TY - JOUR
T1 - T cell immunity to the alkyl hydroperoxide reductase of Burkholderia pseudomallei
T2 - a correlate of disease outcome in acute melioidosis
AU - Reynolds, Catherine
AU - Goudet, Amélie
AU - Jenjaroen, Kemajittra
AU - Sumonwiriya, Manutsanun
AU - Rinchai, Darawan
AU - Musson, Julie
AU - Overbeek, Saskia
AU - Makinde, Julia
AU - Quigley, Kathryn
AU - Manji, Jiten
AU - Spink, Natasha
AU - Yos, Pagnarith
AU - Wuthiekanun, Vanaporn
AU - Bancroft, Gregory
AU - Robinson, John
AU - Lertmemongkolchai, Ganjana
AU - Dunachie, Susanna
AU - Maillere, Bernard
AU - Holden, Matthew
AU - Altmann, Daniel
AU - Boyton, Rosemary
N1 - This work was supported by National Institutes of Health–National Institute of Allergy and Infectious Diseases Large Scale T Cell Epitope Discovery Program Contract HHSN27220090046C (to R.B. and D.A.), the Welton Foundation (to R.B.), the National Institute for Health Research Biomedical Research funding scheme (to R.B. and D.A.), and a Wellcome Trust Intermediate Clinical Fellowship award (WT100174AIA; to S.D.).
PY - 2015/5/15
Y1 - 2015/5/15
N2 - There is an urgent need for a better understanding of adaptive immunity to Burkholderia pseudomallei, the causative agent of melioidosis that is frequently associated with sepsis or death in patients in Southeast Asia and Northern Australia. The imperative to identify vaccine targets is driven both by the public health agenda in these regions and biological threat concerns. In several intracellular bacterial pathogens, alkyl hydroperoxidase reductases are upregulated as part of the response to host oxidative stress, and they can stimulate strong adaptive immunity. We show that alkyl hydroperoxidase reductase (AhpC) of B. pseudomallei is strongly immunogenic for T cells of 'humanized' HLA transgenic mice and seropositive human donors. Some T cell epitopes, such as p6, are able to bind diverse HLA class II heterodimers and stimulate strong T cell immunity in mice and humans. Importantly, patients with acute melioidosis who survive infection show stronger T cell responses to AhpC relative to those who do not. Although the sequence of AhpC is virtually invariant among global B. pseudomallei clinical isolates, a Cambodian isolate varies only in C-terminal truncation of the p6 T cell epitope, raising the possibility of selection by host immunity. This variant peptide is virtually unable to stimulate T cell immunity. For an infection in which there has been debate about centrality of T cell immunity in defense, these observations support a role for T cell immunity to AhpC in disease protection.
AB - There is an urgent need for a better understanding of adaptive immunity to Burkholderia pseudomallei, the causative agent of melioidosis that is frequently associated with sepsis or death in patients in Southeast Asia and Northern Australia. The imperative to identify vaccine targets is driven both by the public health agenda in these regions and biological threat concerns. In several intracellular bacterial pathogens, alkyl hydroperoxidase reductases are upregulated as part of the response to host oxidative stress, and they can stimulate strong adaptive immunity. We show that alkyl hydroperoxidase reductase (AhpC) of B. pseudomallei is strongly immunogenic for T cells of 'humanized' HLA transgenic mice and seropositive human donors. Some T cell epitopes, such as p6, are able to bind diverse HLA class II heterodimers and stimulate strong T cell immunity in mice and humans. Importantly, patients with acute melioidosis who survive infection show stronger T cell responses to AhpC relative to those who do not. Although the sequence of AhpC is virtually invariant among global B. pseudomallei clinical isolates, a Cambodian isolate varies only in C-terminal truncation of the p6 T cell epitope, raising the possibility of selection by host immunity. This variant peptide is virtually unable to stimulate T cell immunity. For an infection in which there has been debate about centrality of T cell immunity in defense, these observations support a role for T cell immunity to AhpC in disease protection.
U2 - 10.4049/jimmunol.1402862
DO - 10.4049/jimmunol.1402862
M3 - Article
C2 - 25862821
SN - 0022-1767
VL - 194
SP - 4814
EP - 4824
JO - The Journal of Immunology
JF - The Journal of Immunology
IS - 10
ER -