The fungal opportunistic pathogen, Pneumocystis jirovecii (formerly Pneumocystis carinii f. sp. hominis) (Pc) is the causative agent of Pneumocystis Pneumonia (PcP) in immunocompromised persons. Despite improvements in anti-retroviral treatments and Pc prophylaxis, Pc remains an important pathogen in immunocompromised populations. Pc colonization, the presence of Pc in subjects without clinical signs or symptoms of PcP, is common in HIV+ subjects; however, the clinical consequences of colonization are undefined. The non-human primate model of Pc infection in simian immunodeficiency virus (SIV)- or chimeric simian-human immunodeficiency virus (SHIV)-infected macaques has been developed to study Pc colonization pathogenesis in the context of AIDS immunosuppression.
Using this model, immunologic parameters associated with natural Pc colonization of macaques were evaluated to gain understanding of protective immune responses to Pc. Humoral immunity to the recombinant Pc-antigen, kexin (KEX1), correlated with protection from subsequent Pc colonization, despite declining CD4+ T cells. Furthermore, macaques that remained Pc-negative were protected against lung injury observed in macaques that became Pc-colonized, supporting a role for Pc in pulmonary obstruction development. These experiments suggest KEX1-specific antibodies may provide protection of immunocompromised individuals from developing obstructive pulmonary disease.
Because B cell deficits and dysfunctions are reported in HIV+ subjects, we examined peripheral blood B cell populations in SHIV-infected macaques. We report declines in total (CD20+), memory (CD20+CD27+) and IgM+ memory B cell numbers, increased percentages of activated (CD95+) B cells, and hypergammaglobulinemia in SHIV-infected macaques, similar to what has been reported for HIV+ patients, suggesting the relevance of this model for studying HIV-related B cell dysfunctions. Pc colonization status did not correlate with deficits in total B cell populations. Rather, protection from Pc-colonization appears associated with a KEX1-specific memory B cell pool, despite early loss of total CD27+ B cells. These results suggest exposure to Pc prior to immunosuppression, resulting in high levels of circulating antibodies/plasma cells, contributes to maintenance of a Pc-specific memory B cell pool following immunosuppression.
These results demonstrate importance of a Pc-specific humoral response in protection from Pc colonization and pulmonary damage, thereby providing a rationale for Pc-KEX1 vaccine development to protect at-risk populations against this opportunistic pathogen.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04292010-114433 |
| Date | 30 April 2010 |
| Creators | Kling, Heather Marie |
| Contributors | Ronald C. Montelaro, PhD, Jay K. Kolls, MD, Lisa Borghesi, PhD, Kelly Stefano-Cole, PhD, Karen A. Norris, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04292010-114433/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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