Pneumocystis genome project (PGP)
The fungal pathogen, Pneumocystis jirovecii, causes a potentially lethal infection, Pneumocystis pneumonia (PCP), in humans. PCP is an opportunistic infection and primarily occurs in patients with a compromised immune system, including those infected with the human immunodeficiency virus (HIV/AIDS), with chronic obstructive pulmonary disease (COPD), and in other immunosuppressed populations, e.g., those receiving anti-TNF therapy for autoimmune diseases or immunosuppressive therapies after organ transplantation. Currently, available therapeutic options for PCP are limited. These fungi are not susceptible to the commonly used antifungal agents, such as the azoles or amphotericin B, and despite concerted efforts to identify additional chemotherapeutic agents, the combination trimethoprim-sulfamethoxazole (TMP-SMX) continues to be the standard prophylactic and therapeutic modality in use today, as it was for the last few decades. However, TMP-SMX treatment can cause serious side effects while other second-line therapies are not as efficacious or are more toxic, like pentamidine isethionate.
The Pneumocystis genus is comprised of obligate fungal pathogens that live only in the lungs of their mammalian hosts. The lack of a long term in vitro culture indicates that some crucial nutrients are missing or under-supplemented in the culture medium. Previous metabolic studies indicated that the pathogen does not synthesize ergosterol and has to scavenge cholesterol from its host to thrive. More recent genome sequencing studies pointed out that the fungus has dramatic under-representation of amino acid synthesis pathways. Despite the years of trials to supplement Pneumocystis culture with various sterols, amino acids and other nutrients the goal of obtaining a long term in vitro culture of the fungus has remained beyond reach.
- Cushion MT, Smulian AG, Slaven BE, Sesterhenn T, Arnold J, Staben C, Porollo A, Adamczak R, Meller J. Transcriptome of Pneumocystis carinii during fulminate infection: carbohydrate metabolism and the concept of a compatible parasite. PLoS One. 2007 May 9;2(5):e423. PubMed PMID: 17487271.
- Porollo A, Meller J, Joshi Y, Jaiswal V, Smulian AG, Cushion MT. Analysis of current antifungal agents and their targets within the Pneumocystis carinii genome. Curr Drug Targets. 2012 Nov;13(12):1575-85. Review. PubMed PMID: 22934582.
- Porollo A, Sesterhenn TM, Collins MS, Welge JA, Cushion MT. Comparative Genomics of Pneumocystis Species Suggests the Absence of Genes for myo-Inositol Synthesis and Reliance on Inositol Transport and Metabolism. MBio. 2014 Nov 4;5(6). PubMed PMID: 25370490.