Investigation of a Lomentospora prolificans case cluster with whole genome sequencing.
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ABSTRACT:
SUBMITTER: Boan P
PROVIDER: S-EPMC7248584 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Investigation of a <i>Lomentospora prolificans</i> case cluster with whole genome sequencing.
Boan Peter P Pang Stanley S Gardam Dianne J DJ Darragh Helen H Wright Matthew M Coombs Geoffrey W GW
Medical mycology case reports 20200519
<i>Lomentospora prolificans</i> has caused outbreaks in immunocompromised patients. We performed whole genome sequencing (WGS) on 4 <i>L. prolificans</i> isolates from infections occurring during an 8-month period in the haematology unit at Hospital 1., and 2 isolates from unrelated infections at Hospital 2., showing a high number of mutational differences (>10,000 single nucleotide polymorphisms) between <i>L. prolificans</i> isolates from Hospital 1. Novel typing of isolates by WGS did not dem ...[more]
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Project description:Lomentospora prolificans (formally Scedosporium prolificans) is an environmental mould with a global distribution. Endocarditis caused by L. prolificans is a rare but serious emerging disease in immunocompromised patients. Prior to this case there have only been eight cases reported in the literature. Diagnosis can be challenging and there are no evidence-based guidelines for treatment.We report a 75-year-old woman with ovarian carcinoma who presented with fever after chemotherapy. Repeated sterile site cultures remained negative until day 22 of admission, when Lomentospora prolificans was isolated from blood cultures. Following extensive investigations, including Fluoro-D-glucose positron emission tomography (FDG-PET) and transoephageal echocardiography (TOE), the patient was diagnosed with endocarditis complicated by cerebral emboli. The patient was considered unsuitable for surgical intervention and passed away five days after the fungus was isolated.Endocarditis caused by Lomentospora prolificans is a rare but emerging condition, with limited treatment options and a high mortality. Awareness of the increasing incidence of Lomentospora prolificans infection, diagnosed often at an advanced stage, with potential for endocarditis may prompt earlier echocardiography or FDG-PET imaging. Further studies are needed to determine the optimal combination and duration of anti-fungal agents, used in conjunction with aggressive surgical excision where feasible.
| S-EPMC4731902 | biostudies-other
Project description:Here we describe the sequencing and assembly of the pathogenic fungus Lomentospora prolificans using a combination of short, highly accurate Illumina reads and additional coverage in very long Oxford Nanopore reads. The resulting assembly is highly contiguous, containing a total of 37,627,092 bp with over 98% of the sequence in just 26 scaffolds. Annotation identified 8896 protein-coding genes. Pulsed-field gel analysis suggests that this organism contains at least 7 and possibly 11 chromosomes, the two longest of which have sizes corresponding closely to the sizes of the longest scaffolds, at 6.6 and 5.7 Mb.
| S-EPMC5677167 | biostudies-literature
Project description:Lomentospora prolificans strain:JHH-5317 Genome sequencing and assembly
| PRJNA392827 | ENA
Project description:Lomentospora prolificans is an opportunistic fungal pathogen with low susceptibility to current antifungal drugs. Here, we tested the in vitro susceptibility of 8 drugs against 42 clinical L. prolificans isolates. All isolates showed high MICs to voriconazole (MIC90>16 μg/ml), itraconazole (MIC90>16 μg/ml), posaconazole (MIC90>16 μg/ml), isavuconazole (MIC90>16 μg/ml), amphotericin B (MIC90>16 μg/ml), and terbinafine (MIC90>64 μg/ml) and high minimum effective concentrations (MECs) to micafungin (MEC90>8 μg/ml), with the exception of miltefosine showing an MIC90 value of 4 μg/ml. We examined six different in vitro drug combinations and found that the combination of voriconazole and terbinafine achieved the most synergistic effort against L. prolificans We then annotated the L. prolificans whole genome and located its Cyp51 and Fks1 genes. We completely sequenced the two genes to determine if any mutation would be related to azole and echinocandin resistance in L. prolificans We found no amino acid changes in Cyp51 protein and no tandem repeats in the 5' upstream region of the Cyp51 gene. However, we identified three intrinsic amino acid residues (G138S, M220I, and T289A) in the Cyp51 protein that were linked to azole resistance. Likewise, two intrinsic amino acid residues (F639Y, W695F) that have reported to confer echinocandin resistance were found in Fks1 hot spot regions. In addition, three new amino acid alterations (D440A, S634R, and H1245R) were found outside Fks1 hot spot regions, and their contributions to echinocandin resistance need future investigation. Overall, our findings support the notion that L. prolificans is intrinsically resistant to azoles and echinocandins.
| S-EPMC7577128 | biostudies-literature
Project description:BackgroundLomentospora prolificans, a rare, highly virulent filamentous fungus with high rates of intrinsic resistance to antifungals, has been associated with different types of infections in immunocompromised as well as immunocompetent individuals.ObjectiveTo systematically address all relevant evidence regarding L. prolificans disseminated infections in the literature.MethodsWe searched Medline via PubMed and Scopus databases through July 2022. We performed a qualitative synthesis of published articles reporting disseminated infections from L. prolificans in humans.ResultsA total of 87 studies describing 142 cases were included in our systematic review. The pathogen was most frequently reported in disseminated infections in Spain (n = 47), Australia (n = 33), the USA (n = 21), and Germany (n = 10). Among 142 reported cases, 48.5% were males. Underlying conditions identified for the majority of patients included malignancy (72.5%), hemopoietic stem cell transplantation (23.2%), solid organ transplantation (16%), and AIDS (2%). Lungs, central nervous system, skin, eyes, heart and bones/joints were the most commonly affected organs. Neutropenia was recorded in 52% of patients. The mortality rate was as high as 87.3%.ConclusionsTo the best of our knowledge, this is the first systematic review conducted on disseminated infections due to this rare microorganism. Physicians should be aware that L. prolificans can cause a diversity of infections with high mortality and primarily affects immunocompromised and neutropenic patients.
| S-EPMC9861501 | biostudies-literature
Project description:Abstract Background Management of Scedosporium/Lomentospora prolificans infections remains challenging. We described predisposing factors, clinical manifestations, and outcomes of these rare mold infections, including predictors of early (1-month) and late (18-month) all-cause mortality and treatment failure. Methods We conducted a retrospective Australian-based observational study of proven/probable Scedosporium/L prolificans infections from 2005 to 2021. Data on patient comorbidities, predisposing factors, clinical manifestations, treatment, and outcomes up to 18 months were collected. Treatment responses and death causality were adjudicated. Subgroup analyses, multivariable Cox regression, and logistic regression were performed. Results Of 61 infection episodes, 37 (60.7%) were attributable to L prolificans. Forty-five of 61 (73.8%) were proven invasive fungal diseases (IFDs), and 29 of 61 (47.5%) were disseminated. Prolonged neutropenia and receipt of immunosuppressant agents were documented in 27 of 61 (44.3%) and 49 of 61 (80.3%) episodes, respectively. Voriconazole/terbinafine was administered in 30 of 31 (96.8%) L prolificans infections, and voriconazole alone was prescribed for 15 of 24 (62.5%) Scedosporium spp infections. Adjunctive surgery was performed in 27 of 61 (44.3%) episodes. Median time to death post–IFD diagnosis was 9.0 days, and only 22 of 61 (36.1%) attained treatment success at 18 months. Those who survived beyond 28 days of antifungal therapy were less immunosuppressed with fewer disseminated infections (both P < .001). Disseminated infection and hematopoietic stem cell transplant were associated with increased early and late mortality rates. Adjunctive surgery was associated with lower early and late mortality rates by 84.0% and 72.0%, respectively, and decreased odds of 1-month treatment failure by 87.0%. Conclusions Outcomes associated with Scedosporium/L prolificans infections is poor, particularly with L prolificans infections or in the highly immunosuppressed population. Higher rates of mortality and treatment failure were observed in Lomentospora prolificans infections or in the highly immunosuppressed patients with hematological malignancy or hematopoietic stem cell transplant. Adjunctive surgery was associated with lower mortality and decreased odds of 1-month treatment failure.
| S-EPMC9970007 | biostudies-literature
Project description:BackgroundPeptidorhamnomannan is a glycoconjugate that consists of a peptide chain substituted by O- and N-linked glycans, present on the cell surface of Lomentospora prolificans, a saprophytic fungus which is widely distributed in regions with temperate climates. O-linked oligosaccharides from peptidorhamnomannan isolated from Lomentospora prolificans conidia are recognized by macrophages mediating macrophage - conidia interaction. In this work, peptidorhamnomannan was isolated from L. prolificans mycelium cell wall and its role in macrophage - Candida albicans interaction was evaluated.ResultsPurified peptidorhamnomannan inhibits the reactivity of rabbit immune sera to mycelial and conidia forms of L. prolificans, indicating that this glycoconjugate is exposed on the fungal surface and can mediate interaction with host immune cells. We demonstrated that peptidorhamnomannan leads to TNF-α production in J774 macrophages for 1, 2 and 3 h of incubation, suggesting that this glycoconjugate may have a beneficial role in the response to fungal infections. In order to confirm this possibility, the effect of peptidorhamnomannan on the macrophage - C. albicans interaction was evaluated. Macrophages treated with peptidorhamnomannan led to a lower fungal survival, suggesting that peptidorhamnomannan induces an increased fungicidal activity in macrophages. Furthermore, TNF-α levels were measured in supernatants after macrophage - C. albicans interaction for 1, 2 and 3 h. Peptidorhamnomannan treatment led to a higher TNF-α production at the beginning of the interaction. However, the release of TNF-α was not maintained after 1 h of incubation. Besides, peptidorhamnomannan did not show any inhibitory or fungicidal effect in C. albicans when used at 100 μg/ml but it was able to kill C. albicans at a concentration of 400 μg/ml.ConclusionWe suggest that peptidorhamnomannan acts as a molecular pattern on the invading pathogen, promotes TNF-α production and, thus, increases macrophage fungicidal activity against Candida albicans.
| S-EPMC7412847 | biostudies-literature
Project description:BackgroundNeonatal listeriosis is a rare but severe disease manifesting as septicemia and central nervous system (CNS) infections with a high fatality rate of around 20 to 30%. Whole genome sequencing (WGS) is a promising technique for pathogen identification and infection source tracing with its high resolution.Case presentationA case of neonatal sepsis with listeriosis was reported with positive blood culture for Listeria monocytogenes. The case was investigated to confirm the vertical transmission of the infection and identify the potential food source of the maternal L. monocytogenes infection using WGS. L. monocytogenes was isolated from the neonate's blood sample the day after caesarean delivery and from the mother's genital and pudenda swab samples 5 days and 13 days after caesarean delivery. WGS showed that the isolate from the neonate was identical to the genome type of the isolates from the mother, with only one of the 4 isolates from the mother differing by one single nucleotide polymorphism (SNP). By WGS, one L. monocytogenes isolate from a ready-to-eat (RTE) meat sample in the patients' community market shared the same sequence type but was ruled out as the cause of infection, with 57 SNP differences to the strain causing the maternal-neonatal infection. The food isolate also carried a novel plasmid pLM1686 that harbored heavy metal resistance genes. After caesarean section, the mother was treated with a third generation cephalosporin which L. monocytogenes is naturally resistant to, which may explain why genital and pudenda swabs were still culture-positive for L. monocytogenes 13 days after delivery.ConclusionsGenital swab culture for L. monocytogenes had been informative in the diagnosis of maternal listeriosis in this case. The high resolution of WGS confirmed the maternal-neonatal transmission of L. monocytogenes infection and ruled out the L. monocytogenes contaminated RTE meat from the local market as the direct source of the mother's infection.
| S-EPMC6815428 | biostudies-literature
Project description:The filamentous fungus Lomentospora (Scedosporium) prolificans is an emerging opportunistic pathogen associated with fatal infections in patients with disturbed immune function. Unfortunately, conventional therapies are hardly of any use against this fungus due to its intrinsic resistance. Therefore, we performed an integrated study of the L. prolificans responses to the first option to treat these mycoses, namely voriconazole, with the aim of unveiling mechanisms involved in the resistance to this compound. To do that, we used a wide range of techniques, including fluorescence and electron microscopy to study morphological alterations, ion chromatography to measure changes in cell-wall carbohydrate composition, and proteomics-based techniques to identify the proteins differentially expressed under the presence of the drug. Significantly, we showed drastic changes occurring in cell shape after voriconazole exposure, L. prolificans hyphae being shorter and wider than under control conditions. Interestingly, we proved that the architecture and carbohydrate composition of the cell wall had been modified in the presence of the drug. Specifically, L. prolificans constructed a more complex organelle with a higher presence of glucans and mannans. In addition to this, we identified several differentially expressed proteins, including Srp1 and heat shock protein 70 (Hsp70), as the most overexpressed under voriconazole-induced stress conditions. The mechanisms described in this study, which may be directly related to L. prolificans antifungal resistance or tolerance, could be used as targets to improve existing therapies or to develop new ones in order to successfully eliminate these mycoses.
| S-EPMC5376303 | biostudies-literature
Project description:Lomentospora prolificans is a pathogenic and multidrug-resistant fungus that can infect both immunocompetent and immunocompromised patients, with mortality rates up to 87%. The World Health Organization (WHO) included this fungal species in its first list of 19 priority fungal pathogens, which focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections. Therefore, there is a growing interest in finding new therapeutic alternatives. In this work, the synthesis of twelve α-aminophosphonates by the microwave-assisted Kabachnik-Fields reaction and twelve α-aminophosphonic acids by a monohydrolysis reaction is reported. All compounds were evaluated by the agar diffusion method as a preliminary screening in comparison with voriconazole, showing inhibition halos for compounds 7, 11, 13, 22 and 27. The five active compounds in the preliminary tests were evaluated against five strains of L. prolificans following protocol M38-A2 from CLSI. The results showed that these compounds exhibit antifungal activity in the concentration range of 900->900 μg/mL. Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay, and it was shown that compound 22 was the least cytotoxic, with a viability of 67.91%, comparable to the viability exhibited by voriconazole (68.55%). Docking studies showed that the possible mechanism of action of the active compounds could be through the inhibition of the enzyme lanosterol-14-alpha-demethylase in an allosteric hydrophobic cavity.
| S-EPMC10224343 | biostudies-literature