Inbred mouse strains differ in resistance to lethal Coccidioides immitis infection
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Abstract:
Inbred strains of mice were infected intraperitoneally with Coccidioides immitis, and the mean lethal dose was determined after 28 days. DBA/2N mice had a mean lethal dose of greater than 10(5) arthroconidia, whereas BALB/cAnN, C57BL/6N, and C57L/J mice had a mean lethal dose of less than or equal to 10(3). Since both BALB/c and DBA/2 mice are the H-2d haplotype, resistance is not primarily determined by the major histocompatibility locus. Resistance was the dominant phenotype. The pattern of C. immitis-resistant strains does not correspond to the strain distribution of the lsh gene or to the pattern of resistance to Blastomyces dermatitidis or Cryptococcus neoformans. Both resistant and susceptible mice, however, could be successfully immunized with a killed spherule vaccine, and susceptible BALB/cAnN mice were protected from an otherwise lethal infection by prior immunization with an attenuated mutant of C. immitis. Despite the evidence that BALB/cAnN mice could respond to immunization, nonimmune mice did not control the later phase of intraabdominal infection as well as DBA/2N mice. Dissemination of C. immitis to the lung occurred frequently in BALB/cAnN but not in DBA/2N mice. This suggests that BALB/cAnN mice cannot mount an effective immune response to C. immitis during the course of infection.
Insights
Genetic resistance to Coccidioides immitis infection varies among mouse strains. DBA/2N mice exhibit high resistance, while BALB/cAnN mice are susceptible, indicating factors beyond the major histocompatibility complex influence immunity.
Area of Science:
- Immunology
- Infectious Diseases
- Genetics
Background:
- Coccidioides immitis causes a significant fungal infection in the US Southwest.
- Understanding host genetic factors influencing Coccidioides immitis infection is crucial for developing effective treatments.
- Inbred mouse strains provide a valuable model for studying host-pathogen interactions and genetic resistance.
Purpose of the Study:
- To investigate the genetic basis of resistance to Coccidioides immitis infection in different inbred mouse strains.
- To determine the role of the major histocompatibility complex (MHC) and other genetic factors in Coccidioides immitis susceptibility.
- To evaluate the potential of vaccination strategies in conferring protection against Coccidioides immitis.
Main Methods:
- Intraperitoneal infection of inbred mouse strains with Coccidioides immitis.
- Determination of the mean lethal dose (MLD) after 28 days.
- Analysis of resistance patterns in relation to known genetic loci (H-2, lsh) and other fungal pathogens.
- Assessment of immune response through immunization with killed spherule vaccine and attenuated C. immitis mutant.
Main Results:
- DBA/2N mice demonstrated high resistance (MLD > 10^5 arthroconidia), while BALB/cAnN, C57BL/6N, and C57L/J mice showed susceptibility (MLD <= 10^3).
- Resistance was a dominant phenotype, and MHC haplotype (H-2d) did not solely determine resistance.
- Both resistant and susceptible mice responded to immunization; susceptible BALB/cAnN mice were protected by an attenuated mutant vaccine.
- Non-immune BALB/cAnN mice exhibited poor control of infection and lung dissemination, suggesting an inadequate immune response during infection.
Conclusions:
- Genetic factors independent of the MHC play a significant role in determining resistance to Coccidioides immitis.
- While vaccination can induce protection, non-immune responses in susceptible strains like BALB/cAnN are insufficient to control infection.
- Further research into the specific genetic mechanisms underlying Coccidioides immitis resistance is warranted.