Browsing by Subject "Antigens, Bacterial"

Now showing 1 - 4 of 4

Open Access
Differential Killing of Salmonella enterica Serovar Typhi by Antibodies Targeting Vi and Lipopolysaccharide O:9 Antigen.
(PLoS One, 2016) Hart, Peter J; O'Shaughnessy, Colette M; Siggins, Matthew K; Bobat, Saeeda; Kingsley, Robert A; Goulding, David A; Crump, John A; Reyburn, Hugh; Micoli, Francesca; Dougan, Gordon; Cunningham, Adam F; MacLennan, Calman A
Salmonella enterica serovar Typhi expresses a capsule of Vi polysaccharide, while most Salmonella serovars, including S. Enteritidis and S. Typhimurium, do not. Both S. Typhi and S. Enteritidis express the lipopolysaccharide O:9 antigen, yet there is little evidence of cross-protection from anti-O:9 antibodies. Vaccines based on Vi polysaccharide have efficacy against typhoid fever, indicating that antibodies against Vi confer protection. Here we investigate the role of Vi capsule and antibodies against Vi and O:9 in antibody-dependent complement- and phagocyte-mediated killing of Salmonella. Using isogenic Vi-expressing and non-Vi-expressing derivatives of S. Typhi and S. Typhimurium, we show that S. Typhi is inherently more sensitive to serum and blood than S. Typhimurium. Vi expression confers increased resistance to both complement- and phagocyte-mediated modalities of antibody-dependent killing in human blood. The Vi capsule is associated with reduced C3 and C5b-9 deposition, and decreased overall antibody binding to S. Typhi. However, purified human anti-Vi antibodies in the presence of complement are able to kill Vi-expressing Salmonella, while killing by anti-O:9 antibodies is inversely related to Vi expression. Human serum depleted of antibodies to antigens other than Vi retains the ability to kill Vi-expressing bacteria. Our findings support a protective role for Vi capsule in preventing complement and phagocyte killing of Salmonella that can be overcome by specific anti-Vi antibodies, but only to a limited extent by anti-O:9 antibodies.
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High-throughput identification of chemical inhibitors of E. coli Group 2 capsule biogenesis as anti-virulence agents.
(PLoS One, 2010-07-19) Goller, Carlos C; Seed, Patrick C
Rising antibiotic resistance among Escherichia coli, the leading cause of urinary tract infections (UTIs), has placed a new focus on molecular pathogenesis studies, aiming to identify new therapeutic targets. Anti-virulence agents are attractive as chemotherapeutics to attenuate an organism during disease but not necessarily during benign commensalism, thus decreasing the stress on beneficial microbial communities and lessening the emergence of resistance. We and others have demonstrated that the K antigen capsule of E. coli is a preeminent virulence determinant during UTI and more invasive diseases. Components of assembly and export are highly conserved among the major K antigen capsular types associated with UTI-causing E. coli and are distinct from the capsule biogenesis machinery of many commensal E. coli, making these attractive therapeutic targets. We conducted a screen for anti-capsular small molecules and identified an agent designated "C7" that blocks the production of K1 and K5 capsules, unrelated polysaccharide types among the Group 2-3 capsules. Herein lies proof-of-concept that this screen may be implemented with larger chemical libraries to identify second-generation small-molecule inhibitors of capsule biogenesis. These inhibitors will lead to a better understanding of capsule biogenesis and may represent a new class of therapeutics.
Open Access
HIV-1 envelope gp41 antibodies can originate from terminal ileum B cells that share cross-reactivity with commensal bacteria.
(Cell Host Microbe, 2014-08-13) Trama, A; Moody, MA; Alam, SM; Jaeger, F; Lockwood, B; Parks, R; Lloyd, K; Stolarchuk, C; Scearce, R; Foulger, A; Marshall, D; Whitesides, J; Jeffries, T; Wiehe, K; Morris, L; Lambson, B; Soderberg, K; Hwang, K; Tomaras, G; Vandergrift, N; Jackson, KL; Roskin, K; Boyd, S; Kepler, T; Liao, H; Haynes, B
Monoclonal antibodies derived from blood plasma cells of acute HIV-1-infected individuals are predominantly targeted to the HIV Env gp41 and cross-reactive with commensal bacteria. To understand this phenomenon, we examined anti-HIV responses in ileum B cells using recombinant antibody technology and probed their relationship to commensal bacteria. The dominant ileum B cell response was to Env gp41. Remarkably, a majority (82%) of the ileum anti-gp41 antibodies cross-reacted with commensal bacteria, and of those, 43% showed non-HIV-1 antigen polyreactivity. Pyrosequencing revealed shared HIV-1 antibody clonal lineages between ileum and blood. Mutated immunoglobulin G antibodies cross-reactive with both Env gp41 and microbiota could also be isolated from the ileum of HIV-1 uninfected individuals. Thus, the gp41 commensal bacterial antigen cross-reactive antibodies originate in the intestine, and the gp41 Env response in HIV-1 infection can be derived from a preinfection memory B cell pool triggered by commensal bacteria that cross-react with Env.
Open Access
Thymic requirement for cyclical idiotypic and reciprocal anti-idiotypic immune responses to a T-independent antigen.
(J Exp Med, 1980-02-01) Kelsoe, G; Isaak, D; Cerny, J
The role of the thymus in the cyclical appearance of the dominant idiotype of the myeloma protein secreted by the TEPC-15 plasmacytoma (T-15)-bearing plaque-forming cells (PFC) and anti-idiotypic cells (i.e., cells with receptors for T-15) in the spleen during a primary response to the phosphorylcholine determinant of Streptococcus pneumoniae, strain R36a (Pn) was studied using normal mice, thymus-deficient nude mice, and thymus gland-grafted nude mice (TG-nude). The nude mice and their phenotypically normal littermates (LM) were backcrossed on the BALB/c genetic background. The kinetics of the anti-Pn PFC response of BALB/c inbred mice, littermates of nude mice, and TG-nude mice were essentially the same. There was an initial peak on day 5-6 followed by a decline to near background, and then a second peak on day 12. In nude mice, the first peak of anti-Pn PFC (day 5) was comparable in magnitude to that of mice with an intact thymus; however, there was no second peak. In contrast to the cellular response measured at the level of PFC, the serum antibody response to Pn (assayed by passive hemagglutination of sheep erythrocytes coated with Pn polysaccharide) was comparable in all groups of mice and did not show a measurable oscillation. The anti-idiotypic cellular activity was determined by the ability of spleen cells to bind radiolabeled (125I) TEPC-15 myeloma protein (IgA, kappa) which carries an idiotypic determinant indistinguishable from that of most anti-phosphorylcholine antibodies in BALB/c mice. Binding of radiolabeled McPC-603 (IgA, kappa) and MOPC-315 (IgA, lambda 2) myeloma proteins (which lack the T-15 idiotypic determinant) served as controls. The changes in T-15 binding by splenic lymphocytes following the Pn immunization differed between normal and athymic mice. BALB/c, LM, and TG-nude mice showed a biphasic pattern with peaks at days 3--4 and 10--11 that was nearly reciprocal to the PFC curve. On the other hand, T-15 binding in nude mice either declined and remained depressed or was not affected by the ongoing anti-Pn response. These observations demonstrate that mature T cells are required for cyclical idiotypic and anti-idiotypic responses to immunization with a T-independent antigen and suggest that the cyclical immune response may result from an interaction between idiotypic and anti-idiotypic cell clones.