OBJECTIVES: This study evaluated the implications of clinically acquired miltefosine resistance (MIL-R) by assessing virulence in mice and sand flies to reveal the potential of MIL-R strains to circulate. METHODS: Experimental infections with the MIL-R clinical Leishmania infantum isolate MHOM/FR/2005/LEM5159, having a defect in the LiROS3 subunit of the MIL-transporter, and its syngeneic experimentally reconstituted MIL-S counterpart (LEM5159LiROS3) were performed in BALB/c mice and Lutzomyia longipalpis and Phlebotomus perniciosus sand flies. In mice, the amastigote burdens in liver and spleen were compared microscopically using Giemsa smears and by bioluminescent imaging. During the sand fly infections, the percentage of infected flies, parasite load, colonization of the stomodeal valve and metacyclogenesis were evaluated. The stability of the MIL-R phenotype after sand fly and mouse passage was determined as well. RESULTS: The fitness of the MIL-R strain differed between the mouse and sand fly infection model. In mice, a clear fitness loss was observed compared to the LiROS3-reconstituted susceptible strain. This defect could be rescued by episomal reconstitution with a wildtype LiROS3 copy. However, this fitness loss was not apparent in the sand fly vector, resulting in metacyclogenesis and efficient colonization of the stomodeal valve. Resistance was stable after passage in both sand fly and mouse. CONCLUSION: The natural MIL-R strain is significantly hampered in its ability to multiply and cause a typical visceral infection pattern in BALB/c mice. However, this LiROS3-deficient strain efficiently produced mature infections and metacyclic promastigotes in the sand fly vector highlighting the transmission potential of this particular MIL-R clinical Leishmania strain.

• MeSH
• antiprotozoální látky farmakologie   MeSH
• fosforylcholin analogy a deriváty   farmakologie   MeSH
• hmyz - vektory parazitologie   MeSH
• Leishmania infantum * účinky léků   genetika   patogenita   MeSH
• leishmanióza viscerální farmakoterapie   patologie   MeSH
• léková rezistence genetika   MeSH
• membránové transportní proteiny genetika   MeSH
• myši inbrední BALB C parazitologie   MeSH
• myši MeSH
• Phlebotomus parazitologie   MeSH
• protozoální geny MeSH
• Psychodidae parazitologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• biologické modely MeSH
• cytokiny analýza   biosyntéza   MeSH
• Encephalitozoon cuniculi imunologie   MeSH
• myši inbrední BALB C imunologie   parazitologie   MeSH
• myši SCID imunologie   parazitologie   MeSH
• myši MeSH
• syndromy imunologické nedostatečnosti MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH