title: All-trans retinoic acid in combination with primaquine clears pneumocystis infection.
abstract: Pneumocystis pneumonia (PcP) develops in immunocompromised patients. Alveolar macrophages play a key role in the recognition, phagocytosis, and degradation of Pneumocystis, but their number is decreased in PcP. Our study of various inflammatory components during PcP found that myeloid-derived suppressor cells (MDSCs) accumulate in the lungs of mice and rats with Pneumocystis pneumonia (PcP). We hypothesized that treatment with all-trans retinoic acid (ATRA), a metabolite of vitamin A, may effectively control Pneumocystis (Pc) infection by inducing MDSCs to differentiate to AMs. In rodent models of PcP, we found that 5 weeks of ATRA treatment reduced the number of MDSCs in the lungs and increased the number of AMs which cleared Pc infection. We also found that ATRA in combination with primaquine was as effective as the combination of trimethoprim and sulfamethaxazole for treatment of PcP and completely eliminated MDSCs and Pc organisms in the lungs in two weeks. No relapse of PcP was seen after three weeks of the ATRA-primaquine combination treatment. Prolonged survival of Pc-infected animals was also achieved by this regimen. This is the very first successful development of a therapeutic regimen for PcP that combines an immune modulator with an antibiotic, enabling the hosts to effectively defend the infection. Results of our study may serve as a model for development of novel therapies for other infections with MDSC accumulation.
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors: Guang-Sheng
authors: GS
authors: Lei
authors: Chen
authors: C
authors: Zhang
authors: Shoujin
authors: S
authors: Shao
authors: Hsin-Wei
authors: HW
authors: Jung
authors: Pamela J
authors: PJ
authors: Durant
authors: Chao-Hung
authors: CH
authors: Lee
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D011010:Pneumocystis / Q000187:drug effects* / Q000502:physiology; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D011319:Primaquine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis; D014212:Tretinoin / Q000494:pharmacology*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology
chemical_list: D014212:Tretinoin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D011319:Primaquine