The Host Response to Coccidioidomycosis.

Coccidioidomycosis is an important fungal disease that is found in many desert regions of the western hemisphere. The inhaled organisms are highly pathogenic, but only half of infected, immunologically intact people develop symptomatic pneumonia; most symptomatic infections resolve spontaneously, although some resolve very slowly. Furthermore, second infections are very rare and natural immunity after infection is robust. Therefore, the host response to this organism is very effective at resolving the infection in most cases and immunizing to prevent second infections. People who are immunocompromised are much more likely to develop disseminated infection. This is a comprehensive review of the innate and acquired immune responses to Coccidioides spp., the genetics of resistance to severe infection, and the search for an effective vaccine.

Invasive fungal infections and oomycoses in cats 2. Antifungal therapy.

CLINICAL RELEVANCE: Invasive fungal infections (IFIs) and oomycoses (hereafter termed invasive fungal-like infections [IFLIs]) are characterised by penetration of tissues by fungal elements. The environment is the most common reservoir of infection. IFIs and IFLIs can be frustrating to treat because long treatment times are usually required and, even after attaining clinical cure, there may be a risk of relapse. Owner compliance with medication administration and recheck examinations can also decline over time. In addition, some antifungal drugs are expensive, have variable interpatient pharmacokinetic properties, can only be administered parenterally and/or have common adverse effects (AEs). Despite these limitations, treatment can be very rewarding, especially when an otherwise progressive and fatal disease is cured. AIM: In the second of a two-part article series, the spectrum of activity, mechanisms of action, pharmacokinetic and pharmacodynamic properties, and AEs of antifungal drugs are reviewed, and the treatment and prognosis of specific IFIs/IFLIs - dermatophytic pseudomycetoma, cryptococcosis, sino-orbital aspergillosis, coccidioidomycosis, histoplasmosis, sporotrichosis, phaeohyphomycosis, mucormycosis and oomycosis - are discussed. Part 1 reviewed the diagnostic approach to IFIs and IFLIs. EVIDENCE BASE: Information on antifungal drugs is drawn from pharmacokinetic studies in cats. Where such studies have not been performed, data from 'preclinical' animals (non-human studies) and human studies are reviewed. The review also draws on the wider published evidence and the authors' combined expertise in feline medicine, mycology, dermatology, clinical pathology and anatomical pathology. ABBREVIATIONS FOR ANTIFUNGAL DRUGS: AMB (amphotericin B); FC (flucytosine); FCZ (fluconazole); ISA (isavuconazole); ITZ (itraconazole); KCZ (ketoconazole); PCZ (posaconazole); TRB (terbinafine); VCZ (voriconazole).

Invasive Fungal Infections and Oomycoses in Cats: 1. Diagnostic approach.

CLINICAL RELEVANCE: In contrast to superficial fungal infections, such as dermatophytosis, invasive fungal infections (IFIs) are characterised by penetration of tissues by fungal elements. Disease can spread locally within a region or can disseminate haematogenously or via the lymphatics. The environment is the most common reservoir of infection. Since fungal spores are airborne, indoor cats are also susceptible to IFIs. Some environmental fungi are ubiquitous and present globally, while others are endemic or hyperendemic within specific geographic regions. Zoonotic pathogens include Microsporum canis, Sporothrix schenckii and Sporothrix brasiliensis. AIM: In the first of a two-part article series, the approach to the investigation of feline IFIs and oomycoses is reviewed. As well as tips for diagnosis, and information on the ecological niche and distribution of fungal pathogens, the review covers clinical presentation of the most common IFIs, including cryptococcosis, histoplasmosis, blastomycosis, coccidioidomycosis, sporotrichosis, phaeohyphomycosis, aspergillosis and dermatophytic pseudomycetoma, as well as the oomycoses pythiosis, lagenidiosis and paralagenidiosis. In Part 2, the spectrum of activity, mechanisms of action, pharmacokinetic and pharmacodynamic properties and adverse effects of antifungal drugs are reviewed, and the treatment and prognosis for specific IFIs and oomycoses are discussed. EVIDENCE BASE: The review draws on published evidence and the authors' combined expertise in feline medicine, mycology, dermatology, clinical pathology and anatomical pathology.

Modeling Chronic Coccidioidomycosis in Mice.

Coccidioidomycosis, caused by the dimorphic pathogens Coccidioides posadasii and C. immitis, is a fungal disease endemic to the southwestern United States, Mexico, and some regions of Central and South America. The mouse is the primary model for studying pathology and immunology of disease. Mice in general are extremely susceptible to Coccidioides spp., which creates challenges in studying the adaptive immune responses that are required for host control of coccidioidomycosis. Here, we describe how to infect mice to model asymptomatic infection with controlled, chronic granulomas and a slowly progressive but ultimately fatal infection that has kinetics more similar to the human disease.

Evaluation of Host Constitutive and Ex Vivo Coccidioidal Antigen-Stimulated Immune Response in Dogs with Naturally Acquired Coccidioidomycosis.

The early innate immune response to coccidioidomycosis has proven to be pivotal in directing the adaptive immune response and disease outcome in mice and humans but is unexplored in dogs. The objectives of this study were to evaluate the innate immune profile of dogs with coccidioidomycosis and determine if differences exist based on the extent of infection (i.e., pulmonary or disseminated). A total of 28 dogs with coccidioidomycosis (pulmonary, n = 16; disseminated, n = 12) and 10 seronegative healthy controls were enrolled. Immunologic testing was performed immediately, without ex vivo incubation (i.e., constitutive), and after coccidioidal antigen stimulation of whole blood cultures. Whole blood cultures were incubated with a phosphate-buffered solution (PBS) (negative control) or a coccidioidal antigen (rCTS1 (105-310); 10 µg/mL) for 24 h. A validated canine-specific multiplex bead-based assay was used to measure 12 cytokines in plasma and cell culture supernatant. Serum C-reactive protein (CRP) was measured with an ELISA assay. Leukocyte expression of toll-like receptors (TLRs)2 and TLR4 was measured using flow cytometry. Dogs with coccidioidomycosis had higher constitutive plasma keratinocyte chemotactic (KC)-like concentrations (p = 0.02) and serum CRP concentrations compared to controls (p < 0.001). Moreover, dogs with pulmonary coccidioidomycosis had higher serum CRP concentrations than those with dissemination (p = 0.001). Peripheral blood leukocytes from dogs with coccidioidomycosis produced higher concentrations of tumor necrosis factor (TNF)-α (p = 0.0003), interleukin (IL)-6 (p = 0.04), interferon (IFN)-γ (p = 0.03), monocyte chemoattractant protein (MCP)-1 (p = 0.02), IL-10 (p = 0.02), and lower IL-8 (p = 0.003) in supernatants following coccidioidal antigen stimulation when compared to those from control dogs. There was no detectable difference between dogs with pulmonary and disseminated disease. No differences in constitutive or stimulated leukocyte TLR2 and TLR4 expression were found. These results provide information about the constitutive and coccidioidal antigen-specific stimulated immune profile in dogs with naturally acquired coccidioidomycosis.

Serum 25-hydroxyvitamin D concentrations in dogs with coccidioidomycosis and variables associated with extent of clinically evident disease.

BACKGROUND: Clinicopathologic variables predictive of disseminated coccidioidomycosis are known in humans but have not been explored in dogs. Serum 25-hydroxyvitamin (OH)D correlates with severity of disease of various etiologies in dogs but its role in coccidioidomycosis is unknown. OBJECTIVE: Determine whether serum 25(OH)D concentrations are different in dogs with coccidioidomycosis compared with healthy controls and if clinicopathologic variables are associated with extent of disease. ANIMALS: Thirty-five dogs with coccidioidomycosis (pulmonary, n = 13; disseminated, n = 15; uncharacterized, n = 7), and 25 healthy control dogs. METHODS: Prospective cohort study. Serum 25(OH)D and C-reactive protein (CRP) concentrations were measured with modified-HPLC and a commercial ELISA kit, respectively. RESULTS: There was no difference in 25(OH)D concentrations between dogs with coccidioidomycosis (median, interquartile range [IQR]; 31.9 ng/mL, 23.3-49.2) and controls (29.5 ng/mL, 25.6-40.8, P = .73). Serum 25(OH)D concentration was lower in dogs with coccidioidomycosis and IgG titers ≥1:32 than dogs with titers below this cut-off (P = .02). Dogs with IgG titers ≥1:32 were more likely to have disseminated disease (OR, 7.5; 95% CI: 1.1-68; P = .03). Serum CRP concentrations were higher in dogs with IgG titers ≥1:16 (median, IQR; 4474.8 ng/mL, 2885.8-8236.1) than in those below this cut-off (151.2 ng/mL, 30.4-2907.3; P = .02). There was a significant inverse association between serum 25(OH)D and CRP at 25(OH)D concentrations ≤33 ng/mL. CONCLUSION AND CLINICAL IMPORTANCE: Serum 25(OH)D concentration was lower for dogs with IgG titers ≥1:32, indicating a potential association between semi-quantitative titers and 25(OH)D concentrations in dogs with coccidioidomycosis. IgG titers ≥1:32 yielded higher odds of disseminated disease, but was inadequate as a standalone test to determine form of disease.

Reactivation of Coccidioidomycosis in a Mouse Model of Asymptomatic Controlled Disease.

The majority of human coccidioidomycosis infections are asymptomatic or self-limited but may have sequestered spherules in highly structured granulomas. Under immunosuppression, reactivation of fungal growth can result in severe disease. B6D2F1 mice asymptomatically infected with C. posadasii strain 1038 were immunosuppressed with dexamethasone (DXM) in drinking water. Treated mice died 16−25 days later, while untreated mice survived (p < 0.001). Flow cytometry of lung granulomas on days 5, 10, 15, and 20 of DXM treatment showed immune cell populations decreased 0.5−1 log compared with untreated mice though neutrophils and CD19+IgD−IgM− cells rebounded by day 20. Histopathology demonstrated loss of granuloma structure by day 5 and increasing spherules through day 20. On day 20, T-cells were nearly absent and disorganized pyogranulomatous lesions included sheets of plasma cells and innumerable spherules. Mice given DXM for 14 days then stopped (DXM stop) survived 6 weeks (9/10). Lung fungal burdens were significantly lower (p = 0.0447) than mice that continued treatment (DXM cont) but higher than untreated mice. Histopathologically, DXM stop mice did not redevelop controlled granulomas by sacrifice, though T-cells were densely scattered throughout the lesions. This demonstrates a mouse model suitable for further study to understand the immunologic components responsible for maintenance control of coccidioidomycosis.

Immunogenetics associated with severe coccidioidomycosis.

Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in ß-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of ß-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired ß-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Vaccines to Prevent Coccidioidomycosis: A Gene-Deletion Mutant of Coccidioides Posadasii as a Viable Candidate for Human Trials.

Coccidioidomycosis is an endemic fungal infection that is reported in up to 20,000 persons per year and has an economic impact close to $1.5 billion. Natural infection virtually always confers protection from future exposure, and this suggests that a preventative vaccine strategy is likely to succeed. We here review progress toward that objective. There has been ongoing research to discover a coccidioidal vaccine over the past seven decades, including one phase III clinical trial, but for reasons of either efficacy or feasibility, a safe and effective vaccine has not yet been developed. This review first summarizes the past research to develop a coccidioidal vaccine. It then details the evidence that supports a live, gene-deletion vaccine candidate as suitable for further development as both a veterinary and a human clinical product. Finally, a plausible vaccine development plan is described which would be applicable to this vaccine candidate and also useful to other future candidates. The public health and economic impact of coccidioidomycosis fully justifies a public private partnership for vaccine development, and the development of a vaccine for this orphan disease will likely require some degree of public funding.

Coccidioides Species: A Review of Basic Research: 2022.

Coccidioides immitis and posadasii are closely related fungal species that cause coccidioidomycosis. These dimorphic organisms cause disease in immunocompetent as well as immunocompromised individuals and as much as 40% of the population is infected in the endemic area. Although most infections resolve spontaneously, the infection can be prolonged and, in some instances, fatal. Coccidioides has been studied for more than 100 years and many aspects of the organism and the disease it causes have been investigated. There are over 500 manuscripts concerning Coccidioides (excluding clinical articles) referenced in PubMed over the past 50 years, so there is a large body of evidence to review. We reviewed the most accurate and informative basic research studies of these fungi including some seminal older studies as well as an extensive review of current research. This is an attempt to gather the most important basic research studies about this fungus into one publication. To focus this review, we will discuss the mycology of the organism exclusively rather than the studies of the host response or clinical studies. We hope that this review will be a useful resource to those interested in Coccidioides and coccidioidomycosis.

The WOPR family protein Ryp1 is a key regulator of gene expression, development, and virulence in the thermally dimorphic fungal pathogen Coccidioides posadasii.

Coccidioides spp. are mammalian fungal pathogens endemic to the Southwestern US and other desert regions of Mexico, Central and South America, with the bulk of US infections occurring in California and Arizona. In the soil, Coccidioides grows in a hyphal form that differentiates into 3-5 micron asexual spores (arthroconidia). When arthroconidia are inhaled by mammals they undergo a unique developmental transition from polar hyphal growth to isotropic expansion with multiple rounds of nuclear division, prior to segmentation, forming large spherules filled with endospores. Very little is understood about the molecular basis of spherule formation. Here we characterize the role of the conserved transcription factor Ryp1 in Coccidioides development. We show that Coccidioides Δryp1 mutants have altered colony morphology under hypha-promoting conditions and are unable to form mature spherules under spherule-promoting conditions. We analyze the transcriptional profile of wild-type and Δryp1 mutant cells under hypha- and spherule-promoting conditions, thereby defining a set of hypha- or spherule-enriched transcripts ("morphology-regulated" genes) that are dependent on Ryp1 for their expression. Forty percent of morphology-regulated expression is Ryp1-dependent, indicating that Ryp1 plays a dual role in both hyphal and spherule development. Ryp1-dependent transcripts include key virulence factors such as SOWgp, which encodes the spherule outer wall glycoprotein. Concordant with its role in spherule development, we find that the Δryp1 mutant is completely avirulent in the mouse model of coccidioidomycosis, indicating that Ryp1-dependent pathways are essential for the ability of Coccidioides to cause disease. Vaccination of C57BL/6 mice with live Δryp1 spores does not provide any protection from lethal C. posadasii intranasal infection, consistent with our findings that the Δryp1 mutant fails to make mature spherules and likely does not express key antigens required for effective vaccination. Taken together, this work identifies the first transcription factor that drives mature spherulation and virulence in Coccidioides.

Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis.

STAT4 plays a critical role in the generation of both innate and adaptive immune responses. In the absence of STAT4, Th1 responses, critical for resistance to fungal disease, do not occur. Infection with the dimorphic fungus, Coccidioides, is a major cause of community-acquired pneumonia in the endemic regions of Arizona and California. In some people and often for unknown reasons, coccidioidal infection results in hematogenous dissemination and progressive disease rather than the typical self-limited pneumonia. Members of three generations in a family developed disseminated coccidioidomycosis, prompting genetic investigation. All affected family members had a single heterozygous base change in STAT4, c.1877A>G, causing substitution of glycine for glutamate at AA626 (STAT4E626G/+ ). A knockin mouse, heterozygous for the substitution, developed more severe experimental coccidioidomycosis than did wild-type mice. Stat4E626G/+ T cells were deficient in production of IFN-γ after anti-CD3/CD28 stimulation. Spleen cells from Stat4E626G mice showed defective responses to IL-12/IL-18 stimulation in vitro. In vivo, early postinfection, mutant Stat4E626G/+ mice failed to produce IFN-γ and related cytokines in the lung and to accumulate activated adaptive immune cells in mediastinal lymph nodes. Therefore, defective early induction of IFN-γ and adaptive responses by STAT4 prevents normal control of coccidioidomycosis in both mice and humans.

A preliminary study of the plasma concentrations of orally administered fluconazole in alpacas (Vicugna pacos).

Alpacas residing in the region endemic for Coccidioides spp. are susceptible to serious, disseminated coccidioidomycosis that may result in death. There is currently no oral antifungal dose recommendation for this species. We used a steady-state study design to assess the pharmacokinetics of oral generic fluconazole in alpacas dosed q 24 h for 14 days. Cohorts of 2-3 animals received fluconazole from 6 to 15 mg/kg/day, and pharmacokinetic analysis was performed after each group of animals in order to make dose adjustments for the next group. The final three animals were used as confirmation of our dose recommendation. The median Tmax was 7 h, and the median Cmax was 1.25 µg/ml per mg/kg dose. The mean dose-normalized 24-h AUC was 41.7 µg h/ml per mg/kg dose (CV = 72%). Based on these results, we recommend alpacas receive a starting dose of oral fluconazole at 10-15 mg/kg/day based on the fluconazole AUC in humans (313-625 µg h/ml). Testing to ascertain putative therapeutic plasma concentrations and monitoring of serum transaminases should be performed.

FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

The utility of Coccidioides antigen and antibody detection in cerebrospinal fluid in the diagnosis of canine central nervous system coccidioidomycosis.

OBJECTIVE: To evaluate the utility of enzyme immunoassays (EIAs) for the detection of Coccidioides antigen and antibody in CSF in the diagnosis of CNS coccidioidomycosis in dogs. ANIMALS: 51 dogs evaluated for CNS disease in a single specialty center in Tucson in 2016. PROCEDURES: Excess CSF after routine analysis was banked after collection from dogs presented to the neurology service. Samples were tested by EIA for presence of Coccidioides antigen and antibody. Clinical data were collected from medical records retrospectively. RESULTS: 22 dogs were diagnosed with CNS coccidioidomycosis (CCM) or another neurologic disease (non-CCM). These groups of dogs overlapped in the presenting complaints, MRI results, and routine CSF analysis results. Four dogs, all with CCM, had positive antigen EIA results. With clinical diagnosis used as the reference standard, CSF antigen testing had low sensitivity (20%) but high specificity (100%) for diagnosis of CCM. Ten dogs with CCM and 4 dogs with other diagnoses had antibody detected in CSF by EIA. Sensitivity of CSF antibody testing was 46%, specificity was 86%, and positive and negative predictive values for the study population were 71% and 68%, respectively. CLINICAL RELEVANCE: Diagnosis of CNS coccidioidomycosis in dogs in an endemic region was hampered by overlap of clinical signs with other neurologic disorders and the low sensitivity of confirmatory diagnostics. The evaluated Coccidioides-specific EIAs performed on CSF can aid in the diagnosis. A prospective study is warranted to corroborate and refine these preliminary findings.

Δcps1 vaccine protects dogs against experimentally induced coccidioidomycosis.

Coccidioidomycosis is a significant health problem of dogs and humans in endemic regions, especially California and Arizona in the U.S. Both species would greatly benefit from a vaccine to prevent this disease. A live avirulent vaccine candidate, Δcps1, was tested for tolerability and efficacy to prevent pulmonary coccidioidomycosis in a canine challenge model. Vaccine injection-site reactions were transient and there were no systemic effects observed. Six of seven vaccine sites tested and all draining lymph nodes were sterile post-vaccination. Following infection with Coccidioides posadasii, strain Silveira, arthroconidia into the lungs, dogs given primary and booster vaccinations had significantly reduced lung fungal burdens (P = 0.0003) and composite disease scores (P = 0.0002) compared to unvaccinated dogs. Dogs vaccinated once had fungal burdens intermediate between those given two doses or none, but disease scores were not significantly different from unvaccinated (P = 0.675). Δcps1 was well-tolerated in the dogs and it afforded a high level of protection when given as prime and boost. These results drive the Δcps1 vaccine toward a licensed veterinary vaccine and support continued development of this vaccine to prevent coccidioidomycosis in humans.

Posaconazole treatment of refractory coccidioidomycosis in dogs.

BACKGROUND: The majority of dogs with coccidioidomycosis recover with administration of fluconazole or itraconazole, although some cases are refractory or the dogs do not tolerate administration of these medications. OBJECTIVES: The objective was to describe the treatment outcomes and therapeutic monitoring of 8 dogs with refractory coccidioidomycosis treated with posaconazole. ANIMALS: Eight dogs with refractory coccidioidomycosis. METHODS: Retrospective case series. Medical records from Veterinary Specialty Center of Tucson were searched to identify dogs with refractory coccidioidomycosis that were treated with posaconazole. Clinical information and the results of monitoring trough serum posaconazole concentrations were retrieved. RESULTS: Eight dogs with refractory coccidioidomycosis were treated with 2.5 to 10 mg/kg per day of posaconazole. Six of 8 dogs recovered or developed clinical remission while administered posaconazole. Thirteen serum concentrations from 8 dogs tested were >1 µg/mL (range, 1.52 to >6 µg/mL) and the drug was well-tolerated by 7 dogs. One dog required dosage reductions and treatment was ultimately discontinued because of hepatotoxicosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Posaconazole should be considered as a treatment option for dogs with refractory coccidioidomycosis. Monitoring of indicators of liver function or injury along with therapeutic drug monitoring is recommended to tailor dosage in the event of hepatic toxicosis.

Vaccine Protection of Mice With Primary Immunodeficiencies Against Disseminated Coccidioidomycosis.

Disseminated coccidioidomycosis (DCM), often a severe and refractory disease leading to poor outcomes, is a risk for people with certain primary immunodeficiencies (PID). Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice. To determine if vaccination could provide these mice protection, mice with mutations in Stat4, Stat3, Ifngr1, Clec7a (Dectin-1), and Rag-1 (T- and B-cell deficient) knockout (KO) mice were vaccinated with the live, avirulent, Δcps1 vaccine strain and subsequently challenged intranasally with pathogenic Coccidioides posadasii Silveira strain. Two weeks post-infection, vaccinated mice of all strains except Rag-1 KO had significantly reduced lung and spleen fungal burdens (p<0.05) compared to unvaccinated control mice. Splenic dissemination was prevented in most vaccinated immunodeficient mice while all unvaccinated B6 mice and the Rag-1 KO mice displayed disseminated disease. The mitigation of DCM by Δcps1 vaccination in these mice suggests that it could also benefit humans with immunogenetic risks of severe disease.

TNFα Blockade Inhibits Both Initial and Continued Control of Pulmonary Coccidioides.

Tumor necrosis factor alpha (TNFα) is a pluripotent cytokine that is important in many infections, though its role in Coccidioides infection remains poorly understood. The need to understand TNFα in Coccidioides infection has increased recently with the widespread use of TNFα inhibitors for a wide variety of autoimmune conditions. Here, we couple the newly developed Coccidioides infection model using strain Cp1038 and C57BL/6 × DBA/2J F1 (B6D2F1) mice. B6D2F1 mice develop long-lasting control of Cp1038. Treatment of B6D2F1 mice with anti-TNFα antibodies permits significant fungal proliferation and death. Additionally, we show that antibody treatment limited to the first 2 weeks of infection was sufficient to induce this same loss of fungal control. Importantly, anti-TNFα antibody treatment initiated after fungal control leads to a loss of host control. These results highlight the importance of TNFα in both the initial control of murine Coccidioides and ongoing suppression of the fungal disease.

A Chronic Murine Disease Model of Coccidioidomycosis Using Coccidioides posadasii, Strain 1038.

Murine infections with most Coccidioides spp. strains are lethal by 3 weeks, limiting the study of immune responses. Coccidioides posadasii, strain 1038 (Cp1038), while slowly lethal, resulted in protracted survival of C57BL/6 (B6) mice. In resistant (B6D2)F1/J mice, lung fungal burdens stabilized by week 4 without progression through week 16, better modeling human coccidioidal infections after their immunologic control. Immunodeficient tumor necrosis factor (Tnf) α knockout (KO) and interferon (Ifn) γ receptor 1 (Ifn-γr1) KO mice survived a median of 22.5 and 34 days, compared with 70 days in B6 mice (P = .001 and P < .01, respectively), though 14-day lung fungal burden studies showed little difference between Ifn-γr1 KO and B6 mice. B6 mice showed peak concentrations of key inflammatory lung cytokines, including interleukin 6, 23, and 17A, Tnf-α, and Ifn-γ, only after 4 weeks of infection. The slower progression in B6 and the acquired fungal burden stability in B6D2 mice after Cp1038 infection greatly increases the array of possible immunologic studies.