Discovery of highly reactive self-splicing group II introns within the mitochondrial genomes of human pathogenic fungi.

Fungal pathogens represent an expanding global health threat for which treatment options are limited. Self-splicing group II introns have emerged as promising drug targets, but their development has been limited by a lack of information on their distribution and architecture in pathogenic fungi. To meet this challenge, we developed a bioinformatic workflow for scanning sequence data to identify unique RNA structural signatures within group II introns. Using this approach, we discovered a set of ubiquitous introns within thermally dimorphic fungi (genera of Blastomyces, Coccidioides and Histoplasma). These introns are the most biochemically reactive group II introns ever reported, and they self-splice rapidly under near-physiological conditions without protein cofactors. Moreover, we demonstrated the small molecule targetability of these introns by showing that they can be inhibited by the FDA-approved drug mitoxantrone in vitro. Taken together, our results highlight the utility of structure-based informatic searches for identifying riboregulatory elements in pathogens, revealing a striking diversity of reactive self-splicing introns with great promise as antifungal drug targets.

Disseminated coccidioidomycosis in immunocompetent patients in non-endemic areas: a case series and literature review.

Coccidioidomycosis is caused by the dimorphic fungi Coccidioides species which is endemic in the Western hemisphere. Reports on the characteristics of travel-related disseminated coccidioidomycosis in immunocompetent patients are rare, especially in non-endemic regions. The multifaceted symptoms of this condition present a diagnostic challenge to clinicians. This study aimed to review immunocompetent patients diagnosed with disseminated coccidioidomycosis in a tertiary hospital in Eastern China and other non-endemic areas, and to emphasize the importance of combining travel history with clinical manifestations and proper diagnostic examinations. This study retrospectively reviewed a case series of disseminated coccidioidomycosis diagnosed in an academic hospital in Eastern China. We conducted a global literature review of disseminated coccidioidomycosis in immunocompetent patients with travel history. We identified six patients in our case series and reviewed 42 cases in the literature. Travel history included Mexico, Arizona, California, and regions of low endemicity. Extrapulmonary sites of infection, which presented with diverse signs and symptoms, involved the skin and soft tissue, musculoskeletal system, lymph nodes, and central nervous system. Misdiagnoses and diagnostic delays were common. Next-generation sequencing substantially promoted precise diagnosis in our series. The overall prognosis for immunocompetent individuals was positive, mainly benefited from long-term azole therapies. The patients that succumbed had either central nervous system involvement or multiorgan dissemination. Progressive pneumonia with varied symptoms and travel history should alert healthcare professionals in non-endemic areas to consider the possibility of Coccidioides species infection. We recommend detailed history-taking and hypothesis-free detection of pathogens for cases with diagnostic delay.

Early Events in Coccidioidomycosis.

Since its description nearly 130 years ago, hundreds of studies have deepened our understanding of coccidioidomycosis, also known as valley fever (VF), and provided useful diagnostic tests and treatments for the disease caused by the dimorphic fungi Coccidioides spp. In general, most of the literature has addressed well-established infections and has described patients who have experienced major complications. In contrast, little attention has been given to the earliest consequences of the pathogen-host interaction and its implications for disease manifestation, progression, and resolution. The purpose of this review is to highlight published studies on early coccidioidomycosis, identify gaps in our knowledge, and suggest new or former research areas that might be or remain fertile ground for insight into the early stages of this invasive fungal disease.

Risk factors and outcomes of culture-proven acute Coccidioides spp. infection in San Diego, California, United States.

BACKGROUND: Coccidioides spp. are dimorphic fungi endemic to parts of the United States, Mexico, Central and South America. Infection can cause a range of disease from self-limited acute pneumonia to severe disseminated disease. METHODS: We performed a retrospective chart review of medical records of cases of culture-proven acute coccidioidomycosis at the University of California San Diego between 1 April 2015 and 31 December 2019 and described the demographics, risk factors and outcomes of these cases. RESULTS: Over the study period, fifteen evaluable cases of culture-proven acute coccidioidomycosis were identified. Of these, 87% (13/15) had traditional risk factors for coccidioidomycosis infection while two lacked known risk factors, including one patient with cirrhosis and one with chronic hepatitis C infection. Seven of fifteen (47%) had primary coccidioidomycosis of the lungs without dissemination and 7/15 (47%) disseminated disease. Of those with disseminated disease, 6/7 (86%) had either high-risk ethnicity or blood type as their only risk factor. At 90 days, 11/15 (73%) were alive, 3/15 (20%) deceased and 1/15 (7%) lost to follow-up. Of those not alive at 90 days, 1/3 (33%) had disseminated disease and 2/3 (67%) primary coccidioidomycosis, both on immunosuppressive therapy. DISCUSSION: Coccidioides spp. infection occurs in a variety of hosts with varying underlying risk factors, with the majority in our cohort overall and 86% with disseminated disease lacking traditional risk factors for invasive fungal infection other than ethnicity and/or blood phenotype. Clinicians should be aware of these non-traditional risk factors in patients with coccidioidomycosis infection.

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.

Autochthonous Transmission of Coccidioides in Animals, Washington, USA.

We report 5 cases of coccidioidomycosis in animals that were acquired within Washington, USA, and provide further evidence for the environmental endemicity of Coccidioides immitis within the state. Veterinarians should consider coccidioidomycosis in animals with compatible clinical signs that reside in, or have traveled to, south central Washington.

The endozoan, small-mammal reservoir hypothesis and the life cycle of Coccidioides species.

The prevailing hypothesis concerning the ecology of Coccidioides immitis and C. posadasii is that these human pathogenic fungi are soil fungi endemic to hot, dry, salty regions of the New World and that humans and the local, small-mammal fauna are only accidental hosts. Here we advance an alternative hypothesis that Coccidioides spp. live in small mammals as endozoans, which are kept inactive but alive in host granulomas and which transform into spore-producing hyphae when the mammal dies. The endozoan hypothesis incorporates results from comparative genomic analyses of Coccidioides spp. and related taxa that have shown a reduction in gene families associated with deconstruction of plant cell walls and an increase in those associated with digestion of animal protein, consistent with an evolutionary shift in substrate from plants to animals. If true, the endozoan hypothesis requires that models of the prevalence of human coccidioidomycosis account not only for direct effects of climate and soil parameters on the growth and reproduction of Coccidioides spp. but also consider indirect effects on these fungi that come from the plants that support the growth and reproduction of the small mammals that, in turn, support these endozoic fungi.

A Coccidioides posadasii CPS1 Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection.

The CPS1 gene was identified as a virulence factor in the maize pathogen Cochliobolus heterostrophus Hypothesizing that the homologous gene in Coccidioides posadasii could be important for virulence, we created a Δcps1 deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,γc(null) [NSG]). Only a single colony was recovered from 1 of 60 C57BL/6 mice following intranasal infections of up to 4,400 spores. Following administration of very high doses (10,000 to 2.5 × 10(7) spores) to NSG and BALB/c mice, spherules were observed in lung sections at time points from day 3 to day 10 postinfection, but nearly all appeared degraded with infrequent endosporulation. Although the role of CPS1 in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in the Δcps1 strain versus C. posadasii is consistent with both metabolic and regulatory functions for the gene. The in vitro phenotype of the Δcps1 strain showed slower growth of mycelia with delayed and lower spore production than C. posadasii, and in vitro spherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Δcps1 spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of <1,000 CFU from an otherwise lethal C. posadasii intranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance to C. posadasii infection when used as a vaccine, the Δcps1 strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals.

Card9- and MyD88-Mediated Gamma Interferon and Nitric Oxide Production Is Essential for Resistance to Subcutaneous Coccidioides posadasii Infection.

Coccidioidomycosis is a potentially life-threatening respiratory disease which is endemic to the southwestern United States and arid regions of Central and South America. It is responsible for approximately 150,000 infections annually in the United States alone. Almost every human organ has been reported to harbor parasitic cells of Coccidioides spp. in collective cases of the disseminated form of this mycosis. Current understanding of the mechanisms of protective immunity against lung infection has been largely derived from murine models of pulmonary coccidioidomycosis. However, little is known about the nature of the host response to Coccidioides in extrapulmonary tissue. Primary subcutaneous coccidioidal infection is rare but has been reported to result in disseminated disease. Here, we show that activation of MyD88 and Card9 signal pathways are required for resistance to Coccidioides infection following subcutaneous challenge of C57BL/6 mice, which correlates with earlier findings of the protective response to pulmonary infection. MyD88(-/-) andCard9(-/-) mice recruited reduced numbers of T cells, B cells, and neutrophils to the Coccidioides-infected hypodermis com pared to wild-type mice; however, neutrophils were dispensable for resistance to skin infection. Further studies have shown that gamma interferon (IFN-γ) production and activation of Th1 cells characterize resistance to subcutaneous infection. Furthermore, activation of a phagosomal enzyme, inducible nitric oxide synthase, which is necessary for NO production, is a requisite for fungal clearance in the hypodermis. Collectively, our data demonstrate that MyD88- and Card9-mediated IFN-γ and nitric oxide production is essential for protection against subcutaneous Coccidioides infection.

The habitat of Coccidioides spp. and the role of animals as reservoirs and disseminators in nature.

BACKGROUND: Coccidioidomycosis, a potentially fatal fungal infection, is considered an emergent mycotic disease because of the increased incidence of fungal infections registered over recent years. Infection occurs through the inhalation of arthroconidia from two main species of Coccidioides: Coccidioides immitis and C. posadasii, which are both endemic to arid and semi-arid regions of North America. Coccidioides species not only infect humans but can also infect other mammals (land, aquatic, wild or domestic), reptiles and birds. OBJECTIVE: To obtain information regarding the habitat of Coccidioides spp. and the animals infected by this fungus and to identify the role that infected animals play as reservoirs and disseminators of this fungus in nature. MATERIALS: A literature review was conducted to identify the habitat of Coccidioides spp. and the infected non-human animal species targeted by this fungus. RESULTS AND CONCLUSIONS: This review allows us to suggest that Coccidioides spp. may be classified as halotolerant organisms; nevertheless, to perpetuate their life cycle, these organisms depend on different animal species (reservoirs) that serve as a link with the environment, by acting as disseminators of the fungi in nature.

MAGNETIC RESONANCE IMAGING FEATURES AND OUTCOME FOR SOLITARY CENTRAL NERVOUS SYSTEM COCCIDIOIDES GRANULOMAS IN 11 DOGS AND CATS.

Little published information is available to guide therapy for canine and feline patients with Coccidioides infections involving the central nervous system (CNS). The purpose of this cross-sectional retrospective study was to describe magnetic resonance imaging (MRI) features and outcome for a group of dogs and cats with solitary CNS Coccidiodes granulomas. Nine canine and two feline cases met inclusion criteria; four diagnosed and treated with surgery and fluconazole and seven diagnosed by serology or cytology and treated medically. Three cases had left Coccidioides endemic areas long before developing neurological disease. The MRI lesions shared many features with neoplastic masses. The extra-axial granulomas often had a lack of a distinct border between the mass and neural parenchyma. Four cases were extra-axial and seven were intra-axial, but distinguishing between extra-axial and intra-axial locations was sometimes challenging. The surgical cases had good outcomes and histology allowed definitive diagnosis. Medically managed patients also had generally good outcomes, with resolution of clinical signs in most cases. Findings indicated that distinction between neoplasia and focal Coccidioides granulomas based on MRI features is likely to be imprecise. Demonstration of the organism by cytology or histology is required for definitive diagnosis. The role of surgery for improving the outcome of brain or spinal coccidioidomycosis granulomas warrants further study.

Recent advances in our understanding of the environmental, epidemiological, immunological, and clinical dimensions of coccidioidomycosis.

Coccidioidomycosis is the endemic mycosis caused by the fungal pathogens Coccidioides immitis and C. posadasii. This review is a summary of the recent advances that have been made in the understanding of this pathogen, including its mycology, genetics, and niche in the environment. Updates on the epidemiology of the organism emphasize that it is a continuing, significant problem in areas of endemicity. For a variety of reasons, the number of reported coccidioidal infections has increased dramatically over the past decade. While continual improvements in the fields of organ transplantation and management of autoimmune disorders and patients with HIV have led to dilemmas with concurrent infection with coccidioidomycosis, they have also led to advances in the understanding of the human immune response to infection. There have been some advances in therapeutics with the increased use of newer azoles. Lastly, there is an overview of the ongoing search for a preventative vaccine.

Parasitic polymorphism of Coccidioides spp.

BACKGROUND: Coccidioides spp. is the ethiological agent of coccidioidomycosis, an infection that can be fatal. Its diagnosis is complicated, due to that it shares clinical and histopathological characteristics with other pulmonary mycoses. Coccidioides spp. is a dimorphic fungus and, in its saprobic phase, grows as a mycelium, forming a large amount of arthroconidia. In susceptible persons, arthroconidia induce dimorphic changes into spherules/endospores, a typical parasitic form of Coccidioides spp. In addition, the diversity of mycelial parasitic forms has been observed in clinical specimens; they are scarcely known and produce errors in diagnosis. METHODS: We presented a retrospective study of images from specimens of smears with 15% potassium hydroxide, cytology, and tissue biopsies of a histopathologic collection from patients with coccidioidomycosis seen at a tertiary-care hospital in Mexico City. RESULTS: The parasitic polymorphism of Coccidioides spp. observed in the clinical specimens was as follows: i) spherules/endospores in different maturation stages; ii) pleomorphic cells (septate hyphae, hyphae composed of ovoid and spherical cells, and arthroconidia), and iii) fungal ball formation (mycelia with septate hyphae and arthroconidia). CONCLUSIONS: The parasitic polymorphism of Coccidioides spp. includes the following: spherules/endospores, arthroconidia, and different forms of mycelia. This knowledge is important for the accurate diagnosis of coccidioidomycosis. In earlier studies, we proposed the integration of this diversity of forms in the Coccidioides spp. parasitic cycle. The microhabitat surrounding the fungus into the host would favor the parasitic polymorphism of this fungus, and this environment may assist in the evolution toward parasitism of Coccidioides spp.

Does the presence of mediastinal adenopathy confer a risk for disseminated infection in immunocompetent persons with pulmonary coccidioidomycosis?

Pulmonary coccidioidomycosis is caused by inhaling airborne arthroconidia of Coccidioides, a soil-dwelling fungus endemic to the desert southwestern United States. Although uncommon, disseminated coccidioidal infection can be associated with well-defined risk factors, such as cell-mediated immunodeficiency, certain racial heritages (e.g. African or Filipino), male sex, or pregnancy. Before widespread use of computed tomography (CT), the presence or persistence of mediastinal lymphadenopathy was postulated to be a risk factor for disseminated coccidioidal infection. To investigate the use of CT scanning to identify the presence of mediastinal lymphadenopathy in patients with pulmonary coccidioidomycosis, and to correlate such lymphadenopathy with disseminated coccidioidal infection, we performed a retrospective review of patients with pulmonary coccidioidomycosis who were evaluated by chest CT. Two radiologists independently interpreted 150 CT scans from patients with pulmonary coccidioidomycosis. Forty-nine patients met CT criteria for mediastinal lymphadenopathy, whereas 101 patients did not. Disseminated coccidioidal infection was observed in 5 (10%) of the 49 patients with mediastinal lymphadenopathy and in 6 of the 101 (6%; P = .34) without such adenopathy. Among patients with coccidioidomycosis, patients with mediastinal lymphadenopathy, as assessed by CT, had a higher rate of disseminated infection, but the difference was not statistically significant.

Coccidioides releases a soluble factor that suppresses nitric oxide production by murine primary macrophages.

We studied the effect of the presence of Coccidioides on the production of nitric oxide (NO) by primary macrophages previously activated by IFN-γ and LPS. The fungal cells were isolated from cultures of arthroconidia that had been incubated for 24 h in a medium that supported parasitic phase growth and were co-cultured with the macrophages. These live, first-generation parasitic cells of Coccidioides, referred to as spherule initials, suppressed NO production as well as iNOS mRNA expression by activated macrophages. Phagocytosis was not required for suppression of NO. We also showed that the culture supernatant of the spherule initials was capable of suppressing NO production, and that this activity was mediated by an as yet unidentified, secreted fungal factor(s). Heat-, paraformaldehyde- or X-ray-treated spherule initials did not show this inhibitory effect. To our surprise, macrophages obtained from iNOS-deficient mice revealed phagocytic activity and killing efficiency which were comparable to that of macrophages isolated from wild type C57BL/6 mice. Although the cultured fungal pathogen can suppress NO production, this oxidative product is apparently not essential for in vitro killing of Coccidioides by activated macrophages. Our results suggest that other unidentified fungicidal mechanisms exist against Coccidioides which are apparently independent of NO production.

Application of laser capture microdissection and PCR sequencing in the diagnosis of Coccidioides spp. infection: A case report and literature review in China.

Coccidioidomycosis is endemic to California, Arizona, and Mexico. In recent years, the reported cases of coccidioidomycosis have increased in nonendemic regions. Here, we reported a case of imported pulmonary coccidioidomycosis in a Chinese patient. A 63-year-old man presented with dry cough and fatigue for 6 months, and a computed tomography scan revealed a solitary nodule in the right lower lung and small nodules in both lungs. The diagnosis of coccidioidomycosis was initially confirmed by histopathologic examination. The pathogen Coccidioides spp. was identified by laser capture microdissection (LCM) combined with subsequent molecular techniques based on the positive histopathologic features. Additionally, we reviewed 47 reported cases of coccidioidomycosis in China. The number of reported cases is increasing, and the incidence of disseminated infection has exhibited a trend of shifting towards healthy young adults in China. Since clinical presentations and imaging findings lack specificity, a majority of domestic cases of coccidioidomycosis were initially misdiagnosed as tumours or tuberculosis. Moreover, the diagnosis of endemic mycoses may be challenging because of their rarity and the limited availability of diagnostic tests. The diagnosis was mainly confirmed by histopathological examination. The species involved were identified based on positive cultures in only 4 cases. To our knowledge, this is the first study to use LCM and molecular techniques to identify Coccidioides spp. in the histopathologically positive but uncultivable specimen. Comparing with previous reported studies, LCM combined with nucleic acid amplification techniques improve the ability of species identification for the timely diagnosis of coccidioidomycosis.

Charles Edward Smith: Coccidioidomycologist and public health leader.

Although Charles Edward Smith did not discover coccidioidomycosis, he defined the disease through his infatigueable studies of the epidemiology, clinical findings, and immunology of this infection. He became its preeminent authority. He also had an important role in the development of public health, and for the last 16 years of his life he was the Dean of the School of Public Health at the University of California at Berkeley, where he was a revered and energetic leader.

Biosynthesis and role in virulence of the histone deacetylase inhibitor depudecin from Alternaria brassicicola.

Depudecin, an eleven-carbon linear polyketide made by the pathogenic fungus Alternaria brassicicola, is an inhibitor of histone deacetylase (HDAC). A chemically unrelated HDAC inhibitor, HC toxin, was earlier shown to be a major virulence factor in the interaction between Cochliobolus carbonum and its host, maize. In order to test whether depudecin is also a virulence factor for A. brassicicola, we identified the genes for depudecin biosynthesis and created depudecin-minus mutants. The depudecin gene cluster contains six genes (DEP1 to DEP6), which are predicted to encode a polyketide synthase (AbPKS9 or DEP5), a transcription factor (DEP6), two monooxygenases (DEP2 and DEP4), a transporter of the major facilitator superfamily (DEP3), and one protein of unknown function (DEP1). The involvement in depudecin production of DEP2, DEP4, DEP5, and DEP6 was demonstrated by targeted gene disruption. DEP6 is required for expression of DEP1 through DEP5 but not the immediate flanking genes, thus defining a coregulated depudecin biosynthetic cluster. The genes flanking the depudecin gene cluster but not the cluster itself are conserved in the same order in the related fungi Stagonospora nodorum and Pyrenophora tritici-repentis. Depudecin-minus mutants have a small (10%) but statistically significant reduction in virulence on cabbage (Brassica oleracea) but not on Arabidopsis. The role of depudecin in virulence is, therefore, less dramatic than that of HC toxin.

Host-Pathogen Interactions in Coccidioidomycosis: Prognostic Clues and Opportunities for Novel Therapies.

PURPOSE: Coccidioidomycosis (CM) is a systemic fungal disease caused by the dimorphic fungi Coccidioides immitis and Coccidioides posadasii. In its endemic areas of the United States, CM is growing as a public health challenge with a marked increase in incidence in the last 15 years. Although Coccidioides infection is asymptomatic in most cases, symptomatic pulmonary disease occurs in ~40% and disseminated coccidioidomycosis (DCM) occurs in ~1% of previously healthy children and adults. DCM is markedly more common in immunocompromised people, who often experience life-threatening disease despite use of antifungal medications. Although options for antifungal therapy have improved, lifelong therapy is needed for those who develop coccidioidal meningitis. The purpose of this article was to review the state of antifungal therapy and recent studies of host-pathogen interactions in CM in light of advances in immunomodulatory therapy. METHODS: The study included a review of PubMed and abstracts of the Coccidioidomycosis Study Group (years 2000-2019). FINDINGS: Current therapy for CM relies upon azole and polyene antifungal agents. Murine models and studies of DCM in patients with monogenic primary immunodeficiency states and acquired immunodeficiency have revealed the importance of both innate and adaptive immune responses in the control of infections with Coccidioides species. In particular, defects in sensing of fungi and induction of cellular immune responses have been frequently reported. More recently, polymorphisms in key signaling pathways and in the generation of Th17 and Th1 immune responses have been linked with DCM. IMPLICATIONS: Antifungal therapy is sufficient to control disease in most cases of CM, but treatment failure occurs in cases of severe pulmonary disease and nonmeningeal disseminated disease. Lifelong therapy is recommended for meningitis in view of the very high risk of recurrence. Corticosteroid therapy is advised by some experts for severe pulmonary disease and for some neurologic complications of DCM. DCM is only rarely the result of a severe monogenic immunodeficiency. Case studies suggest that reorienting cellular immune responses or augmenting effector immune responses may help resolve DCM. Systematic investigation of immunotherapy for coccidioidomycosis is advisable and may help to address the recent marked increase in reports of the disease in endemic areas.

Coccidioidomycosis in alpacas in the southwestern United States.

An anonymous web-based survey of alpaca owners was used to learn more about the clinical presentation, diagnosis, and treatment of coccidioidomycosis in alpacas in the United States. Thirty-seven owners, with 1,117 alpacas, completed the survey. Over 4% of alpacas included in the study were diagnosed with coccidioidomycosis between 2005 and 2016 (5 post mortem, 46 clinically). Immunodiffusion titers ranged from 1:4 to ≥1:256 in sick animals. Alpacas residing in Arizona counties with a high incidence of human disease were 5.8 times more likely to contract coccidioidomycosis than animals residing in other areas of the state. Treatment was reported in 23 alpacas, and 78% of those animals died or were euthanized. Necropsy records from a veterinary diagnostic laboratory in Tucson, AZ were reviewed to estimate the severity of disease in this species. Nine cases identified for review died of disseminated coccidioidomycosis; the disease was extensive in most animals, with the lungs, lymph nodes, and liver the most frequently affected. Alpacas appear to be highly susceptible to severe illness as a result of infection by Coccidioides spp., frequently resulting in death. More research is needed to better understand the epidemiology, clinical signs, and treatment protocols for coccidioidomycosis in alpacas.