Conditional virulence of a p-aminobenzoic acid-requiring mutant of Aspergillus fumigatus

Abstract

The induced auxotrophy for p-aminobenzoic acid (PABA) resulted in a complete loss of virulence of Aspergillus fumigatus for normal as well as cortisone-treated mice. The PABA-requiring mutant of A. fumigatus survived in vivo for 4 to 7 days without causing any infection. However, it showed conditional virulence in animals receiving PABA in very small quantities. Repeated inoculations of the viable spores of the avirulent mutant strain gave favorable results in building immunity against intravenous challenge of the virulent strain. The immunogenicity of the PABA-requiring mutant was comparable with that of a wild strain of the fungus in agar gel double-diffusion tests using clinical and hyperimmune sera and in skin tests on patients with allergic bronchopulmonary aspergillosis.

Signature‐tagged and directed mutagenesis identify PABA synthetase as essential for Aspergillus fumigatus pathogenicity

“…Even in opportunistic pathogens, however, there will still be a small proportion of genes, like pabaA, mutation of which will lead to a marked attenuation in virulence. Both STM and directed mutagenesis of A. fumigatus have identified pabaA as essential for in vivo intrapulmonary growth and confirms earlier work suggesting this pathway may be important in invasive infections due to Aspergillus species (Sandhu et al, 1976;Tang et al, 1994). This validates the STM methodology for fungal pathogens and emphasizes the crucial importance of the folate biosynthetic pathway for fungal growth in the mammalian lung.…”

Virulence studies of Aspergillus nidulans mutants requiring lysine or p-aminobenzoic acid in invasive pulmonary aspergillosis

“…3), and no fungal colonies were recovered after plating lung homogenates onto supplemented S/C medium. To provide further evidence that the lack of pathogenicity of pabaAl strains was attributable to the pabaAl mutation, PABA was added to the drinking water of animals prior to inoculation with strain 392 (22). Immunosuppressed mice inoculated with saline and given PABA supplementation showed no ill effects.…”

“…Although A. nidulans is rarely encountered as an opportunistic human pathogen, its genetic system and the availability of a large number of well-characterized auxotrophic mutations offer the opportunity to study a range of pathways. In previous work with Aspergillus spp., single auxotrophic mutants were administered intravenously to nonimmunosuppressed mice, and auxotrophies for PABA, pyridoxine, and adenine were found to be associated with lack of pathogenicity (20,22). However, it is not possible to interpret these data in relation to growth in lung tissue and, therefore, IPA.…”

“…The pathogenic properties of strains carrying mutations that block some of these pathways have been evaluated. Purnell (20) found that auxotrophic mutants of * Aspergillus nidulans with a requirement for either adenine, pyridoxine, or p-aminobenzoic acid (PABA) had markedly reduced virulence, and Sandhu et al (22) demonstrated that a PABA-requiring mutant of A. fumigatus was nonpathogenic. However the implications of these results for antifungal drug development are not clear because the fungal inoculum was administered intravenously.…”

The Aspergillus fumigatus transcriptional activator CpcA contributes significantly to the virulence of this fungal pathogen

“…Such mutants were unable to cause systemic infections upon intravenous (i.v.) injection in steroid-treated mice (Sandhu et al ., 1976), a finding that has recently been further substantiated by a signature-tagged mutagenesis screen (Brown et al ., 2000). lysA2 mutants of Aspergillus nidulans have wild-type virulence characteristics, indicating that the host's lysine pool is not limiting for fungal colonization.…”