Selection of Pneumocystis jirovecii Inosine 5'-Monophosphate Dehydrogenase Mutants in Solid Organ Transplant Recipients: Implication of Mycophenolic Acid

Mycophenolic acid (MPA) targets the inosine 5'-monophosphate dehydrogenase (IMPDH) of human lymphocytes. It is widely used as an immunosuppressant to prevent rejection in solid organ transplant (SOT) recipients who, incidentally, are at risk for Pneumocystis pneumonia (PCP). We hypothesized that MPA exerts selective pressure on P. jirovecii microorganisms considering its in vitro antifungal activity on other fungi. Thus, we analysed impdh gene in P. jirovecii isolates from SOT recipients. P. jirovecii specimens from 26 patients diagnosed with PCP from 2010 to 2020 were retrospectively examined: 10 SOT recipients treated with MPA and 16 non-SOT patients without prior exposure to MPA. The P. jirovecii impdh gene was amplified and sequenced. Nucleotide sequences were aligned with the reference sequences retrieved from available P. jirovecii whole genomes. The deduced IMPDH protein sequences were aligned with available IMPDH proteins from Pneumocystis spp. and other fungal species known to be in vitro sensitive or resistant to MPA. A total of nine SNPs was identified. One SNP (G1020A) that results in an Ala261Thr substitution was identified in all SOT recipients and in none of the non-SOT patients. Considering that IMPDHs of other fungi, resistant to MPA, harbour Thr (or Ser) at the analogous position, the Ala261Thr mutation observed in MPA-treated patients was considered to represent the signature of P. jirovecii exposure to MPA. These results suggest that MPA may be involved in the selection of specific P. jirovecii strains that circulate in the SOT recipient population.