title: Evidence supporting a role for mammalian chitinases in efficacy of caspofungin against experimental aspergillosis in immunocompromised rats.
abstract: OBJECTIVE
  Caspofungin, currently used as salvage therapy for invasive pulmonary aspergillosis (IPA), strangely only causes morphological changes in fungal growth in vitro but does not inhibit the growth. In vivo it has good efficacy. Therefore the question arises how this in vivo activity is reached. Caspofungin is known to increase the amount of chitin in the fungal cell wall. Mammals produce two chitinases, chitotriosidase and AMCase, which can hydrolyse chitin. We hypothesized that the mammalian chitinases play a role in the in vivo efficacy of caspofungin.
  
  
  METHODS
  In order to determine the role of chitotriosidase and AMCase in IPA, both chitinases were measured in rats which did or did not receive caspofungin treatment. In order to understand the role of each chitinase in the breakdown of the caspofungin-exposed cells, we also exposed caspofungin treated fungi to recombinant enzymes in vitro.
  
  
  RESULTS
  IPA in immunocompromised rats caused a dramatic increase in chitinase activity. This increase in chitinase activity was still noted when rats were treated with caspofungin. In vitro, it was demonstrated that the action of both chitinases were needed to lyse the fungal cell wall upon caspofungin exposure.
  
  
  CONCLUSIONS
  Caspofungin seemed to alter the cell wall in such a way that the two chitinases, when combined, could lyse the fungal cell wall and assisted in clearing the fungal pathogen. We also found that both chitinases combined had a direct effect on the fungus in vitro.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands.
authors.forename: Patricia E B
authors.initials: PE
authors.lastname: Verwer
authors.forename: Marian T
authors.initials: MT
authors.lastname: ten Kate
authors.forename: Franco H
authors.initials: FH
authors.lastname: Falcone
authors.forename: Shaun
authors.initials: S
authors.lastname: Morroll
authors.forename: Henri A
authors.initials: HA
authors.lastname: Verbrugh
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: van de Sande
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000502:physiology; D000077336:Caspofungin; D002688:Chitinases / Q000378:metabolism*; D054714:Echinocandins / Q000494:pharmacology / Q000627:therapeutic use*; D006596:Hexosaminidases / Q000378:metabolism; D025301:Hyphae / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016867:Immunocompromised Host / Q000187:drug effects; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D055666:Lipopeptides; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013194:Staining and Labeling; D016896:Treatment Outcome
chemical_list: D054714:Echinocandins; D055666:Lipopeptides; D011994:Recombinant Proteins; D006596:Hexosaminidases; C086400:chitotriosidase; D002688:Chitinases; D000077336:Caspofungin