<i>DIVISION OF MICROBIOLOGY</i>: IMMUNITY TO COCCIDIOIDOMYCOSIS INDUCED IN MICE BY PURIFIED SPHERULE, ARTHROSPORE, AND MYCELIAL VACCINES*

Levine, Howard B.; Cobb, J.M.; Smith, Charles E.

doi:10.1111/j.2164-0947.1960.tb00711.x

Cited by 141 publications

(70 citation statements)

References 12 publications

(8 reference statements)

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“…In contrast, vaccination of mice with an RYP1 knockout strain of C. posadasii, which does not undergo transition to the spherule phase in C. posadasii (32), did not induce protection to a subsequent coccidioidal infection (M. A. Mandel, M. J. Orbach, and L. F. Shubitz, unpublished data). In earlier studies, spherule vaccines were found to be protective against respiratory murine coccidioidal infections whereas mycelial vaccines were not (33). This pattern is consistent with the possibility that spherule initiation as occurs in the ⌬cps1 strain is critical for a live vaccine to stimulate protective immunity against a respiratory infection.…”

Section: Discussionsupporting

confidence: 66%

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

et al. 2016

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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 ⌬cps1 deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,␥c 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 ⌬cps1 strain versus C. posadasii is consistent with both metabolic and regulatory functions for the gene. The in vitro phenotype of the ⌬cps1 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 ⌬cps1 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 ⌬cps1 strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals. Coccidioides species (C. immitis and C. posadasii) are the causative agents of coccidioidomycosis (valley fever), an important emerging disease endemic to the southwestern United States and elsewhere in the Western Hemisphere (1-3). Inhalation of a 2-to 4-m arthroconidium (spore) initiates a respiratory infection and grows as a unique parasitic phase structure, the spherule, to 80 to 100 m in diameter (4). During spherule maturation, which in mice takes approximately 4 days, internal cell division and septation results in hundreds of endospores that, if released, can reinitiate spherule growth in the infected tissue. Although many infections resolve without medical intervention, about 40% of infections cause respiratory illnesses that often last weeks to many months (5). In a small percentage of patients, infection disseminates from the lungs hematogenously to produce progressive, protracted, and even fatal complications. With or without clinical illness, most infections produce lifelong immunity to a second coccidioidal infection, and it is this observation that suggests a preventative vaccine could be developed (6).Interest in CPS1 came first from a search for general virulence factors in the maize pathogen Cochliobolus heterostrophus. In this and other ascomycete cereal grain pathogens, deletion of the CPS1 gene results in reduced virulence on host plants with prod...

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Section: Discussionsupporting

confidence: 66%

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

et al. 2016

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“…Owing to the lack of a suitable medium for culturing spherules, most of the early work with nonviable vaccines was conducted with mycelium-phase cells (64,124,173,185,186). Following the development of a medium for culturing spherules (61), Levine and coworkers (173, 185) compared the vaccine capacity of the parasitic and saprobic forms of Coccidioides.…”

Section: Nonviable Cellsmentioning

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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“…The difference in response of mycelial and spherule-endospore growth forms has been recognized in other ways, e.g., susceptibility to lysozyme (7,8) and efficacy as protective vaccines (20). Since it has been demonstrated here for only two isolates with respect to the effect of combined amphotericin B and rifampin, it will be necessary to test additional cultures of C. immitis to determine whether the lack ofpotentiation by combined drugs on the spherule-endospore stage is common for this species of fungus.…”

Section: Discussionmentioning

confidence: 99%

Effect of Amphotericin B and Rifampin Against Coccidioides immitis In Vitro and In Vivo

Huppert

Pappagianis

Sun³

et al. 1976

Antimicrob Agents Chemother

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Amphotericin B, the principal drug used for treating systemic mycoses, possesses undesirable toxic properties. The ability of this antibiotic to potentiate antifungal activity of other compounds suggests that lower doses of amphotericin B could be used in combination with a second drug without loss of therapeutic efficacy. In vitro tests demonstrated that amphotericin B potentiated rifampin against the mycelial growth phase of Coccidioides immitis but not against the spherule-endospore phase. Therapy for murine coccidioidomycosis with a combined amphotericin B-rifampin regimen was not better than treatment with amphotericin B alone; in fact, combined drugs may have been even less effective. This would have clinical significance for therapy of concurrent infections.

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DIVISION OF MICROBIOLOGY: IMMUNITY TO COCCIDIOIDOMYCOSIS INDUCED IN MICE BY PURIFIED SPHERULE, ARTHROSPORE, AND MYCELIAL VACCINES*

Cited by 141 publications

References 12 publications

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

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

Coccidioidomycosis: Host Response and Vaccine Development

Effect of Amphotericin B and Rifampin Against Coccidioides immitis In Vitro and In Vivo

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