Open AccessExperimental Persistent Infection of BALB/c Mice with Small-Colony Variants of Burkholderia pseudomallei Leads to Concurrent Upregulation of PD-1 on T Cells and Skewed Th1 and Th17 Responses
Author(s) -
Jia-Xiang See,
Chandramathi Samudi,
Alireza Saeidi,
Nivedita Me,
Leang-Chung Choh,
Jamuna Vadivelu,
Esaki M. Shankar
Publication year - 2016
Publication title -
plos neglected tropical diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.99
H-Index - 135
eISSN - 1935-2735
pISSN - 1935-2727
DOI - 10.1371/journal.pntd.0004503
Subject(s) - burkholderia pseudomallei , balb/c , microbiology and biotechnology , melioidosis , downregulation and upregulation , biology , immunology , immune system , virology , bacteria , genetics , gene
Background Burkholderia pseudomallei ( B . pseudomallei ), the causative agent of melioidosis, is a deadly pathogen endemic across parts of tropical South East Asia and Northern Australia. B . pseudomallei can remain latent within the intracellular compartment of the host cell over prolonged periods of time, and cause persistent disease leading to treatment difficulties. Understanding the immunological mechanisms behind persistent infection can result in improved treatment strategies in clinical melioidosis. Methods Ten-day LD 50 was determined for the small-colony variant (SCV) and its parental wild-type (WT) via intranasal route in experimental BALB/c mice. Persistent B . pseudomallei infection was generated by administrating sub-lethal dose of the two strains based on previously determined LD 50 . After two months, peripheral blood mononuclear cells (PBMCs) and plasma were obtained to investigate host immune responses against persistent B . pseudomallei infection. Lungs, livers, and spleens were harvested and bacterial loads in these organs were determined. Results Based on the ten-day LD 50 , the SCV was ~20-fold less virulent than the WT. The SCV caused higher bacterial loads in spleens compared to its WT counterparts with persistent B . pseudomallei infection. We found that the CD4+ T-cell frequencies were decreased, and the expressions of PD-1, but not CTLA-4 were significantly increased on the CD4+ and CD8+ T cells of these mice. Notably, persistent infection with the SCV led to significantly higher levels of PD-1 than the WT B . pseudomallei . Plasma IFN-γ, IL-6, and IL-17A levels were elevated only in SCV-infected mice. In addition, skewed plasma Th1 and Th17 responses were observed in SCV-infected mice relative to WT-infected and uninfected mice. Conclusion B . pseudomallei appears to upregulate the expression of PD-1 on T cells to evade host immune responses, which likely facilitates bacterial persistence in the host. SCVs cause distinct pathology and immune responses in the host as compared to WT B . pseudomallei .