<i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation

<i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation

Bibliographic Details
Main Author: Clay, Corey Davis
Language:English
Published: The Ohio State University / OhioLINK 2009
Subjects:
Biomedical Research
Immunology
Microbiology
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1253617563
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1253617563
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Biomedical Research
Immunology
Microbiology
spellingShingle Biomedical Research
Immunology
Microbiology
Clay, Corey Davis
<i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation
author Clay, Corey Davis
author_facet Clay, Corey Davis
author_sort Clay, Corey Davis
title <i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation
title_short <i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation
title_full <i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation
title_fullStr <i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation
title_full_unstemmed <i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation
title_sort <i>francisella tularensis</i> lipopolysaccharide o-antigen dictates the outcome of human complement activation
publisher The Ohio State University / OhioLINK
publishDate 2009
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1253617563
work_keys_str_mv AT claycoreydavis ifrancisellatularensisilipopolysaccharideoantigendictatestheoutcomeofhumancomplementactivation
_version_ 1719428378987069440
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu12536175632021-08-03T05:57:21Z <i>Francisella tularensis</i> Lipopolysaccharide O-antigen Dictates the Outcome of Human Complement Activation Clay, Corey Davis Biomedical Research Immunology Microbiology <p><i>Francisella tularensis</i> is a Gram-negative facultative intracellular bacterium that is a potential weapon of bioterrorism when aerosolized. Macrophage infection is necessary for disease progression and efficient phagocytosis by human macrophages requires serum opsonization by complement. Microbial complement activation leads to surface deposition of highly regulated multimeric protein complexes that can promote opsonization or membrane lysis depending on the nature of the complexes formed. Outcomes of complement activation by bacteria largely depend upon the fate of complement component C3 following deposition. Functional cleavage fragments derived from C3 include C3b, which promotes both opsonization and microbial lysis, and C3bi, which specifically promotes opsonization. </p><p>Here, we study interactions between <i>F. tularensis</i> and the human complement cascade to gain a better understanding of the processes of immune evasion and cellular infection employed by this deadly bacterium. We examine mechanisms of resistance to complement-mediated lysis, the nature of C3 component surface deposition, and mechanisms of complement activation. We show that, upon incubation in fresh non-immune human serum, Schu S4 (<i>F. tularensis</i> subsp. <i>tularensis</i>), <i>F. tularensis</i> subsp. <i>novicida</i>, and LVS (<i>F. tularensis</i> subsp. <i>holarctica</i> live vaccine strain) are resistant to complement-mediated lysis. LVSG and LVSR are variant strains derived from LVS that have altered surface carbohydrate structures and are susceptible to complement-mediated lysis in serum. C3b deposition, however, occurs on each strain tested, indicating that complement is not solely activated by variant strains. Complement-susceptible strains fix markedly increased amounts of total C3-derived fragments. Specifically, the presence of C3b is persistent compared to C3bi only on susceptible strains and the deposition of downstream complement components C5 and C7 is significantly greater. These results indicate that upon binding to wildtype strains, C3b becomes rapidly cleaved to form C3bi, which facilitates opsonization and evasion of downstream lytic components of complement. Characterization of differences in the production of important surface glycans between resistant and susceptible strains and employment of targeted mutant strains allowed us to determine that LPS O-antigen plays a significant role in dictating the outcome of complement activation and the nature of C3 deposition on <i>F. tularensis</i>. </p><p>Both O-antigen producing and O-antigen-deficient strains rely heavily on the classical complement activation pathway. C1, a component of the classical pathway, is required for optimal lysis of complement-susceptible strains, and for optimal C3 deposition on all strains. Furthermore, we show that wildtype and O-antigen-deficient strains activate the classical pathway in an uncommon manner that is independent of antibody. The direct binding of C1 is reduced in the presence of O-antigen, which limits the activation of downstream components including C3. We conclude that <i>F. tularensis</i> activates complement in an unusual manner such that the rate of C3b deposition is restricted allowing for the efficient conversion of C3b to C3bi only on virulent strains. In the absence of O-antigen, however, increased activation of C1 leads to a C3b deposition rate that is greater than the rate of C3b to C3bi conversion, which ultimately leads to bacterial lysis by downstream components of the cascade.</p> 2009-09-29 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1253617563 http://rave.ohiolink.edu/etdc/view?acc_num=osu1253617563 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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