Epidemiological, clinical, and genomic landscape of coccidioidomycosis in northeastern Brazil.

Coccidioidomycosis, listed as a priority mycosis by the WHO, is endemic in the United States but often overlooked in Central and South America. Employing a multi-institutional approach, we investigate how disease characteristics, pathogen genetic variation, and environmental factors impact coccidioidomycosis epidemiology and outcomes in South America. We identified 292 cases (1978-2021) and 42 outbreaks in Piauí and Maranhão states, Brazil, the largest series outside the US/Mexico epidemic zone. The male-to-female ratio was 57.4:1 and the most common activity was armadillo hunting (91.1%) 4 to 30 days before symptom onset. Most patients (92.8%) exhibited typical acute pulmonary disease, with cough (93%), fever (90%), and chest pain (77%) as predominant symptoms. The case fatality rate was 8%. Our negative binomial regression model indicates that reduced precipitation levels in the current (p = 0.015) and preceding year (p = 0.001) predict heightened incidence. Unlike other hotspots, acidic soil characterizes this region. Brazilian strains differ genomically from other C. posadasii lineages. Northeastern Brazil presents a distinctive coccidioidomycosis profile, with armadillo hunters facing elevated risks. Low annual rainfall emerges as a key factor in increasing cases. A unique C. posadasii lineage in Brazil suggests potential differences in environmental, virulence, and/or pathogenesis traits compared to other Coccidioides genotypes.

Tracing histoplasmosis genomic epidemiology and species occurrence across the USA.

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.

Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection.

Serine proteases (SP), including furin, trypsin, and TMPRSS2 cleave the SARS-CoV-2 spike (S) protein, enabling the virus to enter cells. Here, we show that factor (F) Xa, an SP involved in blood coagulation, is upregulated in COVID-19 patients. In contrast to other SPs, FXa exerts antiviral activity. Mechanistically, FXa cleaves S protein, preventing its binding to ACE2, and thus blocking viral entry and infection. However, FXa is less effective against variants carrying the D614G mutation common in all pandemic variants. The anticoagulant rivaroxaban, a direct FXa inhibitor, inhibits FXa-mediated S protein cleavage and facilitates viral entry, whereas the indirect FXa inhibitor fondaparinux does not. In the lethal SARS-CoV-2 K18-hACE2 model, FXa prolongs survival yet its combination with rivaroxaban but not fondaparinux abrogates that protection. These results identify both a previously unknown function for FXa and an associated antiviral host defense mechanism against SARS-CoV-2 and suggest caution in considering direct FXa inhibitors for preventing or treating thrombotic complications in COVID-19 patients.

Combating the Dust Devil: Utilizing Naturally Occurring Soil Microbes in Arizona to Inhibit the Growth of Coccidioides spp., the Causative Agent of Valley Fever.

The fungal disease Valley fever causes a significant medical and financial burden for affected people in the endemic region, and this burden is on the rise. Despite the medical importance of this disease, little is known about ecological factors that influence the geographic point sources of high abundance of the pathogens Coccidioides posadasii and C. immitis, such as competition with co-occurring soil microbes. These "hot spots", for instance, those in southern Arizona, are areas in which humans are at greater risk of being infected with the fungus due to consistent exposure. The aim of this study was to isolate native microbes from soils collected from Tucson, Arizona (endemic area for C. posadasii) and characterize their relationship (antagonistic, synergistic, or neutral) to the fungal pathogen with in vitro challenge assays. Secreted metabolites from the microbes were extracted and described using analytical techniques including high-performance liquid chromatography (HPLC) and mass spectrometry. Bacteria belonging to the genus Bacillus and fungi in the Fennellomyces and Ovatospora genera were shown to significantly decrease the growth of Coccidioides spp. In vitro. In contrast, other bacteria in the Brevibacillus genus, as well as one species of Bacillus bacteria, were shown to promote growth of Coccidioides when directly challenged. The metabolites secreted from the antagonistic bacteria were described using HPLC and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The microbes identified in this study as antagonists to Coccidioides and/or the metabolites they secrete have the potential to be used as natural biocontrol agents to limit the amount of fungal burden at geographic point sources, and therefore limit the potential for human infection.

Coccidioidomycosis in Northern Arizona: an Investigation of the Host, Pathogen, and Environment Using a Disease Triangle Approach.

Coccidioides immitis and Coccidioides posadasii are the etiological agents of coccidioidomycosis (Valley fever [VF]). Disease manifestation ranges from mild pneumonia to chronic or extrapulmonary infection. If diagnosis is delayed, the risk of severe disease increases. In this report, we investigated the intersection of pathogen, host, and environment for VF cases in Northern Arizona (NAZ), where the risk of acquiring the disease is much lower than in Southern Arizona. We investigated reported cases and assessed pathogen origin by comparing genomes of NAZ clinical isolates to isolates from other regions. Lastly, we surveyed regional soils for presence of Coccidioides. We found that cases of VF increased in NAZ in 2019, and Coccidioides NAZ isolates are assigned to Arizona populations using phylogenetic inference. Importantly, we detected Coccidioides DNA in NAZ soil. Given recent climate modeling of the disease that predicts that cases will continue to increase throughout the region, and the evidence presented in this report, we propose that disease awareness outreach to clinicians throughout the western United States is crucial for improving patient outcomes, and further environmental sampling across the western U.S. is warranted. IMPORTANCE Our work is the first description of the Valley fever disease triangle in Northern Arizona, which addresses the host, the pathogen, and the environmental source in the region. Our data suggest that the prevalence of diagnosed cases rose in 2019 in this region, and some severe cases necessitate hospitalization. We present the first evidence of Coccidioides spp. in Northern Arizona soils, suggesting that the pathogen is maintained in the local environment. Until disease prevention is an achievable option via vaccination, we predict that incidence of Valley fever will rise in the area. Therefore, enhanced awareness of and surveillance for coccidioidomycosis is vital to community health in Northern Arizona.

PM10 and Other Climatic Variables Are Important Predictors of Seasonal Variability of Coccidioidomycosis in Arizona.

Coccidioidomycosis (Valley fever) is a disease caused by the fungal pathogens Coccidioides immitis and Coccidioides posadasii that are endemic to the southwestern United States and parts of Mexico and South America. Throughout the range where the pathogens are endemic, there are seasonal patterns of infection rates that are associated with certain climatic variables. Previous studies that looked at annual and monthly relationships of coccidioidomycosis and climate suggest that infection numbers are linked with precipitation and temperature fluctuations; however, these analytic methods may miss important nonlinear, nonmonotonic seasonal relationships between the response (Valley fever cases) and explanatory variables (climate) influencing disease outbreaks. To improve our current knowledge and to retest relationships, we used case data from three counties of high endemicity in southern Arizona paired with climate data to construct a generalized additive statistical model that explores which meteorological parameters are most useful in predicting Valley fever incidence throughout the year. We then use our model to forecast the pattern of Valley fever cases by month. Our model shows that maximum monthly temperature, average PM10, and total precipitation 1 month prior to reported cases (lagged model) were all significant in predicting Valley fever cases. Our model fits Valley fever case data in the region of endemicity of southern Arizona and captures the seasonal relationships that predict when the public is at higher risk of being infected. This study builds on and retests relationships described by previous studies regarding climate variables that are important for predicting risk of infection and understanding this fungal pathogen. IMPORTANCE The inhalation of environmental infectious propagules from the fungal pathogens Coccidioides immitis and Coccidioides posadasii by susceptible mammals can result in coccidioidomycosis (Valley fever). Arizona is known to be a region where the pathogen is hyperendemic, and reported cases are increasing throughout the western United States. Coccidioides spp. are naturally occurring fungi in arid soils. Little is known about ecological factors that influence the growth of these fungi, and a higher environmental burden may result in increases in human exposure and therefore case rates. By examining case and climate data from Arizona and using generalized additive statistical models, we were able to examine the relationship between disease outbreaks and climatic variables and predict seasonal time points of increased infection risk.

Agricultural practices drive biological loads, seasonal patterns and potential pathogens in the aerobiome of a mixed-land-use dryland.

Air carries a diverse load of particulate microscopic biological matter in suspension, either aerosolized or aggregated with dust particles, the aerobiome, which is dispersed by winds from sources to sinks. The aerobiome is known to contain microbes, including pathogens, as well as debris or small-sized propagules from plants and animals, but its variability and composition has not been studied comprehensibly. To gain a dynamic insight into the aerobiome existing over a mixed-use dryland setting, we conducted a biologically comprehensive, year-long survey of its composition and dynamics for particles less than 10 µm in diameter based on quantitative analyses of DNA content coupled to genomic sequencing. Airborne biological loads were more dependent on seasonal events than on meteorological conditions and only weakly correlated with dust loads. Core aerobiome species could be understood as a mixture of high elevation (e.g. Microbacteriaceae, Micrococcaceae, Deinococci), and local plant and soil sources (e.g. Sphingomonas, Streptomyces, Acinetobacter). Despite the mixed used of the land surrounding the sampling site, taxa that contributed to high load events were largely traceable to proximal agricultural practices like cotton and livestock farming. This included not only the predominance of specific crop plant signals over those of native vegetation, but also that of their pathogens (bacterial, viral and eukaryotic). Faecal bacterial loads were also seasonally important, possibly sourced in intensive animal husbandry or manure fertilization activity, and this microbial load was enriched in tetracycline resistance genes. The presence of the native opportunistic pathogen, Coccidioides spp., by contrast, was detected only with highly sensitive techniques, and only rarely. We conclude that agricultural activity exerts a much stronger influence that the native vegetation as a mass loss factor to the land system and as an input to dryland aerobiomes, including in the dispersal of plant, animal and human pathogens and their genetic resistance characteristics.

Investigating the Role of Animal Burrows on the Ecology and Distribution of Coccidioides spp. in Arizona Soils.

The lack of knowledge regarding the ecology of Coccidioides spp. makes both modeling the potential for disease outbreaks and predicting the distribution of the organism in the environment challenging. No single ecological parameter explains the biogeography of the pathogen. Previous investigations suggest an association with desert mammals, but these results should be confirmed with modern molecular techniques. Therefore, we used molecular tools to analyze soils associated with animal activity (i.e., burrows) to better define the ecology and biogeography of Coccidioides spp. in Arizona. Soils were collected from locations predicted to have favorable habitat outside of the established endemic regions to better understand the ecological niche of the organism in this state. Our central hypothesis is that soils taken from within animal burrows will have a higher abundance of Coccidioides spp. when compared to soils not directly associated with animal burrows. Our results show that there is a positive relationship with Coccidioides spp. and animal burrows. The organism was detected in two locations in northern Arizona at sites not known previously to harbor the fungus. Moreover, this fungus is able to grow on keratinized tissues (i.e., horse hair). These results provide additional evidence that there is a relationship between Coccidioides spp. and desert animals, which sheds new light on Coccidioides' ecological niche. These results also provide evidence that the geographic range of the organism may be larger than previously thought, and the concept of endemicity should be reevaluated for Coccidioides.

The mysterious desert dwellers: Coccidioides immitis and Coccidioides posadasii, causative fungal agents of coccidioidomycosis.

The genus Coccidioides consists of two species: C. immitis and C. posadasii. Prior to 2000, all disease was thought to be caused by a single species, C. immitis. The organism grows in arid to semiarid alkaline soils throughout western North America and into Central and South America. Regions in the United States, with highest prevalence of disease, include California, Arizona, and Texas. The Mexican states of Baja California, Coahuila, Sonora, and Neuvo Leon currently have the highest skin test positive results. Central America contains isolated endemic areas in Guatemala and Honduras. South America has isolated regions of high endemicity including areas of Colombia, Venezuela, Argentina, Paraguay, and Brazil. Although approximately 15,000 cases per year are reported in the United States, actual disease burden is estimated to be in the hundreds of thousands, as only California and Arizona have dedicated public health outreach, and report and track disease reliably. In this review, we survey genomics, epidemiology, ecology, and summarize aspects of disease, diagnosis, prevention, and treatment.