Coccidioidomycosis during Human Immunodeficiency Virus Infection

Fish, Douglas G.; Ampel, Neil M.; Galgiani, John N.; Dols, Cynthia Lee; Kelly, Peter C.; Johnson, Charles H.; Pappagianis, Demosthenes; Edwards, John E.; Wasserman, Ronald B.; Clark, R. J. H.; Antoniskis, Diana; Larsen, Robert A.; Englender, Steven J.; Petersen, Eskild A.

doi:10.1097/00005792-199011000-00006

Cited by 186 publications

(85 citation statements)

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“…Coccidioidomycosis is a frequent complication for persons who are immunologically compromised by human immunodeficiency virus (HIV) infection (3,6,115,197,315). A prospective study conducted during a 4-year period in Phoenix and Tucson indicated that the risk of active coccidioidomycosis in HIV-infected persons ranged from 8% to 41% (6).…”

Section: Risk Factors For Severe Disseminated Coccidioidomycosismentioning

confidence: 99%

Coccidioidomycosis: Host Response and Vaccine Development

2004

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Coccidioidomycosis is caused by the dimorphic fungi in the genus Coccidioides. These fungi live as mycelia in the soil of desert areas of the American Southwest, and when the infectious spores, the arthroconidia, are inhaled, they convert into the parasitic spherule/endospore phase. Most infections are mild, but these organisms are frank pathogens and can cause severe lethal disease in fully immunocompetent individuals. While there is increased risk of disseminated disease in certain racial groups and immunocompromised persons, the fact that there are hosts who contain the initial infection and exhibit long-term immunity to reinfection supports the hypothesis that a vaccine against these pathogens is feasible. Multiple studies have shown that protective immunity against primary disease is associated with T-helper 1 (Th-1)-associated immune responses. The single best vaccine in animal models, formalin-killed spherules (FKS), was tested in a human trial but was not found to be significantly protective. This result has prompted studies to better define immunodominant Coccidioides antigen with the thought that a subunit vaccine would be protective. These efforts have defined multiple candidates, but the single best individual immunogen is the protein termed antigen 2/proline-rich antigen (Ag2/PRA). Studies in multiple laboratories have shown that Ag2/PRA as both protein and genetic vaccines provides significant protection against mice challenged systemically with Coccidioides. Unfortunately, compared to the FKS vaccine, it is significantly less protective as measured by both assays of reduction in fungal CFU and assays of survival. The capacity of Ag2/PRA to induce only partial protection was emphasized when animals were challenged intranasally. Thus, there is a need to define new candidates to create a multivalent vaccine to increase the effectiveness of Ag2/PRA. Efforts of genomic screening using expression library immunization or bioinformatic approaches to identify new candidates have revealed at least two new protective proteins, expression library immunization antigen 1 (ELI-Ag1) and a β-1,3-glucanosyltransferase (GEL-1). In addition, previously discovered antigens such as Coccidioides-specific antigen (CSA) should be evaluated in assays of protection. While studies have yet to be completed with combinations of the current candidates, the hypothesis is that with increased numbers of candidates in a multivalent vaccine, there will be increased protection. As the genome sequences of the two Coccidioides strains which are under way are completed and annotated, the effort to find new candidates can increase to provide a complete genomic scan for immunodominant proteins. Thus, much progress has been made in the discovery of subunit vaccine candidates against Coccidioides and there are several candidates showing modest levels of protection, but for complete protection against pulmonary challenge we need to continue the search for additional candidates

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Section: Risk Factors For Severe Disseminated Coccidioidomycosismentioning

confidence: 99%

Coccidioidomycosis: Host Response and Vaccine Development

2004

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“…ranges from mild, self-limiting symptoms to fulminant and fatal disease (1). Although most patients will recover without medical intervention, people with progressive or chronic disease and populations with various compromises of the immune system require antifungal therapy (2)(3)(4). The most severe consequence of coccidioidal infection is meningitis, which requires lifetime antifungal therapy (5,6).…”

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confidence: 99%

Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs

Shubitz

Roy²,

Trinh

et al. 2017

Antimicrob Agents Chemother

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Coccidioidomycosis can be a chronic, systemic fungal infection requiring long-term to lifetime medication. Thus, there is a need for improved antifungal agents with greater efficacy and reduced toxicity. VT-1161 has a low affinity for mammalian cytochromes and potently inhibits fungal CYP51 with proven efficacy in murine models of central nervous system (CNS) and respiratory coccidioidomycosis. Dogs experience coccidioidomycosis similar to humans and are a useful preclinical model for naturally occurring disease. Twenty-four client-owned dogs diagnosed with respiratory coccidioidomycosis based on radiography, serology, clinical signs, and clinicopathologic abnormalities were treated with a loading dose of VT-1161 for 14 days, followed by 46 days of a lower maintenance dose. Twelve dogs received a high dose (29 mg/kg loading, 6 mg/kg maintenance) and 12 received a low dose (10 mg/kg loading, 1.6 mg/kg maintenance). Response to treatment was assessed by calculating the reduction in disease scores at exit compared to disease scores at enrollment. Overall, 20 of 24 (83%) dogs had Ն50% reduction in enrollment disease scores at exit (P Ͻ 0.001), with no difference between the high-and low-dose groups (P ϭ 0.66). Time-weighted average plasma concentrations for the high-and low-dose groups were 39 Ϯ 5 g/ml and 19 Ϯ 2 g/ml, respectively. In this openlabel study, VT-1161 was efficacious for the treatment of respiratory coccidioidomycosis in naturally infected dogs. Combined with previously reported murine data, this finding supports the further development of VT-1161 for the treatment of coccidioidomycosis in humans.

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“…Among different mouse strains, BALB/c and C57BL6 mice are susceptible to Coccidioides, whereas DBA/2 mice are resistant to Coccidioides infection (8). The genetic basis of this difference is not clear, but it appears to be associated with depressed Th1 cell reactivity (6,9). For an efficient protective response, the Ags are required to be carried to the lymph nodes where subsequent activation of naive lymphocytes occurs.…”

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confidence: 99%

Efficacy of Antigen 2/Proline-Rich Antigen cDNA-Transfected Dendritic Cells in Immunization of Mice against Coccidioides posadasii

Awasthi

Magee

et al. 2005

The Journal of Immunology

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Coccidioides posadasii causes coccidioidomycosis, or Valley fever, in the endemic regions of the Southwestern United States. The susceptibility to C. posadasii infection has been attributed to a decreased Th1 cellular response. APCs, especially dendritic cells (DCs), play an important role in the activation of Th1 response. In this study, we investigated the efficacy of a DC-based vaccine against C. posadasii in a mouse model of coccidioidomycosis. We intranasally immunized C57BL6 mice with syngeneic, bone marrow-derived DCs (JAWS II cells) transfected with a cDNA encoding the protective Coccidioides-Ag2/proline-rich Ag. The immunized mice were lethally challenged with C. posadasii through either an i.p. or intranasal route. Upon necropsy after 10 days of infection, fungal burden in lung and spleen of immunized mice was significantly reduced as compared with the control animals. The lung tissue homogenates of immunized animals showed higher levels of IFN-γ. Histologically, lung tissues of immunized mice were in better condition than the control mice. To further investigate, we studied the biodistribution and trafficking of injected DCs by nuclear imaging techniques. For this purpose, the transfected DCs were radiolabeled with 111In-oxime. Scintigraphic images showed that most of the label remained in the gastrointestinal tract. A significant amount was also observed in lung, but there were negligible circulating 111In label in blood. The results suggest that the DCs have a potent immunostimulatory activity, and immunization with DCs transfected with Ag2/proline-rich Ag-cDNA induces protective immunity against C. posadasii in C57BL6 mice.

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Coccidioidomycosis during Human Immunodeficiency Virus Infection

Cited by 186 publications

References 0 publications

Coccidioidomycosis: Host Response and Vaccine Development

Coccidioidomycosis: Host Response and Vaccine Development

Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs

Efficacy of Antigen 2/Proline-Rich Antigen cDNA-Transfected Dendritic Cells in Immunization of Mice against Coccidioides posadasii

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