells. Six out of 7 pregnant women asymptomatically infected by C. trachomatis, after 30 days of bLf intravaginal administration, were negative for C. trachomatis and showed a decrease of cervical IL-6 levels. This is the first time that the bLf protective effect against C. trachomatis infection has been demonstrated.

scholarly journals Conjugation of Hydroxyethyl Starch to Desferrioxamine (DFO) Modulates the Dual Role of DFO in Yersinia enterocolitica Infection

2000 ◽  
Vol 7 (3) ◽  
pp. 457-462 ◽  
Author(s):  
Sören Schubert ◽  
Ingo B. Autenrieth
Keyword(s):  
Yersinia Enterocolitica ◽  
Hydroxyethyl Starch ◽  
Growth Promotion ◽  
Iron Chelator ◽  
Dual Role ◽  
Host Cells ◽  
Immunosuppressive Action

ABSTRACT The iron chelator desferrioxamine (DFO) B is widely used in the therapy of patients with iron overload. As a side effect, DFO may favor the occurrence of fulminant Yersinia infections. Previous work from our laboratory showed that this might be due to a dual role of DFO: growth promotion of the pathogen and immunosuppression of the host. In this study, we sought to determine whether conjugation of DFO to hydroxyethyl starch (HES-DFO) may prevent exacerbation ofYersinia infection in mice. We found HES-DFO to promote neither growth of Yersinia enterocolitica nor mitogen-induced T-cell proliferation and gamma interferon production by T cells in vitro. Nevertheless, in vivo HES-DFO promoted growth ofY. enterocolitica possibly due to cleavage of HES and release of DFO. The pretreatment of mice with DFO resulted in death of all mice 2 to 5 days after application of a normally sublethal inoculum of Y. enterocolitica, while none of the mice pretreated with HES-DFO died within the first 7 days postinfection. However, some of the HES-DFO-treated mice died 8 to 14 days postinfection. Thus, due to the delayed in vivo effect HES-DFO failed to triggerYersinia-induced septic shock, which accounts for early mortality in DFO-associated septicemia. Moreover, our data suggest that DFO needs to be taken up by host cells in order to exert its immunosuppressive action. These results strongly suggest that HES-DFO might be a favorable drug with fewer side effects than DFO in terms of DFO-promoted fulminant infections.

scholarly journals Synthetic Porcine Hepcidin Exhibits Different Roles in Escherichia coli and Salmonella Infections

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Dan Liu ◽  
Zhen-Shun Gan ◽  
Wan Ma ◽  
Hai-Tao Xiong ◽  
Yun-Qing Li ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Bacterial Infections ◽  
Iron Status ◽  
Iron Chelator ◽  
Intracellular Iron ◽  
Content Type ◽  
Defense Strategies ◽  
Salmonella Infections

ABSTRACT Hepcidin, an antimicrobial peptide, was discovered to integrate diverse signals from iron status and an infection threat and orchestrate a series of host-protective responses. Several studies have investigated the antimicrobial role of hepcidin, but the results have been controversial. Here, we aimed to examine the role of hepcidin in bacterial adherence and invasion in vitro. We found that porcine hepcidin could decrease the amount of the extracellular pathogen enterotoxigenic Escherichia coli (ETEC) K88 that adhered to cells because it caused the aggregation of the bacteria. However, addition of hepcidin to macrophages infected with the intracellular pathogen Salmonella enterica serovar Typhimurium enhanced the intracellular growth of the pathogen through the degradation of ferroportin, an iron export protein, and then the sequestration of intracellular iron. Intracellular iron was unavailable by use of the iron chelator deferiprone (DFO), which reduced intracellular bacterial growth. These results demonstrate that hepcidin exhibits different functions in extracellular and intracellular bacterial infections, which suggests that different defense strategies should be taken to prevent bacterial infection.

scholarly journals Interferons: Tug of War Between Bacteria and Their Host

2021 ◽  
Vol 11 ◽  
Author(s):  
Noémie Alphonse ◽  
Ruth E. Dickenson ◽  
Charlotte Odendall
Keyword(s):  
Signaling Pathways ◽  
Bacterial Infections ◽  
Host Cells ◽  
Host Responses ◽  
Bacterial Invasion ◽  
Type I ◽  
Viral Immunity ◽  
Diverse Range

Type I and III interferons (IFNs) are archetypally antiviral cytokines that are induced in response to recognition of foreign material by pattern recognition receptors (PRRs). Though their roles in anti-viral immunity are well established, recent evidence suggests that they are also crucial mediators of inflammatory processes during bacterial infections. Type I and III IFNs restrict bacterial infection in vitro and in some in vivo contexts. IFNs mainly function through the induction of hundreds of IFN-stimulated genes (ISGs). These include PRRs and regulators of antimicrobial signaling pathways. Other ISGs directly restrict bacterial invasion or multiplication within host cells. As they regulate a diverse range of anti-bacterial host responses, IFNs are an attractive virulence target for bacterial pathogens. This review will discuss the current understanding of the bacterial effectors that manipulate the different stages of the host IFN response: IFN induction, downstream signaling pathways, and target ISGs.

scholarly journals Iron depletion limits intracellular bacterial growth in macrophages

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 866-874 ◽  
Author(s):  
Prasad N. Paradkar ◽  
Ivana De Domenico ◽  
Nina Durchfort ◽  
Irene Zohn ◽  
Jerry Kaplan ◽  
...  
Keyword(s):  
Bacterial Growth ◽  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Iron Chelator ◽  
Chlamydia Psittaci ◽  
Loss Of Function ◽  
Intracellular Growth ◽  
Intracellular Iron ◽  
Cellular Iron

AbstractMany intracellular pathogens infect macrophages and these pathogens require iron for growth. Here we demonstrate in vitro that the intracellular growth of Chlamydia psittaci, trachomatis, and Legionella pneumophila is regulated by the levels of intracellular iron. Macrophages that express cell surface ferroportin, the only known cellular iron exporter, limit the intracellular growth of these bacteria. Hepcidin is an antimicrobial peptide secreted by the liver in response to inflammation. Hepcidin binds to ferroportin mediating its internalization and degradation. Addition of hepcidin to infected macrophages enhanced the intracellular growth of these pathogens. Macrophages from flatiron mice, a strain heterozygous for a loss-of-function ferroportin mutation, showed enhanced intracellular bacterial growth independent of the presence of exogenous hepcidin. Macrophages, from wild-type or flatiron mice, incubated with the oral iron chelator deferriprone or desferasirox showed reduced intracellular bacterial growth suggesting that these chelators might be therapeutic in chronic intracellular bacterial infections.

scholarly journals In Vitro Probiotic Potential of Hemophilin-producing Strains of Haemophilus haemolyticus

2020 ◽  
Author(s):  
Brianna Atto ◽  
Roger Latham ◽  
Dale Kunde ◽  
David Gell ◽  
Stephen Tristram
Keyword(s):  
Rapid Development ◽  
Host Cells ◽  
Causative Organism ◽  
Chronic Obstructive ◽  
Protective Capacity ◽  
Obstructive Pulmonary Disease ◽  
Effective Prevention ◽  
Tract Infections

ABSTRACTNon-typeable Haemophilus influenzae (NTHi) is a leading causative organism of opportunistic respiratory tract infections, including otitis media and acute exacerbations of chronic obstructive pulmonary disease. Despite the enormous disease burden associated with NTHi infections, there are currently no effective prevention strategies, and the rapid development of antibiotic resistance is compromising treatment.We previously discovered Haemophilus haemolyticus (Hh) strains capable of producing haemophilin (HPL), a heme-binding protein that restricts NTHi growth by limiting its access to an essential growth factor, heme. Thus, these strains may have utility as a probiotic therapy against NTHi infection by limiting colonization, migration and subsequent infection in susceptible individuals. Here, we have assessed the feasibility of this approach by in vitro competition assays between NTHi and Hh strains with varying capacity to produce HPL. HPL-producing strains of Hh exhibited enhanced growth and consistently outcompeted NTHi compared to Hh strains unable to produce the protein. This competitive advantage was maintained over a period of six days, culminating in the complete eradication of NTHi. Expression analysis of HPL during competition coincided with the NTHi-inhibitory capacity of HPL-producers, confirming that inhibition was mediated by the presence of HPL.Together, results suggest that natural levels of HPL production by Hh are sufficient to limit NTHi’s access to heme, even under excess heme conditions unlikely to be encountered in vivo. Further investigation is required to determine the protective capacity of HPL-producers in vivo and their ability to interrupt NTHi colonization of host cells.

ACIS, A Novel KepTide™, Binds to ACE-2 Receptor and Inhibits the Infection of SARS-CoV2 Virus in vitro in Primate Kidney Cells: Therapeutic Implications for COVID-19 (Preprint)

2020 ◽  
Author(s):  
Avik Sotira Scientific
Keyword(s):  
Social Life ◽  
Plaque Assay ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
Crystallographic Structure ◽  
Therapeutic Implications ◽  
Biochemical Assays ◽  
Targeted Medicine

UNSTRUCTURED Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome (SARS) caused by a virus known as SARS-Coronavirus 2 (SARS-CoV2). Without a targeted-medicine, this disease has been causing a massive humanitarian crisis not only in terms of mortality, but also imposing a lasting damage to social life and economic progress of humankind. Therefore, an immediate therapeutic strategy needs to be intervened to mitigate this global crisis. Here, we report a novel KepTide™ (Knock-End Peptide) therapy that nullifies SARS-CoV2 infection. SARS-CoV2 employs its surface glycoprotein “spike” (S-glycoprotein) to interact with angiotensin converting enzyme-2 (ACE-2) receptor for its infection in host cells. Based on our in-silico-based homology modeling study validated with a recent X-ray crystallographic structure (PDB ID:6M0J), we have identified that a conserved motif of S-glycoprotein that intimately engages multiple hydrogen-bond (H-bond) interactions with ACE-2 enzyme. Accordingly, we designed a peptide, termed as ACIS (ACE-2 Inhibitory motif of Spike), that displayed significant affinity towards ACE-2 enzyme as confirmed by biochemical assays such as BLItz and fluorescence polarization assays. Interestingly, more than one biochemical modifications were adopted in ACIS in order to enhance the inhibitory action of ACIS and hence called as KEpTide™. Consequently, a monolayer invasion assay, plaque assay and dual immunofluorescence analysis further revealed that KEpTide™ efficiently mitigated the infection of SARS-CoV2 in vitro in VERO E6 cells. Finally, evaluating the relative abundance of ACIS in lungs and the potential side-effects in vivo in mice, our current study discovers a novel KepTide™ therapy that is safe, stable, and robust to attenuate the infection of SARS-CoV2 virus if administered intranasally. INTERNATIONAL REGISTERED REPORT RR2-https://doi.org/10.1101/2020.10.13.337584

scholarly journals Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

2021 ◽  
Author(s):  
Wen-Dai Bao ◽  
Pei Pang ◽  
Xiao-Ting Zhou ◽  
Fan Hu ◽  
Wan Xiong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Impairment ◽  
Iron Homeostasis ◽  
Critical Role ◽  
Gene Set Enrichment Analysis ◽  
Molecular Characteristics ◽  
Intracellular Iron

AbstractIron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

Sign in / Sign up

Export Citation Format

Share Document