Last data update: Nov 04, 2024. (Total: 48056 publications since 2009)
Records 1-30 (of 88 Records) |
Query Trace: Litvintseva A[original query] |
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Epidemiological and clinical features of a large blastomycosis outbreak at a paper mill in Michigan
Hennessee I , Palmer S , Reik R , Miles-Jay A , Nawaz MY , Blankenship HM , Kramer R , Hughes A , Snyder M , Yin RL , Litvintseva AP , Parnell LA , Gade L , Chiller T , de Perio MA , Stobierski MG , McFadden J , Toda M . Clin Infect Dis 2024 BACKGROUND: Blastomycosis is an environmentally acquired fungal infection that can result in severe pulmonary illness and high hospitalization rates. In 2023, a blastomycosis outbreak was detected among workers at a paper mill in Delta County, Michigan. METHODS: We included patients with clinical and laboratory evidence of blastomycosis who had spent ≥40 hours in Delta County since September 1, 2022 and had illness onset December 1, 2022-July 1, 2023. We assessed epidemiological and clinical features of patients and evaluated factors associated with hospitalization. We performed whole-genome sequencing to characterize genetic relatedness of clinical isolates from eight patients. RESULTS: In total, 131 patients were identified; all had worked at or visited the mill. Sixteen patients (12%) were hospitalized; one died. Compared with non-hospitalized patients, more hospitalized patients had diabetes (p=0.03) and urine antigen titers above the lower limit of quantification (p<0.001). Hospitalized patients were also more likely to have had ≥1 healthcare visits before receiving a blastomycosis diagnostic test (p=0.02) and to have been treated with antibiotics prior to antifungal prescription (p=0.001). All sequenced isolates were identified as Blastomyces gilchristii and clustered into a distinct outbreak cluster. CONCLUSIONS: This was the largest documented blastomycosis outbreak in the United States. Epidemiologic evidence indicated exposures occurred at or near the mill, and genomic findings suggested a common exposure source. Patients with diabetes may have increased risk for hospitalization, and elevated urine antigen titers could indicate greater disease severity. Early suspicion of blastomycosis may prompt earlier diagnosis and treatment, potentially reducing unnecessary antibiotic prescriptions and improving patient outcomes. |
Evaluation of a multiplex real-time PCR targeting the β-tubulin gene for the detection and differentiation of Sporothrix schenckii and Sporothrix brasiliensis
López LF , Gade L , Litvintseva AP , Sexton DJ . Microbiol Spectr 2024 e0116224 Sporothrix sp. is a thermally dimorphic genus of fungi known to cause subacute or chronic subcutaneous lesions in humans and animals and is the cause of increasing public health concern due to spread of feline-associated cases. Here, we adapted and evaluated a recently described real-time PCR assay targeting the β-tubulin gene to rapidly detect and differentiate two related species, S. schenckii and S. brasiliensis. The assay was tested with 55 S. brasiliensis, 19 S. schenckii, and 85 isolates from other clinically relevant fungi, and showed 100% concordance with reference identification methods. The assay showed high analytical sensitivity with a limit of detection of 1 pg of DNA per microliter of sample for both targets. The assay was further evaluated with 11 fresh and 17 formalin-fixed, paraffin-embedded (FFPE) tissues. This multiplex real-time PCR assay successfully detected the DNA from both S. brasiliensis and S. schenckii isolates as well as S. schenckii from fresh and FFPE tissues. Our results demonstrate this assay performs well and could be a helpful molecular tool to support rapid species identification in cultures and primary specimens.IMPORTANCEHaving available molecular tools to identify and differentiate closely related species will allow clinical, veterinarians, and public health labs to provide diagnostic results with accuracy and short turnaround time for the routine and outbreak response activities. |
A global chromoblastomycosis strategy and development of the global chromoblastomycosis working group
Smith DJ , Queiroz-Telles F , Rabenja FR , Hay R , Bonifaz A , Grijsen ML , Blaizot R , Messina F , Song Y , Lockhart SR , Jordan A , Cavanaugh AM , Litvintseva AP , Chiller T , Schito M , de Hoog S , Vicente VA , Cornet M , Dagne DA , Ramarozatovo LS , de Azevedo Cmpes , Santos Dwcl . PLoS Negl Trop Dis 2024 18 (10) e0012562 Chromoblastomycosis, an implantation mycosis, is a neglected tropical disease that causes decreased quality of life, stigma, and disability. The global burden of disease is unknown and data on disease epidemiology and outcomes are severely limited by a lack of access to needed diagnostic tools and therapeutics. The World Health Organization outlined targets for chromoblastomycosis in the Road Map for Neglected Tropical Diseases 2021-2030, but little progress has been made in initiating and implementing an effective control program globally. This lack of guiding policy and progress led to the recent formation of a Global Chromoblastomycosis Working Group which has developed a global chromoblastomycosis strategy. We describe this strategy, which outlines specific steps needed to improve technical progress, strategy and service delivery, and enablers. Clinicians, researchers, public and government officials, patients, and policy makers can align their time, expertise, and resources to improve the lives of communities affected by chromoblastomycosis through this strategy. |
Investigation and successful control of a Candida auris outbreak at a tertiary health care facility in Kenya
Ombajo LA , Kanyua A , Ngugi R , Malcolm C , Berkow E , Gade L , Bancroft E , Osoro J , Njoroge R , Juma P , Ngirita M , Bore RC , Litvintseva A , Lyman M , Toda M . IJID Regions 2024 13 Objectives: This study aimed to conduct an epidemiological and genomic investigation of a hospital outbreak of Candida auris, and implement measures for its control. Methods: We collected demographic and clinical data from medical records of patients with C. auris from January 2017 to June 2019 after identifying increased cases in April 2019. Point-prevalence surveys for C. auris colonisation were conducted in the critical care units (CCU). Antifungal susceptibility testing and genomic sequencing of isolates were performed. A bundle of infection prevention and control measures was instituted. Results: Thirty-two patients with C. auris were identified. All patients had a history of CCU admission. A total of 283 screening swabs were obtained and 57 isolates of C. auris identified. Antifungal susceptibility testing was performed on 48 isolates. All but two isolates were resistant to fluconazole; one isolate was also resistant to amphotericin B. Forty-one of 46 isolate genomes were clonally related and formed a distinct genetic cluster in Clade III. C. auris colonisation reduced from 42% in June 2019 to 1% in August 2019, and no new hospital-acquired colonisation was identified in the subsequent 9 months. Conclusions: We identified a new genetic subcluster of Clade III C. auris. We also show that strict implementation of infection prevention measures can lead to substantial reductions in C. auris transmission. © 2024 The Authors |
Outcomes in solid organ transplant recipients receiving organs from a donor with Fusarium solani species complex meningitis
Griffin IS , Smith DJ , Annambhotla P , Gold JAW , Ostrosky-Zeichner L , Kauffman CA , Gade L , Litvintseva A , Friedman DZ , Nishio Lucar AG , Parpia TC , Lieberman J , Bujan J , Corkrean J , Divatia MK , Grimes K , Lin J , Mobley C , Schwartz MR , Hannawi B , Malilay A , O'Boye A , Lysne J , Subramani MV , Heckmann H , Servellita V , Chiu C , Basavaraju SV . Transpl Infect Dis 2024 e14331 BACKGROUND: Five organs (heart, right lung, liver, right, and left kidneys) from a deceased patient were transplanted into five recipients in four US states; the deceased patient was identified as part of a healthcare-associated fungal meningitis outbreak among patients who underwent epidural anesthesia in Matamoros, Mexico. METHODS: After transplant surgeries occurred, Fusarium solani species complex, a fungal pathogen with a high case-mortality rate, was identified in cerebrospinal fluid from the organ donor by metagenomic next-generation sequencing (mNGS) and fungal-specific polymerase chain reaction and in plasma by mNGS. RESULTS: Four of five transplant recipients received recommended voriconazole prophylaxis; four were monitored weekly by serum (1-3)-β-d-glucan testing. All five were monitored for signs of infection for at least 3 months following transplantation. The liver recipient had graft failure, which was attributed to an etiology unrelated to fungal infection. No fungal DNA was identified in sections of the explanted liver, suggesting that F. solani species complex did not contribute to graft failure. The remaining recipients experienced no signs or symptoms suggestive of fusariosis. CONCLUSION: Antifungal prophylaxis may be useful in preventing donor-derived infections in recipients of organs from donors that are found to have Fusarium meningitis. |
Effects of climate change on fungal infections
Williams SL , Toda M , Chiller T , Brunkard JM , Litvintseva AP . PLoS Pathog 2024 20 (5) e1012219 |
Tracing histoplasmosis genomic epidemiology and species occurrence across the USA
Tenório BG , Kollath DR , Gade L , Litvintseva AP , Chiller T , Jenness JS , Stajich JE , Matute DR , Hanzlicek AS , Barker BM , Teixeira MM . Emerg Microbes Infect 2024 13 (1) 2315960 ABSTRACTHistoplasmosis is an endemic mycosis in North America frequently reported along the Ohio and Mississippi River Valleys, although autochthonous cases occur in non-endemic areas. In the United States, the disease is provoked by two genetically distinct clades of Histoplasma capsulatum sensu lato, Histoplasma mississippiense (Nam1) and H. ohiense (Nam2). To bridge the molecular epidemiological gap, we genotyped 93 Histoplasma isolates (62 novel genomes) including clinical, environmental, and veterinarian samples from a broader geographical range by whole-genome sequencing, followed by evolutionary and species niche modelling analyses. We show that histoplasmosis is caused by two major lineages, H. ohiense and H. mississippiense; with sporadic cases caused by H. suramericanum in California and Texas. While H. ohiense is prevalent in eastern states, H. mississipiense was found to be prevalent in the central and western portions of the United States, but also geographically overlapping in some areas suggesting that these species might co-occur. Species Niche Modelling revealed that H. ohiense thrives in places with warmer and drier conditions, while H. mississippiense is endemic to areas with cooler temperatures and more precipitation. In addition, we predicted multiple areas of secondary contact zones where the two species co-occur, potentially facilitating gene exchange and hybridization. This study provides the most comprehensive understanding of the genomic epidemiology of histoplasmosis in the USA and lays a blueprint for the study of invasive fungal diseases. |
Emergence of zoonotic sporotrichosis in Brazil: a genomic epidemiology study
Ribeiro Dos Santos A , Misas E , Min B , Le N , Bagal UR , Parnell LA , Sexton DJ , Lockhart SR , de Souza Carvalho Melhem M , Takahashi JPF , Oliboni GM , Bonfieti LX , Cappellano P , Sampaio JLM , Araujo LS , Alves Filho HL , Venturini J , Chiller TM , Litvintseva AP , Chow NA . Lancet Microbe 2024 BACKGROUND: Zoonotic sporotrichosis is a neglected fungal disease, whereby outbreaks are primarily driven by Sporothrix brasiliensis and linked to cat-to-human transmission. To understand the emergence and spread of sporotrichosis in Brazil, the epicentre of the current epidemic in South America, we aimed to conduct whole-genome sequencing (WGS) to describe the genomic epidemiology. METHODS: In this genomic epidemiology study, we included Sporothrix spp isolates from sporotrichosis cases from Brazil, Colombia, and the USA. We conducted WGS using Illumina NovaSeq on isolates collected by three laboratories in Brazil from humans and cats with sporotrichosis between 2013 and 2022. All isolates that were confirmed to be Sporothrix genus by internal transcribed spacer or beta-tubulin PCR sequencing were included in this study. We downloaded eight Sporothrix genome sequences from the National Center for Biotechnology Information (six from Brazil, two from Colombia). Three Sporothrix spp genome sequences from the USA were generated by the US Centers for Disease Control and Prevention as part of this study. We did phylogenetic analyses and correlated geographical and temporal case distribution with genotypic features of Sporothrix spp isolates. FINDINGS: 72 Sporothrix spp isolates from 55 human and 17 animal sporotrichosis cases were included: 67 (93%) were from Brazil, two (3%) from Colombia, and three (4%) from the USA. Cases spanned from 1999 to 2022. Most (61 [85%]) isolates were S brasiliensis, and all were reported from Brazil. Ten (14%) were Sporothrix schenckii and were reported from Brazil, USA, and Colombia. For S schenckii isolates, two distinct clades were observed wherein isolates clustered by geography. For S brasiliensis isolates, five clades separated by more than 100 000 single-nucleotide polymorphisms were observed. Among the five S brasiliensis clades, clades A and C contained isolates from both human and cat cases, and clade A contained isolates from six different states in Brazil. Compared with S brasiliensis isolates, larger genetic diversity was observed among S schenckii isolates from animal and human cases within a clade. INTERPRETATION: Our results suggest that the ongoing epidemic driven by S brasiliensis in Brazil represents several, independent emergence events followed by animal-to-animal and animal-to human transmission within and between Brazilian states. These results describe how S brasiliensis can emerge and spread within a country. FUNDING: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil; the São Paulo Research Foundation; Productivity in Research fellowships by the National Council for Scientific and Technological Development, and Ministry of Science and Technology of Brazil. |
Evaluation of CHROMagar Candida Plus for the detection of C. auris with a panel of 206 fungal isolates and 83 colonization screening skin-swabs
Bentz ML , Le N , Min B , Nunnally NS , Sullivan V , Tran M , Lockhart SR , Litvintseva A , Berkow EL , Sexton DJ . Microbiol Spectr 2024 e0356423 CHROMagar Candida Plus is a new formulation of chromogenic media designed for the detection and differentiation of major clinical Candida species, including Candida auris. The objective of this study is to evaluate CHROMagar Candida Plus when used according to manufacturer's instructions with a panel of 206 fungal isolates and 83 skin-swab specimens originally collected for C. auris colonization screening. Of the 68 C. auris isolates tested, 66/68 displayed the expected light-blue colony morphology and blue halo within 48 h. None of the remaining 138 non-auris isolates appeared similar to C. auris. CHROMagarCandida Plus was, therefore, inclusive to 97% of 68 C. auris isolates tested and supported visual exclusion of 100% of the 138 non-C. auris isolates tested. For the 83 colonization screening specimens, direct plating onto CHROMagarCandida Plus was 60% sensitive and 100% specific when compared to the enrichment broth gold-standard reference method. In sum, these findings demonstrate the utility of this media when working with isolates but also notable limitations when working with primary skin-swabs specimens when competing yeast species are present.IMPORTANCECandida auris is an emerging fungal pathogen of public health concern. As it continues to spread, it is important to publish evaluations of new diagnostic tools. In this study, we share our experience with a new chromogenic media which can help distinguish C. auris from related species. |
Detection of fungal DNA in human body fluids and tissues during a multistate outbreak of fungal meningitis and other infections.
Gade L , Scheel CM , Pham CD , Lindsley MD , Iqbal N , Cleveland AA , Whitney AM , Lockhart SR , Brandt ME , Litvintseva AP . Eukaryot Cell 2013 12 (5) 677-83 Exserohilum rostratum was the major cause of an outbreak of fungal infections linked to injections of contaminated methylprednisolone acetate. Because almost 14,000 persons were exposed to product that was possibly contaminated with multiple fungal pathogens, there was unprecedented need for a rapid throughput diagnostic test that could detect both E. rostratum and other unusual agents of fungal infection. Here we report development of a novel PCR test that allowed for rapid and specific detection of fungal DNA in cerebrospinal fluid (CSF), other body fluids and tissues of infected individuals. The test relied on direct purification of free-circulating fungal DNA from fluids and subsequent PCR amplification and sequencing. Using this method, we detected Exserohilum rostratum DNA in 123 samples from 114 case-patients (28% of 413 case-patients for whom 627 samples were available), and Cladosporium DNA in one sample from one case-patient. PCR with novel Exserohilum-specific ITS-2 region primers detected 25 case-patients with samples that were negative using broad-range ITS primers. Compared to fungal culture, this molecular test was more sensitive: of 139 case-patients with an identical specimen tested by culture and PCR, E. rostratum was recovered in culture from 19 (14%), but detected by PCR in 41 (29%), showing a diagnostic sensitivity of 29% for PCR compared to 14% for culture in this patient group. The ability to rapidly confirm the etiologic role of E. rostratum in these infections provided an important contribution in the public health response to this outbreak. |
Genomic description of acquired fluconazole- and echinocandin-resistance in patients with serial Candida glabrata isolates
Misas E , Seagle E , Jenkins EN , Rajeev M , Hurst S , Nunnally NS , Bentz ML , Lyman MM , Berkow E , Harrison LH , Schaffner W , Markus TM , Pierce R , Farley MM , Chow NA , Lockhart SR , Litvintseva AP . J Clin Microbiol 2024 e0114023 Candida glabrata is one of the most common causes of systemic candidiasis, often resistant to antifungal medications. To describe the genomic context of emerging resistance, we conducted a retrospective analysis of 82 serially collected isolates from 33 patients from population-based candidemia surveillance in the United States. We used whole-genome sequencing to determine the genetic relationships between isolates obtained from the same patient. Phylogenetic analysis demonstrated that isolates from 29 patients were clustered by patient. The median SNPs between isolates from the same patient was 30 (range: 7-96 SNPs), while unrelated strains infected four patients. Twenty-one isolates were resistant to echinocandins, and 24 were resistant to fluconazole. All echinocandin-resistant isolates carried a mutation either in the FKS1 or FKS2 HS1 region. Of the 24 fluconazole-resistant isolates, 17 (71%) had non-synonymous polymorphisms in the PDR1 gene, which were absent in susceptible isolates. In 11 patients, a genetically related resistant isolate was collected after recovering susceptible isolates, indicating in vivo acquisition of resistance. These findings allowed us to estimate the intra-host diversity of C. glabrata and propose an upper boundary of 96 SNPs for defining genetically related isolates, which can be used to assess donor-to-host transmission, nosocomial transmission, or acquired resistance.IMPORTANCEIn our study, mutations associated to azole resistance and echinocandin resistance were detected in Candida glabrata isolates using a whole-genome sequence. C. glabrata is the second most common cause of candidemia in the United States, which rapidly acquires resistance to antifungals, in vitro and in vivo. |
Finding Candida auris in public metagenomic repositories
Mario-Vasquez JE , Bagal UR , Lowe E , Morgulis A , Phan J , Sexton DJ , Shiryev S , Slatkevičius R , Welsh R , Litvintseva AP , Blumberg M , Agarwala R , Chow NA . PLoS One 2024 19 (1) e0291406 Candida auris is a newly emerged multidrug-resistant fungus capable of causing invasive infections with high mortality. Despite intense efforts to understand how this pathogen rapidly emerged and spread worldwide, its environmental reservoirs are poorly understood. Here, we present a collaborative effort between the U.S. Centers for Disease Control and Prevention, the National Center for Biotechnology Information, and GridRepublic (a volunteer computing platform) to identify C. auris sequences in publicly available metagenomic datasets. We developed the MetaNISH pipeline that uses SRPRISM to align sequences to a set of reference genomes and computes a score for each reference genome. We used MetaNISH to scan ~300,000 SRA metagenomic runs from 2010 onwards and identified five datasets containing C. auris reads. Finally, GridRepublic has implemented a prospective C. auris molecular monitoring system using MetaNISH and volunteer computing. |
Understanding the exposure risk of aerosolized Coccidioides in a Valley fever endemic metropolis
Porter WT , Gade L , Montfort P , Mihaljevic JR , Bowers JR , Willman A , Klimowski BA , LaFleur BJ , Sunenshine RH , Collins J , Adame G , Brady S , Komatsu KK , Williams S , Toda M , Chiller T , Litvintseva AP , Engelthaler DM . Sci Rep 2024 14 (1) 1311 Coccidioides is the fungal causative agent of Valley fever, a primarily pulmonary disease caused by inhalation of fungal arthroconidia, or spores. Although Coccidioides has been an established pathogen for 120 years and is responsible for hundreds of thousands of infections per year, little is known about when and where infectious Coccidioides arthroconidia are present within the ambient air in endemic regions. Long-term air sampling programs provide a means to investigate these characteristics across space and time. Here we present data from > 18 months of collections from 11 air sampling sites across the Phoenix, Arizona, metropolitan area. Overall, prevalence was highly variable across space and time with no obvious spatial or temporal correlations. Several high prevalence periods were identified at select sites, with no obvious spatial or temporal associations. Comparing these data with weather and environmental factor data, wind gusts and temperature were positively associated with Coccidioides detection, while soil moisture was negatively associated with Coccidioides detection. These results provide critical insights into the frequency and distribution of airborne arthroconidia and the associated risk of inhalation and potential disease that is present across space and time in a highly endemic locale. |
A phylogeographic description of histoplasma capsulatum in the United States
Bagal UR , Gade L , Benedict K , Howell V , Christophe N , Gibbons-Burgener S , Hallyburton S , Ireland M , McCracken S , Metobo AK , Signs K , Warren KA , Litvintseva AP , Chow NA . J Fungi (Basel) 2023 9 (9) Histoplasmosis is one of the most under-diagnosed and under-reported endemic mycoses in the United States. Histoplasma capsulatum is the causative agent of this disease. To date, molecular epidemiologic studies detailing the phylogeographic structure of H. capsulatum in the United States have been limited. We conducted genomic sequencing using isolates from histoplasmosis cases reported in the United States. We identified North American Clade 2 (NAm2) as the most prevalent clade in the country. Despite high intra-clade diversity, isolates from Minnesota and Michigan cases were predominately clustered by state. Future work incorporating environmental sampling and veterinary surveillance may further elucidate the molecular epidemiology of H. capsulatum in the United States and how genomic sequencing can be applied to the surveillance and outbreak investigation of histoplasmosis. |
Public health research priorities for fungal diseases: A multidisciplinary approach to save lives
Smith DJ , Gold JAW , Benedict K , Wu K , Lyman M , Jordan A , Medina N , Lockhart SR , Sexton DJ , Chow NA , Jackson BR , Litvintseva AP , Toda M , Chiller T . J Fungi (Basel) 2023 9 (8) Fungal infections can cause severe disease and death and impose a substantial economic burden on healthcare systems. Public health research requires a multidisciplinary approach and is essential to help save lives and prevent disability from fungal diseases. In this manuscript, we outline the main public health research priorities for fungal diseases, including the measurement of the fungal disease burden and distribution and the need for improved diagnostics, therapeutics, and vaccines. Characterizing the public health, economic, health system, and individual burden caused by fungal diseases can provide critical insights to promote better prevention and treatment. The development and validation of fungal diagnostic tests that are rapid, accurate, and cost-effective can improve testing practices. Understanding best practices for antifungal prophylaxis can optimize prevention in at-risk populations, while research on antifungal resistance can improve patient outcomes. Investment in vaccines may eliminate certain fungal diseases or lower incidence and mortality. Public health research priorities and approaches may vary by fungal pathogen. |
Application of real-time PCR assays for the diagnosis of histoplasmosis in human FFPE tissues using three molecular targets
López LF , Tobón Á M , Cáceres DH , Chiller T , Litvintseva AP , Gade L , González Á , Gómez BL . J Fungi (Basel) 2023 9 (7) Histoplasmosis is a fungal infection caused by the thermally dimorphic fungus Histoplasma capsulatum. This infection causes significant morbidity and mortality in people living with HIV/AIDS, especially in countries with limited resources. Currently used diagnostic tests rely on culture and serology but with some limitations. No molecular assays are commercially available and the results from different reports have been variable. We aimed to evaluate quantitative real-time PCR (qPCR) targeting three protein-coding genes of Histoplasma capsulatum (100-kDa, H and M antigens) for detection of this fungus in formalin-fixed paraffin-embedded (FFPE) samples from patients with proven histoplasmosis. The sensitivity of 100-kDa, H and M qPCR assays were 93.9%, 91% and 57%, respectively. The specificity of 100-kDa qPCR was 93% when compared against samples from patients with other mycoses and other infections, and 100% when samples from patients with non-infectious diseases were used as controls. Our findings demonstrate that real-time PCR assays targeting 100-kDa and H antigen showed the most reliable results and can be successfully used for diagnosing this mycosis when testing FFPE samples. |
Chromosomal rearrangements and loss of subtelomeric adhesins linked to clade-specific phenotypes in Candida auris (preprint)
Muñoz JF , Welsh RM , Shea T , Batra D , Gade L , Litvintseva AP , Cuomo CA . bioRxiv 2019 754143 Candida auris is an emerging fungal pathogen of rising concern due to its increasing incidence, its ability to cause healthcare-associated outbreaks and antifungal resistance. Genomic analysis revealed that early cases of C. auris that were detected contemporaneously were geographically stratified into four major clades. Clade II, also termed East Asian clade, consists of the initial isolates described from cases of ear infection, is less frequently resistant to antifungal drugs and to date, the isolates from this group have not been associated with outbreaks. Here, we generate nearly complete genomes (“telomere-to-telomere”) of an isolate of this clade and of the more widespread Clade IV. By comparing these to genome assemblies of the other two clades, we find that the Clade II genome appears highly rearranged, with 2 inversions and 9 translocations resulting in a substantially different karyotype. In addition, large subtelomeric regions have been lost from 10 of 14 chromosome ends in the Clade II genomes. We find that shorter telomeres and genome instability might be a consequence of a naturally occurring loss-of-function mutation in DCC1 exclusively found in Clade II isolates, resulting in a hypermutator phenotype. We also determine that deleted subtelomeric regions might be linked to clade-specific adaptation as these regions are enriched in Hyr/Iff-like cell surface proteins, novel candidate cell surface proteins, and an ALS-like adhesin. The presence of these cell surface proteins in the clades responsible for global outbreaks causing invasive infections suggests an explanation for the different phenotypes observed between clades.IMPORTANCE Candida auris was unknown prior to 2009 and since then it has quickly spread around the world, causing outbreaks in healthcare facilities and representing a high fraction of candidemia cases in some regions. The emergence of C. auris is a major concern, since it is often multidrug-resistant, easily spread between patients, and causes invasive infections. While isolates from three global clades cause invasive infections, isolates from Clade II primarily cause ear infections and have not been implicated in outbreaks, though cases of Clade II infections have been reported on different continents. Here, we describe genetic differences between Clade II and Clades I, III and IV, including a loss-of-function mutation in a gene associated with telomere length maintenance and genome stability, and the loss of cell wall proteins involved in adhesion and biofilm formation, that may suggest an explanation for the lower virulence and potential for transmission of Clade II isolates. |
Genomic basis of multidrug-resistance, mating, and virulence in Candida auris and related emerging species (preprint)
Munoz JF , Gade L , Chow NA , Loparev VN , Juieng P , Berkow EL , Farrer RA , Litvintseva AP , Cuomo CA . bioRxiv 2018 299917 Candida auris is an emergent fungal pathogen of rising public health concern due to increasing reports of outbreaks in healthcare settings and resistance to multiple classes of antifungal drugs. While distantly related to the more common pathogens C. albicans and C. glabrata, C. auris is closely related to three rarely observed and often multidrug-resistant species, C. haemulonii, C. duobushaemulonii and C. pseudohaemulonii. Here, we generated and analyzed near complete genome assemblies and RNA-Seq-guided gene predictions for isolates from each of the four major C. auris clades and for C. haemulonii, C. duobushaemulonii and C. pseudohaemulonii. Our analyses mapped seven chromosomes and revealed chromosomal rearrangements between C. auris clades and related species. We found conservation of genes involved in mating and meiosis and identified both MTLa and MTLα C. auris isolates, suggesting the potential for mating between clades. Gene conservation analysis highlighted that many genes linked to drug resistance and virulence in other pathogenic Candida species are conserved in C. auris and related species including expanded families of transporters and lipases, as well as mutations and copy number variants in ERG11 that confer drug resistance. In addition, we found genetic features of the emerging species that likely underlie differences in virulence and drug response between these and other Candida species, including genes involved in cell wall structure. To begin to characterize the species-specific genes important for antifungal response, we profiled the gene expression of C. auris in response to voriconazole and amphotericin B and found induction of several transporters and metabolic regulators that may play a role in drug resistance. This study provides a comprehensive view of the genomic basis of drug resistance, potential for mating, and virulence in this emerging fungal clade. |
Tracing the evolutionary history and global expansion of Candida auris using population genomic analyses (preprint)
Chow NA , Munoz JF , Gade L , Berkow EL , Li X , Welsh RM , Forsberg K , Lockhart SR , Adam R , Alanio A , Alastruey-Izquierdo A , Althawadi S , Arauz AB , Ben-Ami R , Bharat A , Calvo B , Desnos-Ollivier M , Escandon P , Gardam D , Gunturu R , Heath CH , Kurzai O , Martin R , Litvintseva AP , Cuomo CA . bioRxiv 2020 2020.01.06.896548 Candida auris has emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela revealed four populations (Clades I, II, III, and IV) corresponding to these geographic regions. Since this description, C. auris has been reported in over 30 additional countries. To trace this global emergence, we compared the genomes of 304 C. auris isolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; Clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure. C. auris isolates from two clades with opposite mating types were detected contemporaneously in a single healthcare facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 339 years; outbreak-causing clusters from Clades I, III, and IV originated 34-35 years ago. We observed high rates of antifungal resistance in Clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F in ERG11 as the most widespread mutation associated with azole resistance and S639P in FKS1 for echinocandin resistance. Copy number variants in ERG11 predominantly appeared in Clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance in C. auris.Importance In less than a decade, C. auris has emerged in healthcare settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other Candida species, C. auris is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new C. auris introductions. Through a global collaboration, we assessed genome evolution of isolates of C. auris from 19 countries. Here, we described estimated timing of the expansion of each C. auris clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology. |
Strong population structure in Venezuelan populations of Coccidioides posadasii (preprint)
Teixeira MM , Alvarado P , Roe CC , Thompson GR 3rd , Patane JSL , Sahl JW , Keim P , Galgiani JN , Litvintseva AP , Matute DR , Barker BM . bioRxiv 2019 719328 Coccidioides posadasii is a pathogenic fungus that causes coccidioidomycosis in many arid regions of the Americas. One of these regions is bordered by the Caribbean Sea, and the surrounding landscape may play an important role in the dispersion of C. posadasii across South America through southeastern Mexico, Honduras, Guatemala and Venezuela. Comparative phylogenomic analyses of C. posadasii reveal that clinical strains from Venezuela are genetically distinct from the North American populations found in Arizona (AZ), Texas, Mexico, and the rest of South America (TX/MX/SA). We find evidence for admixture between the Venezuela and the North American populations of C. posadasii in Central America. As expected, the proportion of Venezuelan alleles in the admixed population decreases as latitude (and distance from Venezuela) increases. Our results indicate that the population in Venezuela may have been subjected to a recent bottleneck, and shows strong population structure. This analysis provides insight into potential for Coccidioides spp. to invade new regions. |
Comparing genomic variant identification protocols for Candida auris
Li X , Muñoz JF , Gade L , Argimon S , Bougnoux ME , Bowers JR , Chow NA , Cuesta I , Farrer RA , Maufrais C , Monroy-Nieto J , Pradhan D , Uehling J , Vu D , Yeats CA , Aanensen DM , d'Enfert C , Engelthaler DM , Eyre DW , Fisher MC , Hagen F , Meyer W , Singh G , Alastruey-Izquierdo A , Litvintseva AP , Cuomo CA . Microb Genom 2023 9 (4) Genomic analyses are widely applied to epidemiological, population genetic and experimental studies of pathogenic fungi. A wide range of methods are employed to carry out these analyses, typically without including controls that gauge the accuracy of variant prediction. The importance of tracking outbreaks at a global scale has raised the urgency of establishing high-accuracy pipelines that generate consistent results between research groups. To evaluate currently employed methods for whole-genome variant detection and elaborate best practices for fungal pathogens, we compared how 14 independent variant calling pipelines performed across 35 Candida auris isolates from 4 distinct clades and evaluated the performance of variant calling, single-nucleotide polymorphism (SNP) counts and phylogenetic inference results. Although these pipelines used different variant callers and filtering criteria, we found high overall agreement of SNPs from each pipeline. This concordance correlated with site quality, as SNPs discovered by a few pipelines tended to show lower mapping quality scores and depth of coverage than those recovered by all pipelines. We observed that the major differences between pipelines were due to variation in read trimming strategies, SNP calling methods and parameters, and downstream filtration criteria. We calculated specificity and sensitivity for each pipeline by aligning three isolates with chromosomal level assemblies and found that the GATK-based pipelines were well balanced between these metrics. Selection of trimming methods had a greater impact on SAMtools-based pipelines than those using GATK. Phylogenetic trees inferred by each pipeline showed high consistency at the clade level, but there was more variability between isolates from a single outbreak, with pipelines that used more stringent cutoffs having lower resolution. This project generated two truth datasets useful for routine benchmarking of C. auris variant calling, a consensus VCF of genotypes discovered by 10 or more pipelines across these 35 diverse isolates and variants for 2 samples identified from whole-genome alignments. This study provides a foundation for evaluating SNP calling pipelines and developing best practices for future fungal genomic studies. |
Genomic description of human clinical Aspergillus fumigatus isolates, California, 2020.
Misas E , Deng JZ , Gold JAW , Gade L , Nunnally NS , Georgacopoulos O , Bentz M , Berkow EL , Litvintseva AP , Chiller TM , Klausner JD , Chow NA . Med Mycol 2023 61 (2) Aspergillus fumigatus, an environmental mold, causes life-threatening infections. Studies on the phylogenetic structure of human clinical A. fumigatus isolates are limited. Here, we performed whole-genome sequencing of 24 A. fumigatus isolates collected from 18 patients in U.S. healthcare facilities in California. Single-nucleotide polymorphism (SNP) differences between patient isolates ranged from 187-70 829 SNPs. For five patients with multiple isolates, we calculated the within-host diversities. Three patients had a within-host diversity that ranged from 4-10 SNPs and two patients ranged from 2-16 977 SNPs. Findings revealed highly diverse A. fumigatus strains among patients and two patterns of diversity for isolates that come from the same patient, low and extremely high diversity. | Aspergillus fumigatus is an environmental mold. It can cause a severe infection called aspergillosis in patients with weakened immune systems. We analyzed A. fumigatus DNA from patients at California hospitals. We described genetic diversity between samples from the same patients and among different patients. Our findings provide insight on using genomic sequencing to investigate aspergillosis in hospitals. | eng |
Role of microbiota in the skin colonization of candida auris
Tharp B , Zheng R , Bryak G , Litvintseva AP , Hayden MK , Chowdhary A , Thangamani S . mSphere 2023 8 (1) e0062322 Candida auris is an emerging multidrug-resistant fungal pathogen that can cause life-threatening infections in humans. Unlike other Candida species that colonize the gut, C. auris efficiently colonizes the skin and contaminates the patient's environment, resulting in rapid nosocomial transmission and outbreaks of systemic infections. As the largest organ of the body, the skin harbors beneficial microbiota that play a critical role to protect from invading pathogens. However, the role of skin microbiota in the colonization and pathogenesis of C. auris remains to be explored. With this perspective, we review and discuss recent insights into skin microbiota and their potential interactions with the immune system in the context of C. auris skin colonization. Understanding microbiota, C. auris, and host interactions in the skin is important to develop microbiome-based therapeutic approaches to prevent and treat this emerging fungal pathogen in humans. |
Genomic Epidemiology Linking Nonendemic Coccidioidomycosis to Travel.
Monroy-Nieto J , Gade L , Benedict K , Etienne KA , Litvintseva AP , Bowers JR , Engelthaler DM , Chow NA . Emerg Infect Dis 2023 29 (1) 110-117 Coccidioidomycosis is a fungal infection endemic to hot, arid regions of the western United States, northern Mexico, and parts of Central and South America. Sporadic cases outside these regions are likely travel-associated; alternatively, an infection could be acquired in as-yet unidentified newly endemic locales. A previous study of cases in nonendemic regions with patient self-reported travel history suggested that infections were acquired during travel to endemic regions. We sequenced 19 Coccidioides isolates from patients with known travel histories from that earlier investigation and performed phylogenetic analysis to identify the locations of potential source populations. Our results show that those isolates were phylogenetically linked to Coccidioides subpopulations naturally occurring in 1 of the reported travel locales, confirming that these cases were likely acquired during travel to endemic regions. Our findings demonstrate that genomic analysis is a useful tool for investigating travel-related coccidioidomycosis. |
Investigation of a Candida auris outbreak in a Skilled Nursing Facility - Virginia, United States, October 2020-June 2021.
Waters A , Chommanard C , Baltozer S , Angel LC , Abdelfattah R , Lyman M , Forsberg K , Misas E , Litvintseva AP , Fields V , Lineberger S , Bernard S . Am J Infect Control 2022 51 (4) 472-474 Candida auris, an emerging multi-drug resistant organism (MDRO), is an urgent public health threat. We report on a C. auris outbreak investigation at a Virginia ventilator skilled nursing facility (vSNF). During October 2020-June 2021, we identified 28 cases among residents in the ventilator unit. Genomic evidence suggested ≥2 distinct C. auris introductions to the facility. We identified multiple infection and prevention control challenges, highlighting the importance of strengthening MDRO prevention efforts at vSNFs. |
Diagnostics to support mycetoma management - Development of two Target Product Profiles
Fongwen N , Asiedu KB , Bakhiet S , Bonifaz A , Cruz I , Argaw D , Estrada-Chavez G , Fahal AH , Litvintseva A , Marks M , Salinas-Carmona MC , Sow D , vandeSande WWJ . Trop Med Int Health 2022 27 (12) 1059-1064 OBJECTIVE: Mycetoma is a neglected tropical disease caused by more than 70 different micro-organisms and identified by WHO as one of the high-priority diseases for developing diagnostic tests. To ensure production of diagnostic assays for use by clinical staff in endemic regions, Target Product Profiles (TPP) were designed. METHODS: We describe the development of two TPPs: one for a diagnostic test able to identify the causative agent of mycetoma and another which would determine when treatment could be stopped. The TPPs were developed by considering product use, design, performance, product configuration and costs. RESULTS: Version 1.0 TPPs for two uses were posted by WHO for a one-month online public consultation on 25 October 2021 and the final TPP was posted online on 05 May 2022. CONCLUSION: A major difficulty encountered in developing both TPPs was the large number of agents able to cause mycetoma and the lack of specific biomarkers for most of them. |
Investigation of a prolonged and large outbreak of healthcare-associated mucormycosis cases in an acute care hospital-Arkansas, June 2019-May 2021
Jordan A , James AE , Gold JAW , Wu K , Glowicz J , Wolfe F , Vyas K , Litvintseva A , Gade L , Liverett H , Alverson M , Burgess M , Wilson A , Li R , Benowitz I , Gulley T , Patil N , Chakravorty R , Chu W , Kothari A , Jackson BR , Garner K , Toda M . Open Forum Infect Dis 2022 9 (10) ofac510 BACKGROUND: Outbreaks of healthcare-associated mucormycosis (HCM), a life-threatening fungal infection, have been attributed to multiple sources, including contaminated healthcare linens. In 2020, staff at Hospital A in Arkansas alerted public health officials of a potential HCM outbreak. METHODS: We collected data on patients at Hospital A who had invasive mucormycosis during January 2017-June 2021 and calculated annual incidence of HCM (defined as mucormycosis diagnosed within ≥7 days after hospital admission). We performed targeted environmental assessments, including linen sampling at the hospital, to identify potential sources of infection. RESULTS: During the outbreak period (June 2019-June 2021), 16 patients had HCM; clinical features were similar between HCM patients and non-HCM patients. Hospital-wide HCM incidence (per 100 000 patient-days) increased from 0 in 2018 to 3 in 2019 and 6 in 2020. For the 16 HCM patients, the most common underlying medical conditions were hematologic malignancy (56%) and recent traumatic injury (38%); 38% of HCM patients died in-hospital. Healthcare-associated mucormycosis cases were not epidemiologically linked by common procedures, products, units, or rooms. At Hospital A and its contracted offsite laundry provider, suboptimal handling of laundered linens and inadequate environmental controls to prevent mucormycete contamination were observed. We detected Rhizopus on 9 (9%) of 98 linens sampled at the hospital, including on linens that had just arrived from the laundry facility. CONCLUSIONS: We describe the largest, single-center, HCM outbreak reported to date. Our findings underscore the importance of hospital-based monitoring for HCM and increased attention to the safe handling of laundered linens. |
Genomics and metagenomics of Madurella mycetomatis, a causative agent of black grain mycetoma in Sudan
Litvintseva AP , Bakhiet S , Gade L , Wagner DD , Bagal UR , Batra D , Norris E , Rishishwar L , Beer KD , Siddig EE , Mhmoud NA , Chow NA , Fahal A . PLoS Negl Trop Dis 2022 16 (11) e0010787 Madurella mycetomatis is one of the main causative agents of mycetoma, a debilitating neglected tropical disease. Improved understanding of the genomic diversity of the fungal and bacterial causes of mycetoma is essential to advances in diagnosis and treatment. Here, we describe a high-quality genome assembly of M. mycetomatis and results of the whole genome sequence analysis of 26 isolates from Sudan. We demonstrate evidence of at least seven genetically diverse lineages and extreme clonality among isolates within these lineages. We also performed shotgun metagenomic analysis of DNA extracted from mycetoma grains and showed that M. mycetomatis reads were detected in all sequenced samples with the average of 11,317 reads (s.d. +/- 21,269) per sample. In addition, 10 (12%) of the 81 tested grain samples contained bacterial reads including Streptococcus sp., Staphylococcus sp. and others. |
Molecular Epidemiology of Blastomyces gilchristii Clusters, Minnesota, USA.
Bagal UR , Ireland M , Gross A , Fischer J , Bentz M , Berkow EL , Litvintseva AP , Chow NA . Emerg Infect Dis 2022 28 (9) 1924-1926 We characterized 2 clusters of blastomycosis cases in Minnesota, USA, using whole-genome sequencing and single-nucleotide polymorphism analyses. Blastomyces gilchristii was confirmed as the cause of infection. Genomic analyses corresponded with epidemiologic findings for cases of B. gilchristii infections, demonstrating the utility of genomic methods for future blastomycosis outbreak investigations. |
The association between Coccidioides immitis and rodent habitats in Washington State remains unresolved
Litvintseva AP , Chow NA , Salah Z . mSphere 2022 7 (4) e0029422 On 22 December 2021, we published a research article describing the distribution of Coccidioides immitis in soil in Washington State (1). There, we used a systematic sampling approach, Coccidioides-specific reverse transcriptase PCR (RT-PCR), amplicon sequencing, and soil chemical analyses to describe the distribution of C. immitis in soil. We identified soil chemical and microbiological signatures associated with the presence of Coccidioides DNA and demonstrated that the same strain can colonize a 46,000-m2 area for 6 years. We also reported no association between rodent habitats and C. immitis, as equal proportions of Coccidioides-positive samples were detected in rodent burrows and in the surrounding soils. |
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