RESUMO
BACKGROUND: The neutrophil-lymphocyte ratio (NLR) in human medicine is an objective biomarker that reflects prognosis. The NLR as an independent biomarker to help predict nonsurvival in hospitalized neonatal foals has not been thoroughly interrogated. OBJECTIVES/HYPOTHESIS: Retrospectively evaluate if the NLR at admission is associated with nonsurvival in sick hospitalized foals <4 days old. We hypothesized that a lower NLR will be associated with nonsurvival. ANIMALS: One thousand one hundred ninety-six client-owned foals <4 days old of any breed and sex: 993 hospitalized foals and 203 healthy foals. METHODS: Retrospective multicenter study. Medical records of foals presenting to 3 equine referral hospitals were reviewed. Foals were included if they had complete CBCs, sepsis scores, and outcome data. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Data were analyzed by nonparametric methods and univariate analysis. RESULTS: Of the 993 sick hospitalized foals, 686 were sick nonseptic and 307 were septic. The median NLR was lower in sick hospitalized foals (median [95% confidence interval], 3.55 [0.5-13.9]) compared with healthy foals (6.61 [3.06-18.1]). Septic foals had the lowest NLR (2.00 [0.20-9.71]). The NLR was lower in nonsurviving (1.97 [1.67-2.45]) compared with surviving foals (4.10 [3.76-4.33]). Nonsurviving septic foals had the lowest NLR (1.47 [1.70-3.01]). Foals with a NLR of <3.06 or <1.6 at admission had odds ratio of 3.21 (2.24-4.29) and 4.03 (2.86-5.67) for nonsurvival, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: A NLR < 3.06 at admission in sick hospitalized foals is readily available and clinically useful variable to provide prognostic information.
Assuntos
Doenças dos Cavalos , Sepse , Animais , Animais Recém-Nascidos , Biomarcadores , Cavalos , Linfócitos , Neutrófilos , Estudos Retrospectivos , Sepse/veterináriaRESUMO
Treatment of Mycobacterium tuberculosis (Mtb) infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy in vivo often fails to match drug efficacy in vitro. This is due to multiple reasons, including inadequate drug concentrations reaching Mtb at the site of infection and physiological changes of Mtb in response to host derived stresses that render the bacteria more tolerant to antibiotics. To more effectively and efficiently treat tuberculosis, it is necessary to better understand the physiologic state of Mtb that promotes drug tolerance in the host. Towards this end, multiple studies have converged on bacterial central carbon metabolism as a critical contributor to Mtb drug tolerance. In this review, we present the evidence that changes in central carbon metabolism can promote drug tolerance, depending on the environment surrounding Mtb. We posit that these metabolic pathways could be potential drug targets to stymie the development of drug tolerance and enhance the efficacy of current antimicrobial therapy.
Assuntos
Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Carbono/metabolismo , Tolerância a Medicamentos , Humanos , Redes e Vias MetabólicasRESUMO
Colicins are specific and potent toxins produced by Enterobacteriaceae that result in the rapid elimination of sensitive cells. Colicin production is commonly found throughout microbial populations, suggesting its potential importance for bacterial survival in complex microbial environments. Nonetheless, as colicin biology has been predominately studied using synthetic models, it remains unclear how colicin production contributes to survival and fitness of a colicin-producing commensal strain in a natural environment. To address this gap, we took advantage of MP1, an E. coli strain that harbors a colicinogenic plasmid and is a natural colonizer of the murine gut. Using this model, we validated that MP1 is competent for colicin production and then directly interrogated the importance of colicin production and immunity for MP1 survival in the murine gut. We showed that colicin production is dispensable for sustained colonization in the unperturbed gut. A strain lacking colicin production or immunity shows minimal fitness defects and can resist displacement by colicin producers. This report extends our understanding of the role that colicin production may play for E. coli during gut colonization and suggests that colicin production is not essential for a commensal to persist in its physiologic niche in the absence of exogenous challenges.
RESUMO
Bacteria have a remarkable ability to survive, persist, and ultimately adapt to environmental challenges. A ubiquitous environmental hazard is DNA damage, and most bacteria have evolved a network of genes to combat genotoxic stress. This network is known as the SOS response and aids in bacterial survival by regulating genes involved in DNA repair and damage tolerance. Recently, the SOS response has been shown to play an important role in bacterial pathogenesis, and yet the role of the SOS response in nonpathogenic organisms and in physiological settings remains underexplored. Using a commensal Escherichia coli strain, MP1, we showed that the SOS response plays a vital role during colonization of the murine gut. In an unperturbed environment, the SOS-off mutant is impaired for stable colonization relative to a wild-type strain, suggesting the presence of genotoxic stress in the mouse gut. We evaluated the possible origins of genotoxic stress in the mouse gut by examining factors associated with the host versus the competing commensal organisms. In a dextran sulfate sodium (DSS) colitis model, the SOS-off colonization defect persisted but was not exacerbated. In contrast, in a germ-free model, the SOS-off mutant colonized with efficiency equal to that seen with the wild-type strain, suggesting that competing commensal organisms might be a significant source of genotoxic stress. This report extends our understanding of the importance of a functional SOS response for bacterial fitness in the context of a complex physiological environment and highlights the SOS response as a possible mechanism that contributes to ongoing genomic changes, including potential antibiotic resistance, in the microbiome of healthy hosts.
Assuntos
Dano ao DNA/fisiologia , Escherichia coli/patogenicidade , Trato Gastrointestinal/microbiologia , Resposta SOS em Genética/fisiologia , Animais , Modelos Animais de Doenças , Regulação Bacteriana da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in promoting survival and the evolution of resistance under antibiotic stress. As a result, targeting the SOS response has been proposed as an adjuvant strategy to revitalize our current antibiotic arsenal. However, the optimal molecular targets and partner antibiotics for such an approach remain unclear. In this study, focusing on the two key regulators of the SOS response, LexA and RecA, we provide the first comprehensive assessment of how to target the SOS response in order to increase bacterial susceptibility and reduce mutagenesis under antibiotic treatment.
RESUMO
Bacterial communication plays an important role in many population-based phenotypes and interspecies interactions, including those in host environments. These interspecies interactions may prove critical to some infectious diseases, and it follows that communication between pathogenic bacteria and commensal bacteria is a subject of growing interest. Recent studies have shown that Escherichia coli uses the signaling molecule indole to increase antibiotic tolerance throughout its population. Here, we show that the intestinal pathogen Salmonella typhimurium increases its antibiotic tolerance in response to indole, even though S. typhimurium does not natively produce indole. Increased antibiotic tolerance can be induced in S. typhimurium by both exogenous indole added to clonal S. typhimurium populations and indole produced by E. coli in mixed-microbial communities. Our data show that indole-induced tolerance in S. typhimurium is mediated primarily by the oxidative stress response and, to a lesser extent, by the phage shock response, which were previously shown to mediate indole-induced tolerance in E. coli. Further, we find that indole signaling by E. coli induces S. typhimurium antibiotic tolerance in a Caenorhabditis elegans model for gastrointestinal infection. These results suggest that the intestinal pathogen S. typhimurium can intercept indole signaling from the commensal bacterium E. coli to enhance its antibiotic tolerance in the host intestine.