scholarly journals Transcriptomic profiling of Streptococcus pyogenes M1T1 strain in a mouse model of necrotizing fasciitis

2019 ◽  
Author(s):  
Yujiro Hirose ◽  
Masaya Yamaguchi ◽  
Daisuke Okuzaki ◽  
Daisuke Motooka ◽  
Hiroshi Hamamoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Necrotizing Fasciitis ◽  
Streptococcus Pyogenes ◽  
Treatment Strategies ◽  
Rna Seq ◽  
Novel Treatment ◽  
Genes Encoding ◽  
Life Threatening ◽  
Novel Treatment Strategies

AbstractStreptococcus pyogenes is a major cause of necrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection. At the host infection site, the local environment and interaction between host and bacteria affect bacterial gene-expression profiles, but the S. pyogenes gene-expression pattern in necrotizing fasciitis remains unknown. In this study, we used a mouse model of necrotizing fasciitis and performed RNA-sequencing (RNA-seq) analysis of S. pyogenes M1T1 strain 5448 by using infected hindlimbs obtained at 24, 48, and 96 h post-infection. The RNA-seq analysis identified 483 bacterial genes whose expression was consistently altered in the infected hindlimbs as compared to their expression under in vitro conditions. The consistently enriched genes during infection included 306 genes encoding molecules involved in virulence, carbohydrate utilization, amino acid metabolism, trace-metal transport and vacuolar ATPase transport system. Surprisingly, drastic upregulation of 3 genes, encoding streptolysin S precursor (sagA), cysteine protease (speB), and secreted DNase (spd), was noted in the mouse model of necrotizing fasciitis (log2 fold-change values: >6.0, >9.4, and >7.1, respectively). Conversely, the consistently downregulated genes included 177 genes, containing genes associated with oxidative-stress response and cell division. These results suggest that S. pyogenes in necrotizing fasciitis changes its metabolism, decreases cell proliferation, and upregulates the expression of major toxins. Our findings could provide critical information for developing novel treatment strategies and vaccines for necrotizing fasciitis.Author summaryNecrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection, principally caused by a Streptococcus pyogenes. At infection sites in hosts, bacterial pathogens are exposed to drastically changing environmental conditions and alter global gene expression patterns for survival and pathogenesis. However, there is no previous report about transcriptomic profiling of S. pyogenes in the necrotizing fasciitis. Here, we conducted comprehensive gene-expression analyses of S. pyogenes in the mouse model of necrotizing fasciitis at three distinct time points during infection. Our results indicated that S. pyogenes drastically upregulates the expression of virulence-associated genes and shifts metabolic-pathway usage during infection. The high-level expressions in particular of toxins, such as cytolysins, proteases, and nucleases, were observed at infection sites. In addition, the consistently enriched genes identified here included genes for metabolism of arginine and histidine, and carbohydrate uptake and utilization. Conversely, the genes associated with oxidative-stress response and cell division were consistently downregulated in the mouse model of necrotizing fasciitis. These data will provide useful information necessary for establishing novel treatment strategies (166 words).

scholarly journals Streptococcus pyogenes Transcriptome Changes in the Inflammatory Environment of Necrotizing Fasciitis

2019 ◽  
Vol 85 (21) ◽  
Author(s):  
Yujiro Hirose ◽  
Masaya Yamaguchi ◽  
Daisuke Okuzaki ◽  
Daisuke Motooka ◽  
Hiroshi Hamamoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Necrotizing Fasciitis ◽  
Treatment Strategies ◽  
Oxidative Stress Response ◽  
Rna Seq ◽  
Content Type ◽  
Novel Treatment ◽  
Life Threatening ◽  
Novel Treatment Strategies ◽  
Bacterial Genes

ABSTRACT Streptococcus pyogenes is a major cause of necrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection. At the host infection site, the local environment and interactions between the host and bacteria have effects on bacterial gene expression profiles, while the gene expression pattern of S. pyogenes related to this disease remains unknown. In this study, we used a mouse model of necrotizing fasciitis and performed RNA-sequencing (RNA-seq) analysis of S. pyogenes M1T1 strain 5448 by isolating total RNA from infected hind limbs obtained at 24, 48, and 96 h postinfection. RNA-seq analysis results identified 483 bacterial genes whose expression was consistently altered in the infected hindlimbs compared to their expression under in vitro conditions. Genes showing consistent enrichment during infection included 306 encoding molecules involved in virulence, carbohydrate utilization, amino acid metabolism, trace-metal transport, and the vacuolar ATPase transport system. Surprisingly, drastic upregulation of 3 genes, encoding streptolysin S precursor (sagA), cysteine protease (speB), and secreted DNase (spd), was noted in the present mouse model (log2 fold change, >6.0, >9.4, and >7.1, respectively). Conversely, the number of consistently downregulated genes was 177, including those associated with the oxidative stress response and cell division. These results suggest that in necrotizing fasciitis, S. pyogenes shows an altered metabolism, decreased cell proliferation, and upregulation of expression of major toxins. Our findings are considered to provide critical information for developing novel treatment strategies and vaccines for necrotizing fasciitis. IMPORTANCE Necrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection, is principally caused by S. pyogenes. The inflammatory environment at the site of infection causes global gene expression changes for survival of the bacterium and pathogenesis. However, no known study regarding transcriptomic profiling of S. pyogenes in cases of necrotizing fasciitis has been presented. We identified 483 bacterial genes whose expression was consistently altered during infection. Our results showed that S. pyogenes infection induces drastic upregulation of the expression of virulence-associated genes and shifts metabolic pathway usage. In particular, high-level expression of toxins, such as cytolysins, proteases, and nucleases, was observed at infection sites. In addition, genes identified as consistently enriched included those related to metabolism of arginine and histidine as well as carbohydrate uptake and utilization. Conversely, genes associated with the oxidative stress response and cell division were consistently downregulated during infection. The present findings provide useful information for establishing novel treatment strategies.

Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3710-3717 ◽  
Author(s):  
Clara Camaschella
Keyword(s):  
Genetic Analysis ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Treatment Strategies ◽  
Molecular Tests ◽  
Genes Encoding ◽  
Life Threatening ◽  
Young Subjects ◽  
Novel Treatment Strategies

Genetic analysis of hemochromatosis has led to the discovery of a number of genes whose mutations disrupt iron homeostasis and lead to iron overload. The introduction of molecular tests into clinical practice has provided a tool for early diagnosis of these conditions. It has become clear that hemochromatosis includes a spectrum of disorders that range from simple biochemical abnormalities to chronic asymptomatic tissue damage in midlife to serious life-threatening diseases in young subjects. Molecular studies have identified the systemic loop that controls iron homeostasis and is centered on the hepcidin-ferroportin interaction. The complexity of this regulatory pathway accounts for the genetic heterogeneity of hemochromatosis and related disorders and raises the possibility that genes encoding components of the pathway may be modifiers of the main genotype. Molecular diagnosis has improved the classification of the genetic conditions leading to iron overload and identified novel entities, characterized by both iron loading and variable degrees of anemia. Despite the progress in the diagnosis, classification, and mechanisms of iron overload disorders, the treatment of affected patients continues to rely on regular phlebotomy. Understanding the molecular circuitry of iron control may lead to the identification of potential therapeutic targets for novel treatment strategies to be used in association with or as an alternative to phlebotomy.

scholarly journals Transcriptomics Analysis ofCandida albicansTreated with Huanglian Jiedu Decoction Using RNA-seq

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Qianqian Yang ◽  
Lei Gao ◽  
Maocan Tao ◽  
Zhe Chen ◽  
Xiaohong Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antifungal Agents ◽  
Enrichment Analysis ◽  
Trichophyton Mentagrophytes ◽  
Inhibition Mechanism ◽  
Pathway Enrichment Analysis ◽  
Rna Seq ◽  
Genes Encoding ◽  
Life Threatening ◽  
Systemic Infections

Candida albicansis the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections that are often life-threatening. Resistance ofC. albicansto antifungal agents and limited antifungal agents has potentially serious implications for management of infections. As a famous multiherb prescription in China, Huanglian Jiedu Decoction (HLJJD,Orengedokutoin Japan) is efficient againstTrichophyton mentagrophytesandC. albicans. But the antifungal mechanism of HLJDD remains unclear. In this study, by using RNA-seq technique, we performed a transcriptomics analysis of gene expression changes forC. albicansunder the treatment of HLJDD. A total of 6057 predicted protein-encoding genes were identified. By gene expression analysis, we obtained a total of 735 differentially expressed genes (DEGs), including 700 upregulated genes and 35 downregulated genes. Genes encoding multidrug transporters such as ABC transporter and MFS transporter were identified to be significantly upregulated. Meanwhile, by pathway enrichment analysis, we identified 26 significant pathways, in which pathways of DNA replication and transporter activity were mainly involved. These results might provide insights for the inhibition mechanism of HLJDD againstC. albicans.

scholarly journals The search for novel treatment strategies for Streptococcus pneumoniae infections

2021 ◽  
Author(s):  
F Cools ◽  
P Delputte ◽  
P Cos
Keyword(s):  
Immune System ◽  
Streptococcus Pneumoniae ◽  
Treatment Strategies ◽  
Host Immune System ◽  
Pneumococcal Infections ◽  
Enzymatic Assays ◽  
Novel Treatment ◽  
Development Costs ◽  
Life Threatening ◽  
Novel Treatment Strategies

Abstract This review provides an overview of the most important novel treatment strategies against Streptococcus pneumoniae infections published over the past 10 years. The pneumococcus causes the majority of community-acquired bacterial pneumonia cases, and it is one of the prime pathogens in bacterial meningitis. Over the last 10 years, extensive research has been conducted to prevent severe pneumococcal infections, with a major focus on i) boosting the host immune system and ii) discovering novel antibacterials. Boosting the immune system can be done in two ways, either by actively modulating host immunity, mostly through administration of selective antibodies, or by interfering with pneumococcal virulence factors, thereby supporting the host immune system to effectively overcome an infection. While several of such experimental therapies are promising, few have evolved to clinical trials. The discovery of novel antibacterials is hampered by the high research and development costs versus the relatively low revenues for the pharmaceutical industry. Nevertheless, novel enzymatic assays and target-based drug design, allow the identification of targets and the development of novel molecules to effectively treat this life-threatening pathogen.

scholarly journals Using gene expression signatures to identify novel treatment strategies in gulf war illness

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Travis J.A. Craddock ◽  
Jeanna M. Harvey ◽  
Lubov Nathanson ◽  
Zachary M. Barnes ◽  
Nancy G. Klimas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Treatment Strategies ◽  
Gulf War ◽  
Gulf War Illness ◽  
Novel Treatment ◽  
Gene Expression Signatures ◽  
Novel Treatment Strategies

Update on Infections in the Immunocompromised Host

1991 ◽  
Vol 4 (5) ◽  
pp. 282-294
Author(s):  
C. Randall Marchbanks ◽  
Karen A. Rowley
Keyword(s):  
Bone Marrow ◽  
Medical Care ◽  
Treatment Strategies ◽  
Immunocompromised Host ◽  
Immunocompromised Patients ◽  
Novel Treatment ◽  
Recent Advances ◽  
Life Threatening ◽  
Immunocompromised State ◽  
Novel Treatment Strategies

Recent advances in medical care have provided more effective therapies for the treatment of various malignancies and increased the number of successful bone marrow and organ transplantations. However, these advances often place the patient in a severely immunocompromised state for several days or weeks resulting in one or more life-threatening infections. This article discusses some general principles, current pharmacotherapeutic strategies, and novel treatment strategies for the management of immunocompromised patients.

scholarly journals Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

2020 ◽  
pp. 972-987
Author(s):  
Ramez N. Eskander ◽  
Julia Elvin ◽  
Laurie Gay ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Current Treatment ◽  
High Grade ◽  
Novel Treatment ◽  
Sample Average ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Sample Range ◽  
Novel Treatment Strategies

PURPOSE High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape. PATIENTS AND METHODS Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs. RESULTS The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors ( P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found. CONCLUSION This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.

Sign in / Sign up

Export Citation Format

Share Document