LcrV plague vaccine with altered immunomodulatory properties.
Yersinia pestis, the causative agent of plague, secretes LcrV (low-calcium-response V or V antigen) during infection. LcrV triggers the release of interleukin 10 (IL-10) by host immune cells and suppresses proinflammatory cytokines such as tumor necrosis factor alpha and gamma interferon as well as innate defense mechanisms required to combat the pathogenesis of plague. Although immunization of animals with LcrV elicits protective immunity, the associated suppression of host defense mechanisms may preclude the use of LcrV as a human vaccine. Here we show that short deletions within LcrV can reduce its immune modulatory properties. An LcrV variant lacking amino acid residues 271 to 300 (rV10) elicited immune responses that protected mice against a lethal challenge with Y. pestis. Compared to full-length LcrV, rV10 displayed a reduced ability to release IL-10 from mouse and human macrophages. Furthermore, the lipopolysaccharide-stimulated release of proinflammatory cytokines by human or mouse macrophages was inhibited by full-length LcrV but not by the rV10 variant. Thus, it appears that LcrV variants with reduced immune modulatory properties could be used as a human vaccine to generate protective immunity against plague.
Overheim
Katie A
KA
Department of Microbiology, University of Chicago, CLSC607B, 920 East 58th Street, Chicago, IL 60637, USA.
Depaolo
R William
RW
Debord
Kristin L
KL
Morrin
Elizabeth M
EM
Anderson
Debra M
DM
Green
Nathaniel M
NM
Brubaker
Robert R
RR
Jabri
Bana
B
Schneewind
Olaf
O
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D010930:Plague / Q000276:immunology / Q000517:prevention & control*; D052899:Pore Forming Cytotoxic Proteins; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment; D015010:Yersinia pestis / Q000235:genetics / Q000276:immunology
D000942:Antigens, Bacterial; D001428:Bacterial Vaccines; C043908:LcrV protein, Yersinia; D052899:Pore Forming Cytotoxic Proteins; D011994:Recombinant Proteins