ABSTRACT
SARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape.
Subject(s)
COVID-19 , Epidemics , Humans , SARS-CoV-2/genetics , COVID-19/epidemiology , Washington/epidemiologyABSTRACT
Tularemia is caused by the highly infectious bacterium Francisella tularensis, which is recognized as a Tier 1 bioterrorism agent. Tularemia has a range of recognized clinical manifestations, but fewer than 20 bone or joint infections from 6 countries have been reported in the literature to date. This series includes 13 cases of F. tularensis septic arthritis or osteomyelitis in the United States during 2004-2023 and describes exposures, clinical presentation, diagnosis, and outcomes for this rare but severe form of tularemia. Clinicians should consider F. tularensis in patients with compatible exposures or a history of joint replacement or immunosuppression.
Subject(s)
Arthritis, Infectious , Francisella tularensis , Tularemia , Humans , United States/epidemiology , Tularemia/diagnosis , Tularemia/epidemiology , Tularemia/microbiology , Arthritis, Infectious/diagnosis , Arthritis, Infectious/epidemiologyABSTRACT
Coccidioidomycosis, histoplasmosis, and blastomycosis are lower respiratory tract fungal infections whose signs and symptoms can resemble those of other respiratory illnesses, including pneumonia caused by bacterial or viral etiologies; this overlap in clinical presentation might lead to missed or delayed diagnoses. The causative fungi live in the environment, often in soil or plant matter. To describe the epidemiologic characteristics of cases of coccidioidomycosis, histoplasmosis, and blastomycosis during the COVID-19 pandemic, CDC analyzed case surveillance data for 2019-2021. During this period, a total of 59,655 coccidioidomycosis cases, 3,595 histoplasmosis cases, and 719 blastomycosis cases were reported to CDC. In 2020, fewer cases of each disease occurred in spring compared with other seasons, and most cases occurred in fall; national seasonality is not typically observed, and cases were seasonally distributed more evenly in 2019 and 2021. Fewer cases coinciding with the start of the COVID-19 pandemic, along with an unusually high blastomycosis case fatality rate in 2021 (17% compared with more typical rates of 8%-10%), suggest that the pandemic might have affected patients' health care-seeking behavior, public health reporting practices, or clinical management of these diseases. Increased awareness and education are needed to encourage health care providers to consider fungal diseases and to identify pneumonia of fungal etiology. Standardized diagnostic guidance and informational resources for fungal testing could be incorporated into broader respiratory disease awareness and preparedness efforts to improve early diagnosis of coccidioidomycosis, histoplasmosis, and blastomycosis.
Subject(s)
Blastomycosis , COVID-19 , Coccidioidomycosis , Histoplasmosis , Respiratory Tract Infections , Humans , United States/epidemiology , Blastomycosis/epidemiology , Histoplasmosis/diagnosis , Histoplasmosis/epidemiology , Histoplasmosis/microbiology , Coccidioidomycosis/diagnosis , Coccidioidomycosis/epidemiology , Pandemics , COVID-19/epidemiology , Respiratory Tract Infections/epidemiologyABSTRACT
BACKGROUND: Long-term care facilities (LTCFs) are vulnerable to disease outbreaks. Here, we jointly analyze SARS-CoV-2 genomic and paired epidemiologic data from LTCFs and surrounding communities in Washington state (WA) to assess transmission patterns during 2020-2022, in a setting of changing policy. We describe sequencing efforts and genomic epidemiologic findings across LTCFs and perform in-depth analysis in a single county. METHODS: We assessed genomic data representativeness, built phylogenetic trees, and conducted discrete trait analysis to estimate introduction sizes over time, and explored selected outbreaks to further characterize transmission events. RESULTS: We found that transmission dynamics among cases associated with LTCFs in WA changed over the course of the COVID-19 pandemic, with variable introduction rates into LTCFs, but decreasing amplification within LTCFs. SARS-CoV-2 lineages circulating in LTCFs were similar to those circulating in communities at the same time. Transmission between staff and residents was bi-directional. CONCLUSIONS: Understanding transmission dynamics within and between LTCFs using genomic epidemiology on a broad scale can assist in targeting policies and prevention efforts. Tracking facility-level outbreaks can help differentiate intra-facility outbreaks from high community transmission with repeated introduction events. Based on our study findings, methods for routine tree building and overlay of epidemiologic data for hypothesis generation by public health practitioners are recommended. Discrete trait analysis added valuable insight and can be considered when representative sequencing is performed. Cluster detection tools, especially those that rely on distance thresholds, may be of more limited use given current data capture and timeliness. Importantly, we noted a decrease in data capture from LTCFs over time. Depending on goals for use of genomic data, sentinel surveillance should be increased or targeted surveillance implemented to ensure available data for analysis.
Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Pandemics/prevention & control , SARS-CoV-2/genetics , Washington/epidemiology , Long-Term Care/methods , Phylogeny , GenomicsABSTRACT
We describe a case of Baylisascaris procyonis roundworm infection in a child in Washington, USA, with autism spectrum disorder. Environmental assessment confirmed nearby raccoon habitation and B. procyonis eggs. B. procyonis infections should be considered a potential cause of human eosinophilic meningitis, particularly among young children and persons with developmental delays.
Subject(s)
Ascaridida Infections , Ascaridoidea , Autism Spectrum Disorder , Animals , Humans , Child , Child, Preschool , Washington/epidemiology , Ascaridida Infections/diagnosis , RaccoonsABSTRACT
Genomic data provides useful information for public health practice, particularly when combined with epidemiologic data. However, sampling bias is a concern because inferences from nonrandom data can be misleading. In March 2021, the Washington State Department of Health, USA, partnered with submitting and sequencing laboratories to establish sentinel surveillance for SARS-CoV-2 genomic data. We analyzed available genomic and epidemiologic data during presentinel and sentinel periods to assess representativeness and timeliness of availability. Genomic data during the presentinel period was largely unrepresentative of all COVID-19 cases. Data available during the sentinel period improved representativeness for age, death from COVID-19, outbreak association, long-term care facility-affiliated status, and geographic coverage; timeliness of data availability and captured viral diversity also improved. Hospitalized cases were underrepresented, indicating a need to increase inpatient sampling. Our analysis emphasizes the need to understand and quantify sampling bias in phylogenetic studies and continue evaluation and improvement of public health surveillance systems.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , COVID-19/epidemiology , Washington/epidemiology , Sentinel Surveillance , Phylogeny , GenomicsABSTRACT
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is dominated by variant viruses; the resulting impact on disease severity remains unclear. Using a retrospective cohort study, we assessed the hospitalization risk following infection with 7 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. METHODS: Our study includes individuals with positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) in the Washington Disease Reporting System with available viral genome data, from 1 December 2020 to 14 January 2022. The analysis was restricted to cases with specimens collected through sentinel surveillance. Using a Cox proportional hazards model with mixed effects, we estimated hazard ratios (HR) for hospitalization risk following infection with a variant, adjusting for age, sex, calendar week, and vaccination. RESULTS: In total, 58 848 cases were sequenced through sentinel surveillance, of which 1705 (2.9%) were hospitalized due to COVID-19. Higher hospitalization risk was found for infections with Gamma (HR 3.20, 95% confidence interval [CI] 2.40-4.26), Beta (HR 2.85, 95% CI 1.56-5.23), Delta (HR 2.28 95% CI 1.56-3.34), or Alpha (HR 1.64, 95% CI 1.29-2.07) compared to infections with ancestral lineages; Omicron (HR 0.92, 95% CI .56-1.52) showed no significant difference in risk. Following Alpha, Gamma, or Delta infection, unvaccinated patients show higher hospitalization risk, while vaccinated patients show no significant difference in risk, both compared to unvaccinated, ancestral lineage cases. Hospitalization risk following Omicron infection is lower with vaccination. CONCLUSIONS: Infection with Alpha, Gamma, or Delta results in a higher hospitalization risk, with vaccination attenuating that risk. Our findings support hospital preparedness, vaccination, and genomic surveillance.
Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , Hospitalization , Humans , Retrospective Studies , SARS-CoV-2/genetics , Washington/epidemiologyABSTRACT
The full geographic range of coccidioidomycosis is unknown, although it is most likely expanding with environmental change. We report an apparently autochthonous coccidioidomycosis patient from Spokane, Washington, USA, a location to which Coccidioides spp. are not known to be endemic.
Subject(s)
Coccidioides/isolation & purification , Coccidioidomycosis/diagnosis , Pneumonia/diagnosis , Aged, 80 and over , Antifungal Agents/therapeutic use , Coccidioidomycosis/diagnostic imaging , Coccidioidomycosis/drug therapy , Cough/etiology , Diagnosis, Differential , Female , Fluconazole/therapeutic use , Humans , Pneumonia/diagnostic imaging , Pneumonia/drug therapy , WashingtonABSTRACT
Tickborne diseases are rare in Washington, USA, and the ecology of these pathogens is poorly understood. We integrated surveillance data from humans and ticks to better describe their epidemiology and ecology. During 2011-2016, a total of 202 tickborne disease cases were reported in Washington residents. Of these, 68 (34%) were autochthonous, including cases of Lyme disease, Rocky Mountain spotted fever, tickborne relapsing fever, and tularemia. During May 2011-December 2016, we collected 977 host-seeking ticks, including Ixodes pacificus, I. angustus, I. spinipalpis, I. auritulus, Dermacentor andersoni, and D. variabilis ticks. The prevalence of Borrelia burgdorferi sensu stricto in I. pacificus ticks was 4.0%; of B. burgdorferi sensu lato, 3.8%; of B. miyamotoi, 4.4%; and of Anaplasma phagocytophilum, 1.9%. We did not detect Rickettsia rickettsii in either Dermacentor species. Case-patient histories and detection of pathogens in field-collected ticks indicate that several tickborne pathogens are endemic to Washington.
Subject(s)
Anaplasma phagocytophilum , Borrelia burgdorferi , Ixodes , Lyme Disease , Anaplasma phagocytophilum/genetics , Animals , Humans , Washington/epidemiologyABSTRACT
Coccidioidomycosis is an emerging fungal infection in Washington, USA, and the epidemiology of the disease in this state is poorly understood. We used whole-genome sequencing to differentiate locally acquired cases in Washington on the basis of the previously identified phylogeographic population structure of Coccidioides spp. Clinical isolates from coccidioidomycosis cases involving possible Washington soil exposure were included. Of 17 human infections with epidemiologic evidence of possible local acquisition, 4 were likely locally acquired infections and 13 were likely acquired outside Washington. Isolates from locally acquired cases clustered within the previously established Washington clade of C. immitis. Genetic differences among these strains suggest multiple environmental reservoirs of C. immitis in the state.
Subject(s)
Coccidioides/genetics , Coccidioidomycosis/epidemiology , Coccidioidomycosis/microbiology , Genome, Bacterial , Whole Genome Sequencing , Coccidioides/classification , Coccidioides/isolation & purification , Computational Biology/methods , Genomics/methods , Humans , Phylogeny , Polymorphism, Single Nucleotide , Public Health Surveillance , Washington/epidemiologySubject(s)
Autopsy , Phoca , Tularemia , Tularemia/diagnosis , Animals , Humans , Washington/epidemiology , Male , Francisella tularensis/isolation & purificationABSTRACT
The often-noted and persistent increased incidence of Escherichia coli O157:H7 infections in rural areas is not well understood. We used a cohort of E. coli O157:H7 cases reported in Washington, USA, during 2005-2014, along with phylogenomic characterization of the infecting isolates, to identify geographic segregation of and temporal trends in specific phylogenetic lineages of E. coli O157:H7. Kernel estimation and generalized additive models demonstrated that pathogen lineages were spatially segregated during the period of analysis and identified a focus of segregation spanning multiple, predominantly rural, counties for each of the main clinical lineages, Ib, IIa, and IIb. These results suggest the existence of local reservoirs from which humans are infected. We also noted a secular increase in the proportion of lineage IIa and IIb isolates. Spatial segregation by phylogenetic lineage offers the potential to identify local reservoirs and intervene to prevent continued transmission.
Subject(s)
Escherichia coli Infections/epidemiology , Escherichia coli Infections/microbiology , Escherichia coli O157/genetics , Adolescent , Adult , Child , Child, Preschool , Demography , Female , Humans , Male , Middle Aged , Phylogeny , Risk Factors , Time Factors , Washington/epidemiology , Young AdultABSTRACT
BACKGROUND: The veracity of the association between antibiotic use and hemolytic uremic syndrome (HUS) caused by Escherichia coli O157:H7 has been a topic of debate. We postulated that criteria used to define HUS affect this association. METHODS: We reviewed 471 hospitalized E. coli O157:H7 cases reported in Washington State, 2005-2014, to determine HUS status by various case definitions and antibiotic treatment. We used age-adjusted logistic regression models to estimate the effect of treatment on HUS status according to four common, but heterogeneous, definitions: the Council of State and Territorial Epidemiologists (CSTE) definition, hematology-focused and age-focused definitions from the literature, and hospital diagnosis. RESULTS: Inter-annual variation in antibiotic use was high, but no meaningful change in antibiotic use was observed over this ten-year period. Thirteen percent of cases <18 years-old received antibiotics, compared to 54% of cases ≥18 years-old. The CSTE, hematology-focused, age-focused, and hospital diagnosis definitions identified 149, 57, 74, and 89 cases of HUS, respectively. The association between antibiotic treatment and HUS varied by definition: CSTE odds ratio (OR) 1.57 [95% confidence interval (CI) 0.98, 2.55]; hematology-focused OR 1.73 (95% CI 0.83, 3.54); age-focused OR 2.29 (95% CI 1.20, 4.39); and hospital diagnosis OR 1.94 (95% CI 1.01, 3.72). CONCLUSIONS: Each definition yielded an estimate of the association in the direction of increased risk of HUS with antibiotics. While the range of OR point estimates was relatively small, confidence intervals for two HUS definitions crossed the null and two did not, potentially altering the inference an investigator makes. Discrepant reports of the association between antibiotic use and HUS in the literature might be due in part to the choice of HUS definition, and a consistent definition of HUS should be adopted for research and public health purposes.
Subject(s)
Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Escherichia coli Infections/complications , Escherichia coli Infections/drug therapy , Escherichia coli O157/isolation & purification , Hemolytic-Uremic Syndrome/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Diagnosis, Differential , Escherichia coli Infections/epidemiology , Female , Hemolytic-Uremic Syndrome/chemically induced , Hemolytic-Uremic Syndrome/diagnosis , Hemolytic-Uremic Syndrome/epidemiology , Humans , Infant , Infant, Newborn , Male , Middle Aged , Odds Ratio , Practice Guidelines as Topic , Retrospective Studies , Washington/epidemiology , Young AdultABSTRACT
BACKGROUND: Multiple case definitions for post-diarrheal hemolytic uremic syndrome (D+ HUS) associated with Shiga toxin-producing Escherichia coli (STEC) are used across public health, research, and clinical practice. METHODS: To identify a single definition of D+ HUS for standardized use, we evaluated the comparability and validity of four common, heterogeneous definitions: the Council of State and Territorial Epidemiologists (CSTE) definition, hematology-focused and age-focused definitions from the literature, and hospital diagnosis. We reviewed medical records from 471 hospitalized E. coli O157:H7 cases reported in Washington State, 2005-2014. We assessed 1) reliability across definitions, 2) comparability of temporal trends, and 3) sensitivity and specificity using an omnibus reference standard, developed using a combination of definition agreement and clinical outcomes. With the standard, we classified cases as definite, borderline, or unlikely/not post-diarrheal D+ HUS. RESULTS: Reliability was highest between the age-focused definition and hospital diagnosis (κ = 0.84), and temporal trends were largely comparable across definitions. For definite D+ HUS cases, the age-focused definition had the highest overall validity [100% sensitivity, 95% confidence interval (CI): 94%, 100%; 96% specificity, 95% CI: 94%, 98%]. The CSTE definition had low specificity (75%, 95% CI: 70%, 79%). CONCLUSIONS: In this review, the CSTE definition overestimated the burden of D+ HUS, and the age-focused definition provided the best overall reliability and validity to define post-diarrheal D+ HUS. Disease monitoring and research activities should consider using the age-focused D+ HUS definition.
Subject(s)
Diarrhea/complications , Escherichia coli Infections/complications , Escherichia coli O157/isolation & purification , Hemolytic-Uremic Syndrome/diagnosis , Hemolytic-Uremic Syndrome/etiology , Diagnosis, Differential , Diarrhea/epidemiology , Female , Hemolytic-Uremic Syndrome/epidemiology , Humans , Incidence , Male , Practice Guidelines as Topic , Retrospective Studies , Sensitivity and Specificity , Shiga-Toxigenic Escherichia coli/isolation & purification , Washington/epidemiologyABSTRACT
Idiopathic granulomatous mastitis (IGM) is a benign, frequently severe chronic inflammatory lesion of the breast. Its etiology remains unknown and reported cases vary in their presentation and histologic findings with an optimal treatment algorithm yet to be described owing mainly to the disease's heterogeneity. IgG4-related disease (IgG4-RD) is a newly recognized systemic fibroinflammatory condition characterized by a dense lymphoplasmacytic infiltrate with many IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Immunosuppressive therapy is considered to be an effective first-line therapy for IgG4-RD. We sought to clarify and classify chronic mastitis according to the histologic findings of IgG4-RD mastitis with respect to IGM and to develop a robust diagnostic framework to help select patients for optimal treatment strategies. Using the largest collection to date (43 cases from Egypt and Morocco), we show that despite sharing many features, IGM and IgG4-RD mastitis are separate diseases. To diagnostically separate the diseases, we created a classification schema-termed the Michigan Classification-based upon our large series of cases, the consensus statement on IgG4-RD, and the histologic description of IGM in the literature. Using our classification, we discerned 17 cases of IgG4-RD and 8 cases of IGM among the 43 chronic mastitis cases, with 18 indeterminate cases. Thus, our Michigan Classification can form the basis of rational stratification of chronic mastitis patients between these two clinically and histopathologically heterogeneous diseases.
Subject(s)
Breast Diseases/etiology , Breast Diseases/pathology , Granulomatous Mastitis/diagnosis , Granulomatous Mastitis/etiology , Adolescent , Adult , Breast Diseases/diagnosis , Breast Diseases/drug therapy , Chronic Disease , Egypt , Female , Granulomatous Mastitis/pathology , Humans , Immunoglobulin G/blood , Immunosuppressive Agents/therapeutic use , Middle Aged , Morocco , Plasma Cells/immunology , Retrospective Studies , Young AdultABSTRACT
CONTEXT: Health care providers are required to report newly diagnosed notifiable conditions including the case's vital status according to state regulations, but it is uncertain how many cases remain unreported. Death certificates could potentially serve as a data source for detecting unreported deaths due to notifiable conditions. OBJECTIVE: We sought to evaluate the usefulness of electronic death records to augment notifiable conditions reporting in Washington State. DESIGN: Cross-sectional study. SETTING: All residents of Washington State. PARTICIPANTS: Decedents from 2010-2012. MAIN OUTCOME MEASURES: Total number of fatal cases of acute infectious notifiable conditions in Washington residents estimated by capture-recapture analysis, proportion of estimated fatal cases reported to Washington's notifiable conditions database (Public Health Issue Management System [PHIMS]), and the proportion of estimated fatal cases identified solely from the death records. Information was obtained by searching multiple cause-of death fields on 2010-2012 death records for keywords for acute infectious notifiable conditions. RESULTS: Capture-recapture analysis estimated 317 fatal cases of these conditions could be expected over the 3 years studied (95% CI: 276,358). Public Health Issue Management System alone identified 38% of total estimated cases; using PHIMS and death record data increased identification to 71%. Electronic filing of death records was very timely, with a median of 4 days to visibility. Death record data were highly complete. CONCLUSIONS: Use of death records will augment the notifiable condition reporting system and potentially improve mortality estimates and disease control.
Subject(s)
Death Certificates , Disease Notification/methods , Population Surveillance/methods , Adolescent , Adult , Child , Child, Preschool , Communicable Diseases/epidemiology , Cross-Sectional Studies , Female , Humans , Infant , Male , Middle Aged , Retrospective Studies , Time Factors , Washington/epidemiology , Young AdultABSTRACT
Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.
Subject(s)
COVID-19 , SARS-CoV-2 , Selection, Genetic , Humans , Phylogeny , SARS-CoV-2/genetics , Viral Proteins/genetics , Selection, Genetic/geneticsABSTRACT
Chlamydia psittaci is a bacterium that causes chlamydiosis in birds and can cause zoonotic psittacosis in people. In November 2017, we received notification of a suspected case of avian chlamydiosis in a captive cockatiel (Nymphicus hollandicus) that was sold by an online pet bird retail and breeding facility in Washington State. We describe the investigation with emphasis on how environmental sampling was used to guide veterinary and public health interventions. Bird samples were collected either from pooled droppings, pooled plumage or individual nasal and choanal swabs. Environmental samples were obtained by swabbing cleaning mops, tables and cage structures. All samples were tested by polymerase chain reaction and positive samples underwent genotyping. Approximately 1000 birds representing four taxonomic orders were kept within an open-space warehouse. Eight of 14 environmental samples and one of two pooled faecal samples were positive for Chlamydia spp. The contaminating strain of Chlamydia spp. was identified as genotype A. The facility was closed for environmental disinfection, and all psittacines were treated with oral doxycycline for 45 days. Ten of 10 environmental and two of two pooled faecal samples were negative for C. psittaci 11 months after the completion of environmental disinfection and antimicrobial treatment. This investigation highlights the importance of preventing and mitigating pathogen incursion in an online pet retail and breeding facility. Environmental sampling is valuable to guide animal and public health interventions for control of C. psittaci, particularly when large numbers of birds are exposed to the pathogen.
Subject(s)
Bird Diseases , Chlamydophila psittaci , Psittacosis , Animals , Psittacosis/veterinary , Psittacosis/microbiology , Bird Diseases/microbiology , Birds , Chlamydophila psittaci/genetics , DoxycyclineABSTRACT
Despite the wealth of knowledge regarding the mechanisms of action and the mechanisms of resistance to azole antifungals, very little is known about how the azoles are imported into pathogenic fungal cells. Here the in-vitro accumulation and import of Fluconazole (FLC) was examined in the pathogenic fungus, Candida albicans. In energized cells, FLC accumulation correlates inversely with expression of ATP-dependent efflux pumps. In de-energized cells, all strains accumulate FLC, suggesting that FLC import is not ATP-dependent. The kinetics of import in de-energized cells displays saturation kinetics with a K(m) of 0.64 µM and V(max) of 0.0056 pmol/min/108 cells, demonstrating that FLC import proceeds via facilitated diffusion through a transporter rather than passive diffusion. Other azoles inhibit FLC import on a mole/mole basis, suggesting that all azoles utilize the same facilitated diffusion mechanism. An analysis of related compounds indicates that competition for azole import depends on an aromatic ring and an imidazole or triazole ring together in one molecule. Import of FLC by facilitated diffusion is observed in other fungi, including Cryptococcus neoformans, Saccharomyces cerevisiae, and Candida krusei, indicating that the mechanism of transport is conserved among fungal species. FLC import was shown to vary among Candida albicans resistant clinical isolates, suggesting that altered facilitated diffusion may be a previously uncharacterized mechanism of resistance to azole drugs.
Subject(s)
Candida albicans/drug effects , Candidiasis/drug therapy , Cryptococcosis/drug therapy , Cryptococcus neoformans/drug effects , Fluconazole/pharmacology , Saccharomyces cerevisiae/drug effects , Antifungal Agents/pharmacology , Candida albicans/isolation & purification , Candida albicans/pathogenicity , Candidiasis/genetics , Candidiasis/microbiology , Cryptococcosis/genetics , Cryptococcosis/microbiology , Cryptococcus neoformans/genetics , Cryptococcus neoformans/pathogenicity , Diffusion , Drug Resistance, Fungal/drug effects , Drug Resistance, Fungal/genetics , Gene Deletion , Humans , Oxygen/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/pathogenicityABSTRACT
SARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape.