Host response to S-adenosylmethionine scavenging by <i>Pneumocystis carinii</i>

2005 2005

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Abstract (summary)

Pneumocystis is a genus of fungal pathogens causing a severe pneumonia in immunosuppressed mammals. The human pathogen, P. jirovecii, is responsible for significant morbidity and mortality worldwide. Pneumocystis is one of very few organisms which lack the ability to manufacture S-adenosylmethionine (AdoMet), a key biochemical intermediate involved in numerous methylation reactions and in the synthesis of polyamines, small cationic molecules with multiple physiological roles. Pneumocystis must scavenge this molecule from the extracellular fluid of its host, depleting the normally stable levels of plasma AdoMet. The work reported in this thesis involved use of a rat model of PCP to study the response of the host to AdoMet scavenging. In particular, expression of several enzymes involved in AdoMet synthesis and polyamine metabolism was studied. The liver is the major site for AdoMet production but the data show that infection does not change the levels of liver mRNA for AdoMet synthetase (MAT).

Dexamethasone, the immunosuppressive agent used in the model, does cause an increase in lung MAT mRNA levels and enzyme activity; however this increase is ablated as infection intensifies. AdoMet decarboxylase, a polyamine synthetic enzyme, is down-regulated by infection but the key polyamine regulatory enzyme, ornithine decarboxylase, is up-regulated. A detailed interpretation of these mRNA and enzymatic changes will require further studies of individual lung cell types and the changes that occur within those cell types. Data in this thesis indicate that the host does not compensate for AdoMet scavenging by Pneumocystis, thus validating extracellular AdoMet as a chemotherapeutic target. Infection with P. carinii, however, does cause changes in lung polyamine metabolic enzymes that may relate to modulation of the immune system; dexamethasone increases lung MAT activity, an action likely to be important in the rat model of Pneumocystis pneumonia.

Indexing (details)

Molecular biology
0307: Molecular biology
Identifier / keyword
Biological sciences; Adenosylmethionine-S; Host response; Pneumocystic carinii
Host response to S-adenosylmethionine scavenging by <i>Pneumocystis carinii</i>
Roosevelt, Michael J.
Number of pages
Publication year
Degree date
School code
DAI-B 66/11, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
9780542403644, 0542403641
Clarkson, Allen B., Jr.
New York University
University location
United States -- New York
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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