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HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.

ABSTRACT: Malaria and babesiosis are bloodborne protozoan infections for which the emergence of drug-resistant strains poses a threat. Our previous phage display cDNA screens established the essentiality of Plasmodium falciparum signal peptide peptidase (SPP) in asexual development at the blood stage of malaria infection. Given the structural similarities between SPP inhibitors and HIV protease inhibitors, we screened ten HIV protease inhibitors and selected Lopinavir and Atazanavir for their ability to inhibit PfSPP activity. Using a transcription-based assay, we observed that Lopinavir inhibits both parasite-and host-derived SPP activities whereas Atazanavir inhibited only parasite derived SPP activity. Consistent with their inhibitory effect on Plasmodium growth, both Lopinavir and Atazanavir strongly inhibited intraerythrocytic Babesia microti growth ex vivo. Moreover, Lopinavir prevented the steep rise in Babesia microti parasitemia typically observed in rag1-deficient mice. Our data provide first evidence that inhibition of parasite-derived SPPs by HIV protease inhibitors offers a promising therapeutic avenue for the treatment of severe babesiosis and infections caused by other Apicomplexa parasites.

SUBMITTER: Schwake C

PROVIDER: S-EPMC6707064 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.

Schwake Christopher C Baldwin Michael R MR Bachovchin William W Hegde Shreeya S Schiemer James J Okure Carolyn C Levin Andrew E AE Vannier Edouard E Hanada Toshihiko T Chishti Athar H AH

Biochemical and biophysical research communications 20190713 1

Malaria and babesiosis are bloodborne protozoan infections for which the emergence of drug-resistant strains poses a threat. Our previous phage display cDNA screens established the essentiality of Plasmodium falciparum signal peptide peptidase (SPP) in asexual development at the blood stage of malaria infection. Given the structural similarities between SPP inhibitors and HIV protease inhibitors, we screened ten HIV protease inhibitors and selected Lopinavir and Atazanavir for their ability to i ...[more]

PMID: 31311649

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Project description:BackgroundThe Babesia microti-like parasite is an emerging tick-borne piroplasm that has been detected in a range of hosts worldwide. Babesia vulpes, which is found in dogs and foxes, has been reclassified from B. microti-like parasites. The relationships among these B. microti-like parasites and B. vulpes with respect to host range and geographical origin have not been elucidated.MethodsBlood samples were collected from 27 raccoon dogs in South Korea and used to screen for B. microti-like parasites based on a PCR assay targeting the 18S rRNA gene of Babesia. For comparative purposes, in addition to 18S rRNA sequences from nine raccoon dogs, we also analyzed 18S rRNA sequences from B. microti-like parasites infecting hosts in different geographical regions worldwide obtained from the GenBank database, giving 123 sequences in total. The genetic variation and evolutionary relationships among these sequences were examined based on analyses using DnaSP, MEGA, Arlequine, and BEAST software.ResultsBabesia microti-like parasites were identified in nine raccoon dogs and found to be related to B. vulpes obtained from Spanish dogs. Among the 123 sequences from 14 countries and various hosts, we identified 43 haplotypes with high genetic variance. Based on the genetic variance and phylogenetic analyses, we established that the B. microti-like parasites isolated in different geographical regions and from hosts belonging to five orders showed higher among-population variation than within-population variation. Babesia vulpes parasites infecting carnivore hosts, including raccoon dogs, foxes, skunks and dogs, appear to be genetically distinct from B. microti-like parasites infecting hosts belonging to the other orders.ConclusionsOur study demonstrated the genetic variation and evolutionary relationships among 18S rRNA sequences obtained from blood samples collected from various hosts and different geographical regions. Babesia vulpes was identified from raccoon dogs in South Korea. In addition, higher genetic variations were observed among populations of different hosts and geographical origins and, in particular, low connectivity was observed among host populations in the order Carnivora and those in other orders. These results suggest the B. vulpes, a piroplasmid species pathogenic in domestic dogs and wild canines, is genetically and evolutionarily different from B. microti-like parasites.

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HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.

Publications

HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.

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