The complex pathogenesis of bacteremia

Christaki, Eirini; Giamarellos‐Bourboulis, Evangelos J.

doi:10.4161/viru.26514

Cited by 68 publications

(33 citation statements)

References 99 publications

(138 reference statements)

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“…In the interest of generality, we keep the detail of immune responses to a minimal level. Thus, the model is inevitably a simplification of the complex interaction between host immunity, bacteria, and antibiotics [ 45 ]. However, the underlying assumptions do capture crucial aspects of the expected immune responses in acute infections.…”

Section: Methodsmentioning

confidence: 99%

Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment

Gjini

Brito

2016

PLoS Comput Biol

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Antimicrobial resistance of infectious agents is a growing problem worldwide. To prevent the continuing selection and spread of drug resistance, rational design of antibiotic treatment is needed, and the question of aggressive vs. moderate therapies is currently heatedly debated. Host immunity is an important, but often-overlooked factor in the clearance of drug-resistant infections. In this work, we compare aggressive and moderate antibiotic treatment, accounting for host immunity effects. We use mathematical modelling of within-host infection dynamics to study the interplay between pathogen-dependent host immune responses and antibiotic treatment. We compare classical (fixed dose and duration) and adaptive (coupled to pathogen load) treatment regimes, exploring systematically infection outcomes such as time to clearance, immunopathology, host immunization, and selection of resistant bacteria. Our analysis and simulations uncover effective treatment strategies that promote synergy between the host immune system and the antimicrobial drug in clearing infection. Both in classical and adaptive treatment, we quantify how treatment timing and the strength of the immune response determine the success of moderate therapies. We explain key parameters and dimensions, where an adaptive regime differs from classical treatment, bringing new insight into the ongoing debate of resistance management. Emphasizing the sensitivity of treatment outcomes to the balance between external antibiotic intervention and endogenous natural defenses, our study calls for more empirical attention to host immunity processes.

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Section: Methodsmentioning

confidence: 99%

Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment

Gjini

Brito

2016

PLoS Comput Biol

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“…Genotype is an important determinant factor in human host susceptibility to major diseases, including infections [ 1 ]. There is increasing evidence that some inter-population and inter-individual differences in the attack rate and prognosis of specific infectious organisms are due to inherited genetic variants and, for the most part, to multicomplex genetic traits (polygenetic traits) [ 2 ]. These findings are changing our view of infections as we can now assume that pathogens are not the sole determinants of the corresponding infectious diseases.…”

Section: Introductionmentioning

confidence: 99%

Host genetic diversity influences the severity of Pseudomonas aeruginosa pneumonia in the Collaborative Cross mice

Lorè¹,

Iraqi²,

Bragonzi³

2015

BMC Genet

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BackgroundPseudomonas aeruginosa is one of the top three causes of opportunistic infections in humans. Patients with a compromised immune system, due to immunosuppressive therapies or underlying diseases such as cancer, AIDS or the hereditary disease cystic fibrosis, are at risk of developing P. aeruginosa infection. However, clinical evidence indicates extremely variable outcomes of P. aeruginosa infections in individuals at risk, suggesting that host multi-complex genetic traits may influence the severity of this opportunistic infection. Here, we have used an innovative experimental model to dissect whether host genetic background, such as those found in the outbred population, could influence the risk of morbidity and mortality to P. aeruginosa pneumonia.ResultsA highly genetically-diverse mouse resource population, Collaborative Cross (CC) mice, was infected with a clinical strain of P. aeruginosa and subsequently monitored for mortality, mean survival time, and morbidity, change in body weight for seven days post infection. Disease phenotypes ranged from complete resistance and recovery of body weight to lethal disease. Initial variables, including body weight, age and gender, have limited influence on P. aeruginosa outcome, emphasizing the role of host genetic background in defining the risk of morbidity and mortality. When broad-sense heritability of phenotypic traits was evaluated, it confirmed the influence of genetic profile rather than environmental factors among the CC lines during P. aeruginosa infection.ConclusionThis innovative model system can potentially reproduce the variables responses of disease severity observed in humans during P. aeruginosa pneumonia. Our results demonstrated that a widely-marked differential response to P. aeruginosa airway infection in term of morbidity and mortality, is mainly affected by host genetic factors, as multiple genetic loci or polymorphic variations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0260-6) contains supplementary material, which is available to authorized users.

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“…Non-self pathogenic products, or pathogen-associated molecular patterns (PAMPs), interact with pattern recognition receptors (PRRs) to produce a signal that causes an increase in pro-inflammatory cytokine secretion. Binding of PAMPs to PRRs such as Toll-like receptors 2 and 4 (TLR-2 and TLR-4) initiates the transcription of pro-inflammatory cytokines such as interleukin 1 (IL-1β) and tumor necrosis factor alpha (TNF-α) (Gogos et al, 2000;Montes et al, 2006;Christaki and Giamarellos-Bourboulis, 2014). These cytokines activate the host immune system to eliminate the infectious pathogens.…”

Section: Introductionmentioning

confidence: 99%

“…They are located within the coding and promoter regions of genes, and thereby affect gene function. Several SNPs are associated with susceptibility to infectious disease (Lu et al, 2005;Reale et al, 2011;Oliveira et al, 2012;Christaki and Giamarellos-Bourboulis, 2014). Although their functional role remains to be established, several SNPs are believed to affect the production of cytokines (Tsezou et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Association of single nucleotide polymorphisms in pro-inflammatory cytokine and toll-like receptor genes with pediatric hematogenous osteomyelitis

et al. 2016

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ABSTRACT. Hematogenous osteomyelitis (H O ) is a bone infectionwherein bacteria penetrate to the bone through the blood stream. Several single nucleotide polymorphisms (SNPs) have been associated with susceptibility to infectious diseases. In this study, we investigated the contribution of SNPs in interleukin (IL)-1B1 (rs16944), IL1A (rs1800587), IL1B (rs1143634), toll-like receptor (TLR)-2 (rs3804099), TLR4 (rs4986790), TLR4 (rs4986791), IL1R (rs2234650), tumor necrosis factor (TNF)-α (rs1800629), TNF (rs361525), and IL1RN (rs315952) towards the development of H O in Saudi patients and compared to healthy controls. Fifty-two patients diagnosed with H O and 103 healthy individuals were genotyped. The frequencies of genotypes GG (rs16944) and AA (rs16944) were lower and higher in patients [odds ratio (OR) = 0.34, Pc = 0.05] and controls (OR = 1.33, Pc = 0.05), respectively, suggesting that SNPs at this locus could alter H O susceptibility. In addition, the patients and controls exhibited lower and higher frequencies of the alleles G (rs16944) (OR = 0.43, Pc = 0.007) and A (rs16944) (OR = 2.32, Pc = 0.007), respectively. The expression of alleles C (rs3804099) and T (rs3804099) were higher in patients (OR = 2.05, Pc = 0.04) and controls (OR = 0.49, Pc = 0.04), respectively. In conclusion, SNPs at rs16944 and rs3804099 were found to be associated with H O in the Saudi population.

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The complex pathogenesis of bacteremia

Cited by 68 publications

References 99 publications

Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment

Integrating Antimicrobial Therapy with Host Immunity to Fight Drug-Resistant Infections: Classical vs. Adaptive Treatment

Host genetic diversity influences the severity of Pseudomonas aeruginosa pneumonia in the Collaborative Cross mice

Association of single nucleotide polymorphisms in pro-inflammatory cytokine and toll-like receptor genes with pediatric hematogenous osteomyelitis

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