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Humoral Immunity to the Opportunistic Pathogen, Pneumocystis, in a Simian Model of HIV Infection.

Kling, Heather Marie (2010) Humoral Immunity to the Opportunistic Pathogen, Pneumocystis, in a Simian Model of HIV Infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kling, Heather
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNorris, Karen Akan1@pitt.eduKAN1
Committee MemberKolls, Jay
Committee MemberStefano-Cole, Kellystefcole@cvr.pitt.eduSTEFCOLE
Committee MemberBorghesi, Lisaborghesi@pitt.eduBORGHESI
Committee MemberMontelaro, Ronald Crmont@pitt.eduRMONT
Date: 30 April 2010
Date Type: Completion
Defense Date: 8 April 2010
Approval Date: 30 April 2010
Submission Date: 29 April 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: B cells; COPD; Humoral Response; Pneumocystis; SHIV; SIV
Other ID:, etd-04292010-114433
Date Deposited: 10 Nov 2011 19:43
Last Modified: 15 Nov 2016 13:42


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