Roles of gamma interferon and interleukin-4 in genetically determined resistance to Coccidioides immitis

Experimental models of coccidioidomycosis performed using various laboratory animals have been, and remain, a critical component of elucidation and understanding of the pathogenesis and host resistance to infection with Coccidioides spp., as well as to development of more efficacious antifungal therapies. The general availability of genetically defined strains, immunological reagents, ease of handling, and costs all contribute to the use of mice as the primary laboratory animal species for models of this disease. Five types of murine models are studied and include primary pulmonary disease, intraperitoneal with dissemination, intravenous infection emulating systemic disease, and intracranial or intrathecal infection emulating meningeal disease. Each of these models has been used to examine various aspects of host resistance, pathogenesis, or antifungal therapy. Other rodent species, such as rat, have been used much less frequently. A rabbit model of meningeal disease, established by intracisternal infection, has proven to model human meningitis well. This model is useful in studies of host response, as well as in therapy studies. A variety of other animal species including dogs, primates, and guinea pigs have been used to study host response and vaccine efficacy. However, cost and increased needs of animal care and husbandry are limitations that influence the use of the larger animal species.

Section: Host Responsementioning

confidence: 99%

Experimental Animal Models of Coccidioidomycosis

Clemons¹,

Capilla²,

Stevens³

2007

“…17 Further studies in mice have shown that increased levels of Th1associated cytokines (IFN-␥ ) correlate with greater resistance while Th2associated cytokines (IL-4) correlate with susceptibility. 11,18 Therefore an adjuvant was selected that would promote a Th1 immune response. Previous studies have demonstrated that CpG adjuvants, including ISS, result in the secretion of Th1 cytokines IFN-␥ and IL-12 and increased vaccine efficacy when used in combination with Montanide ISA-51, a water-in-oil emulsion.…”

Section: Discussionmentioning

confidence: 99%

Safety, Antigenicity, and Efficacy of a Recombinant Coccidioidomycosis Vaccine in Cynomolgus Macaques (Macaca fascicularis)

Johnson

Lerche

Pappagianis

et al. 2007

The safety, immunogenicity and efficacy of recombinant Ag2/PRA106 + CSA chimeric fusion protein (CFP) vaccine in ISS/Montanide adjuvant-administered intramuscular (IM) was assessed in adult female cynomolgus macaques challenged with Coccidioides posadasii. Animals received three immunizations with either 5 microg CFP, 50-microg CFP, or adjuvant alone and were challenged 4 weeks following the final immunization. Although significant antibody response was produced in response to vaccination, there were no discernable adverse effects, suggesting that the vaccine was well tolerated. Upon intratracheal challenge, all animals showed evidence of disease. Two animals that received 5-microg doses of CFP were euthanatized prior to the study's end because of severe symptoms. Animals vaccinated with 50-microg doses of CFP showed evidence of enhanced sensitization compared to adjuvant controls and animals vaccinated with 5-microg doses of CFP. This was based on higher serum anti-CFP titers, enhanced secretion of interferon-gamma (IFN-gamma) from stimulated bronchoalveolar lavage mononuclear cells (BALMC), reduced pulmonary radiologic findings following intratracheal challenge, reduced terminal complement fixation titers, and reduced necropsy findings. Overall the vaccine was well tolerated, induced sensitization, and resulted in a protective response when given at the higher 50-microg dose. Additional experiments may be needed to optimize the vaccination and to confer greater protection against lethal challenge.

“…Among different mouse models, BALB/c and C57BL6 mouse strains are susceptible and DBA/2 mouse strain is resistant to coccidioidomycosis. 10,11 The difference in their susceptibility is related to differences in Th1 response against Coccidioides. 11 Similar to mouse strains, it has been established in humans that the susceptibility to coccidioidomycosis is determined by racial or genetic predispositions, age, pregnancy, and immunological status of people in the endemic areas.…”

Section: The Susceptibility To Coccidioides Infection Is Associated Wmentioning

confidence: 99%

“…10,11 The difference in their susceptibility is related to differences in Th1 response against Coccidioides. 11 Similar to mouse strains, it has been established in humans that the susceptibility to coccidioidomycosis is determined by racial or genetic predispositions, age, pregnancy, and immunological status of people in the endemic areas. 6 For example, patients with AIDS, 12 pregnant women, 13 and patients with deficient T cell reactivity 14 are more at risk of developing severe disseminated form of coccidioidomycosis.…”

Section: The Susceptibility To Coccidioides Infection Is Associated Wmentioning

confidence: 99%

Dendritic Cell‐Based Vaccine against Coccidioides Infection

Awasthi

2007

Coccidioides causes coccidioidomycosis in the southwestern United States. Its clinical manifestations range from the primary asymptomatic to progressive pulmonary and extrapulmonary disease. Because of endemicity, frequent relapse, and virulent nature of Coccidioides, there is an urgent need for the development of effective therapy or vaccine. It has been recognized from studies in human patients and in murine models that the divergence in their susceptibility to Coccidioides infection is related to differences in T cell response. Dendritic cells (DCs) are most potent antigen-presenting cells that play a critical role in activating naïve T cells. On account of their unique immunostimulatory capacity, DCs have been used for the development of immunotherapy and vaccines against cancer and infectious diseases. We recently investigated the immunostimulatory potential of a DC-based vaccine in a murine model against Coccidioides posadasii (C. posadasii). Our results suggest that DCs act as a potent adjuvant and activate protective responses in mice against C. posadasii.