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Echinocandin treatment of pneumocystis pneumonia in rodent models depletes cysts leaving trophic burdens that cannot transmit the infection.

Cushion MT, Linke MJ, Ashbaugh A, Sesterhenn T, Collins MS, Lynch K, Brubaker R, Walzer PD - PLoS ONE (2010)

Bottom Line: Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung.Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse.Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.

View Article: PubMed Central - PubMed

Affiliation: College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America. melanie.cushion@uc.edu

ABSTRACT
Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express beta -1,3-D-glucan synthetase and contain abundant beta -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of beta -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased beta -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.

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β-1,3-D-glucan in the lungs of mice treated prophylactically with echinocandins.β-1,3-D-glucan contents in the lungs of treated and untreated mice and rats were quantified with the GLUCATELL™ kit. Red bar (C/S) = untreated, immunosuppressed mice; Green bars = anidulafungin; Yellow bars = caspofungin; Pink bar = prophylactic dose of TMP/SMX (12.5/62.5 mg/kg). Dose regimens are described on the X-axis. (*) The average of the untreated mouse group was statistically different (P<0.001) from all groups treated prophylactically except anidulafungin 0.1 mg/kg/1x/wk and the TMP/SMX prophylactically -treated mice. (**)The average of the mice prophylactically treated with anidulafungin 0.1 mg/kg/1x/wk was statistically different from all of the echinocandin-treated mouse groups (P<0.001) but not from the TMP/SMX treated or the untreated mice. (†) The mice treated prophylactically with TMP/SMX treated were significantly different from all of the echinocandin-treated mice except for anidulafungin 0.1 mg/kg/1x/wk and the untreated control group (P<0.001).
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pone-0008524-g006: β-1,3-D-glucan in the lungs of mice treated prophylactically with echinocandins.β-1,3-D-glucan contents in the lungs of treated and untreated mice and rats were quantified with the GLUCATELL™ kit. Red bar (C/S) = untreated, immunosuppressed mice; Green bars = anidulafungin; Yellow bars = caspofungin; Pink bar = prophylactic dose of TMP/SMX (12.5/62.5 mg/kg). Dose regimens are described on the X-axis. (*) The average of the untreated mouse group was statistically different (P<0.001) from all groups treated prophylactically except anidulafungin 0.1 mg/kg/1x/wk and the TMP/SMX prophylactically -treated mice. (**)The average of the mice prophylactically treated with anidulafungin 0.1 mg/kg/1x/wk was statistically different from all of the echinocandin-treated mouse groups (P<0.001) but not from the TMP/SMX treated or the untreated mice. (†) The mice treated prophylactically with TMP/SMX treated were significantly different from all of the echinocandin-treated mice except for anidulafungin 0.1 mg/kg/1x/wk and the untreated control group (P<0.001).

Mentions: The β-1,3-D-glucan content was measured in the lungs of the prophylactically treated mouse groups (shown in Fig. 5.) and the therapeutically treated rat groups (discussed above). As expected, the loss of cysts in the echinocandin-treated animals correlated with a reduction of β-1,3-D-glucan content (Fig. 6). The same 3 groups of mice that had elevated cyst numbers apparent in Fig. 5a also had dramatically higher β-1,3-D-glucan content (untreated control mice, mice treated with 0.1 mg/kg/1x/wk anidulafungin or low-dose TMP-SMX), shown in Fig. 6. In rats treated therapeutically with anidulafungin, the β-1,3-D-glucan content was significantly different from the untreated rat lungs, as were the cyst counts (857.4 pg/ml±611.3 SD in the untreated group and 90.6 pg/ml±134.3 S.D. in the anidulafungin treated group). These data show that the loss of cysts was proportional to the decrease in β-1,3-D-glucan content.


Echinocandin treatment of pneumocystis pneumonia in rodent models depletes cysts leaving trophic burdens that cannot transmit the infection.

Cushion MT, Linke MJ, Ashbaugh A, Sesterhenn T, Collins MS, Lynch K, Brubaker R, Walzer PD - PLoS ONE (2010)

β-1,3-D-glucan in the lungs of mice treated prophylactically with echinocandins.β-1,3-D-glucan contents in the lungs of treated and untreated mice and rats were quantified with the GLUCATELL™ kit. Red bar (C/S) = untreated, immunosuppressed mice; Green bars = anidulafungin; Yellow bars = caspofungin; Pink bar = prophylactic dose of TMP/SMX (12.5/62.5 mg/kg). Dose regimens are described on the X-axis. (*) The average of the untreated mouse group was statistically different (P<0.001) from all groups treated prophylactically except anidulafungin 0.1 mg/kg/1x/wk and the TMP/SMX prophylactically -treated mice. (**)The average of the mice prophylactically treated with anidulafungin 0.1 mg/kg/1x/wk was statistically different from all of the echinocandin-treated mouse groups (P<0.001) but not from the TMP/SMX treated or the untreated mice. (†) The mice treated prophylactically with TMP/SMX treated were significantly different from all of the echinocandin-treated mice except for anidulafungin 0.1 mg/kg/1x/wk and the untreated control group (P<0.001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2813285&req=5

pone-0008524-g006: β-1,3-D-glucan in the lungs of mice treated prophylactically with echinocandins.β-1,3-D-glucan contents in the lungs of treated and untreated mice and rats were quantified with the GLUCATELL™ kit. Red bar (C/S) = untreated, immunosuppressed mice; Green bars = anidulafungin; Yellow bars = caspofungin; Pink bar = prophylactic dose of TMP/SMX (12.5/62.5 mg/kg). Dose regimens are described on the X-axis. (*) The average of the untreated mouse group was statistically different (P<0.001) from all groups treated prophylactically except anidulafungin 0.1 mg/kg/1x/wk and the TMP/SMX prophylactically -treated mice. (**)The average of the mice prophylactically treated with anidulafungin 0.1 mg/kg/1x/wk was statistically different from all of the echinocandin-treated mouse groups (P<0.001) but not from the TMP/SMX treated or the untreated mice. (†) The mice treated prophylactically with TMP/SMX treated were significantly different from all of the echinocandin-treated mice except for anidulafungin 0.1 mg/kg/1x/wk and the untreated control group (P<0.001).
Mentions: The β-1,3-D-glucan content was measured in the lungs of the prophylactically treated mouse groups (shown in Fig. 5.) and the therapeutically treated rat groups (discussed above). As expected, the loss of cysts in the echinocandin-treated animals correlated with a reduction of β-1,3-D-glucan content (Fig. 6). The same 3 groups of mice that had elevated cyst numbers apparent in Fig. 5a also had dramatically higher β-1,3-D-glucan content (untreated control mice, mice treated with 0.1 mg/kg/1x/wk anidulafungin or low-dose TMP-SMX), shown in Fig. 6. In rats treated therapeutically with anidulafungin, the β-1,3-D-glucan content was significantly different from the untreated rat lungs, as were the cyst counts (857.4 pg/ml±611.3 SD in the untreated group and 90.6 pg/ml±134.3 S.D. in the anidulafungin treated group). These data show that the loss of cysts was proportional to the decrease in β-1,3-D-glucan content.

Bottom Line: Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung.Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse.Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.

View Article: PubMed Central - PubMed

Affiliation: College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America. melanie.cushion@uc.edu

ABSTRACT
Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express beta -1,3-D-glucan synthetase and contain abundant beta -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of beta -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased beta -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.

Show MeSH
Related in: MedlinePlus