Vaccine-Induced Cellular Immune Responses Differ from Innate Responses in Susceptible and Resistant Strains of Mice Infected withCoccidioides posadasii

Abstract

Susceptibility to Coccidioides spp. varies widely in humans and other mammals and also among individuals within a species. Among strains of mice with various susceptibilities, immunohistopathology revealed that C57BL/6 mice were highly susceptible to the disease following intranasal infection, DBA/2n mice were intermediate, and Swiss-Webster mice were innately resistant. Resistant Swiss-Webster mice developed prominent perivascular/peribronchiolar lymphocytic cuffing and well-formed granulomas with few fungal elements and debris in the necrotic center, surrounded by a mantle of macrophages, lymphocytes, and fibrocytes. Susceptible C57BL/6 mice became moribund between 14 and 18 days postinfection, with overwhelming numbers of neutrophils and spherules and very few T cells, the drastic reduction of which was associated with failure and death, while intermediate DBA/2n mice controlled the fungal burden but demonstrated progressive lung inflammation with prominent suppuration, and they deteriorated clinically. Vaccinated C57BL/6 mice had an early and robust lymphocyte response, which included significantly higher Mac2 ؉ , CD3 ؉ , and CD4 ؉ cell scores on day 18 than those of innately resistant SW mice and DBA/2n mice; they also had prominent perivascular/ peribronchiolar lymphocytic infiltrates not present in their unvaccinated counterparts, and they appeared to be resolving lesions by day 56 compared to the other two strains, based on significantly lower disease scores and observably smaller and fewer lesions with few spherules and neutrophils.

Recent Advances in Our Understanding of the Environmental, Epidemiological, Immunological, and Clinical Dimensions of Coccidioidomycosis

“…Several thorough reviews on progress toward a candidate vaccine have been published previously (4,5,208). Since then, additional studies, particularly in mice vaccinated with a variety of recombinant antigens and administered a Th1-biased adjuvant, have resulted in various degrees of protection and an increasing understanding of how protection is induced (14,120,132,136,(209)(210)(211)(212)(213)(214)(215)(216)(217)(218). This work continues to support the possibility that a vaccine candidate could be identified as suitable for clinical trials.…”

“…When spherules rupture, the endospores are released, and each is capable of developing into new spherules until the host's immune system (or medical intervention) represses the growth of the fungus. Though the primary route of infection is pulmonary, the organism can disseminate hematogenously to any organ (12)(13)(14).…”

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

“…The NSG mice, given 1,030 spores, were sacrificed on days 6 and 14, and 5-m sections were cut through the entire lungs with every fifth section affixed to slides and stained with H&E. For the studies of BALB/c and NSG mice infected with 10,000 or 25 million spores, five pairs of sections, also separated by five serial sections, were prepared on slides. One slide from each pair was stained with H&E, and the other was immunohistochemically stained with a polyclonal goat antiAg2/PRA antibody that is specific for Coccidioides as previously described (21). Historical immunohistochemically stained slides of early development of C. posadasii in mouse lungs were used for comparison (22).…”

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis

“…(15), C. immitis hybrid isolate RS (16), and C. posadasii isolate Silveira (17,18) were used in this study. Female 6-to 8-week-old BALB/c mice were anesthetized with ketamine-xylene and intranasally inoculated with 100,000 arthroconidia suspended in 30 l phosphate-buffered saline (PBS) as described previously (19). Control mice were inoculated with PBS alone.…”