Rapaka, Rekha R
(2008)
Mechanisms of Antibody-based defense against Pneumocystis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Pneumocystis (PC) pneumonia is a life-threatening opportunistic fungal infection observed in individuals with severe immunodeficiencies, such as AIDS. This dissertation evaluates functions of antibodies and conserved fungal cell wall carbohydrate antigens in host defense against PC. We demonstrate that a novel recombinant protein consisting of the extracellular domain of the beta-glucan receptor dectin-1 fused to the constant portion of murine IgG1, binds beta-glucan and recognizes Fc-γ receptors; and functionally, impairs growth of PC in the lungs of immunocompromised mice. As an antibody-like molecule targeting a conserved fungal cell wall carbohydrate enhanced host defense against PC, we questioned whether the host produces similar antibodies. We identified natural IgM antibodies, conserved across species and not requiring microbial stimulation for production, that recognize fungal cell wall carbohydrates beta-glucan and chitosan/chitin. In mice, naïve serum containing natural antibodies impairs the growth of PC organisms in the lungs at intermediate stages of infection, while at earliest stages limits pulmonary neutrophil recruitment. Mice unable to secrete IgM, sIgM(-/-), manifest similar impairments in pathogen clearance at intermediate stages of infection. Additionally, sIgM(-/-) mice demonstrate diminished trafficking of fungal cell wall carbohydrate antigen by CD11c+ cells to draining lymph nodes, impaired production of Th2 and Th17 cytokines in lymph nodes after PC challenge, and altered adaptive antibody responses, with diminished anti-PC IgG1 (Th2 associated) while enhanced IgG2a (Th1 associated) adaptive antibody responses. Thus, sIgM, of which a significant component is natural antibody, influences PC Ag presentation at earliest stages of infection, enhancing host defense and biasing the host towards Th2 adaptive responses. Additionaly, we observe that beta-glucan and chitosan/chitin are targets of induced antibody responses. PC challenge leads to the induction of specific serum IgG, and increased quantities of multiple isotypes at the lung mucosa against these carbohydrates. Mucosal responses against beta-glucan and chitosan/chitin after PC challenge are regulated by CD4+ T cells, and we provide evidence that functional memory B cell responses against fungal wall carbohydrates are generated as a consequence of PC challenge. Collectively, these studies demonstrate the importance of conserved fungal cell wall carbohydrate antigens, and primitive antibody isotypes, in host defense responses against PC.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
21 August 2008 |
| Date Type: |
Completion |
| Defense Date: |
7 August 2008 |
| Approval Date: |
21 August 2008 |
| Submission Date: |
19 August 2008 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
antibody; carbohydrate; dectin-1; Fc receptors; IgM; lung; microbe; mucosal immunology; natural antibody; Pneumocystis; fungi |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08192008-125430/, etd-08192008-125430 |
| Date Deposited: |
10 Nov 2011 20:00 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9199 |
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