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Infection and immunoregulation of T lymphocytes by parainfluenza virus type 3

Sieg, Scott F.

Abstract Details

1996, Doctor of Philosophy, Case Western Reserve University, Pathology.
Parainfluenza virus type 3 (PIV3) is a paramyxovirus that is recognized as a significant cause of severe respiratory infections in children and infants. Unlike other paramyxoviruses such as mumps and measles, infection with PIV3 does not result in long-lasting immunity. PIV3 readily reinfects previously exposed individuals even in the presence of neutralizing antibodies. In addition, persistent infections have been reported in a number of clinical situations. The mechanism(s) by which PIV3 can avoid immunological clearance and prevent the establishment of life-long immunity from a natural infection have not been elucidated. The capacity of PIV3 to cause reinfection and persistence is likely to be associated with the dynamic interactions of this pathogen with the host immune system. The possibility that PIV3 can disrupt immunological function has not been previously considered. In the experiments described in this dissertation, we characterize the interactions between PIV3 and human T lymphocytes. T lymphocytes are a central component of viral immunity and have been shown to be particularly important for the clearance of PIV3 infections. The addition of carbohydrate structures to cell surface glycoproteins is often a stochastic process, with structurally related carbohydrate moieties frequently added to a variety of cell surface glycoproteins. In contrast, long chain polymers of α-2,8-polysialic acid (PSA) in vertebrate systems are largely, if not exclusively, restricted to the neural cell adhesion molecule (NCAM). Furthermore, PSA is restricted to specific core glycosylations within a restricted portion of the polypeptide. In these studies, we have identified precise sites of polysialic acid addition to the NCAM molecule and have defined regions of the NCAM that play a role in recognition of the polypeptide by PSA biosynthetic enzymes. These questions were addressed utilizing a transfection strategy and rodent cells that are capable of synthesizing PSA. These cells were transfected with a variety of chicken NCAM cDNA constructs containing a variety of relevant site-directed and domain mutations. The expressed chicken NCAM protein by this method was specifically analyzed for the presence of polysialic acid through electrophoretic and Western blotting analysis. These analyses revealed two sites of polysialic acid addition and a sub-region of the extracellular domain of NCAM that is sufficient for recognition and modification of NCAM by PSA addition enzymes. This sub-region includes the fourth and fifth immunoglobulin domains and the first (more amino-terminal) fibronectin type-III repeat A naturally occurring, alternative splicing-induced introduction of a ten-amino acid sequence (the VASE sequence) in Ig4 has been observed to be generally correlated with down-regulation of PSA during development. A more detailed analysis of this correlation was carried out on several brain regions. In the brain regions analyzed, VASE expression was found to be closely correlated to the onset of PSA down-regulation, although the onset of VASE expression did not invariably precede PSA down-regulation. The possibility of a causative role for VASE in the regulation of NCAM polysialylation was directly tested (utilizing the transfection approach described above). This analysis revealed a limited reduction in the extent of polysialylation when VASE sequence was present in Ig4. However, VASE does not appear to be sufficient to preclude NCAM polysialylation
David Kaplan (Advisor)
105 p.

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Citations

  • Sieg, S. F. (1996). Infection and immunoregulation of T lymphocytes by parainfluenza virus type 3 [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1057593999

    APA Style (7th edition)

  • Sieg, Scott. Infection and immunoregulation of T lymphocytes by parainfluenza virus type 3. 1996. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1057593999.

    MLA Style (8th edition)

  • Sieg, Scott. "Infection and immunoregulation of T lymphocytes by parainfluenza virus type 3." Doctoral dissertation, Case Western Reserve University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=case1057593999

    Chicago Manual of Style (17th edition)