Browsing by Subject "Pneumocystis pneumonia"

Now showing 1 - 3 of 3
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    All-Trans Retinoic Acid in Combination with Primaquine Clears Pneumocystis Infection
    (Public Library of Science, 2013) Lei, Guang-Sheng; Zhang, Chen; Shao, Shoujin; Jung, Hsin-Wei; Durant, Pamela J.; Lee, Chao-Hung; Pathology and Laboratory Medicine, School of Medicine
    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.
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    Infectious Diseases
    (Springer Nature, 2018) Zhang, Chen; Myers, Jeffrey L.; Pathology and Laboratory Medicine, School of Medicine
    Pulmonary infections are caused by a wide range of pathogenic microorganisms, including bacteria, viruses, fungi, and parasites. The most common lung infections in immunocompetent hosts are caused by pyogenic bacteria (e.g., Streptococcus pneumoniae), common respiratory viruses, and mycoplasma. These infections are usually diagnosed by clinical and microbiologic studies, including cultures and serology tests. Lung biopsy is rarely used in these diagnoses. Patients with life-threatening pneumonia, especially those who are immunocompromised, are more likely to undergo lung biopsy to rule out unusual infections not easily diagnosed using conventional microbiologic methods and for which treatment strategies may be different. Pathogens more likely to be diagnosed using lung biopsy for which there are characteristic pathologic changes are highlighted in this chapter and listed in Table 4.1.
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    Targeting species specific amino acid residues: Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors and potential anti-opportunistic infection agents
    (Elsevier, 2018-05-15) Shah, Khushbu; Lin, Xin; Queener, Sherry F.; Cody, Vivian; Pace, Jim; Gangjee, Aleem; Pharmacology and Toxicology, School of Medicine
    To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC50) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold.