TY - JOUR
T1 - Natural killer T (NKT) cells accelerate Shiga toxin type 2 (Stx2) pathology in mice
AU - Obata, Fumiko
AU - Subrahmanyam, Priyanka B.
AU - Vozenilek, Aimee E.
AU - Hippler, Lauren M.
AU - Jeffers, Tynae
AU - Tongsuk, Methinee
AU - Tiper, Irina
AU - Saha, Progyaparamita
AU - Jandhyala, Dakshina M.
AU - Kolling, Glynis L.
AU - Latinovic, Olga
AU - Webb, Tonya J.
N1 - Publisher Copyright:
© 2015 Obata, Subrahmanyam, Vozenilek, Hippler, Jeffers, Tongsuk, Tiper, Saha, Jandhyala, Kolling, Latinovic and Webb.
PY - 2015
Y1 - 2015
N2 - Shiga toxin-producing Escherichia coli (STEC) is a leading cause of childhood renal disease Hemolytic Uremic Syndrome (HUS). The involvement of renal cytokines and chemokines is suspected to play a critical role in disease progression. In current article, we tested the hypothesis that NKT cells are involved in Stx2-induced pathology in vivo. To address this hypothesis we compared Stx2 toxicity in WT and CD1 knockout (KO) mice. In CD1KO mice, which lack natural killer T (NKT) cells, Stx2-induced pathologies such as weight loss, renal failure, and death were delayed. In WT mice, Stx2-specific selective increase in urinary albumin occurs in later time points, and this was also delayed in NKT cell deficient mice. NKT cell-associated cytokines such as IL-2, IL-4, IFN-γ, and IL-17 were detected in kidney lysates of Stx2-injected WT mice with the peak around 36 h after Stx2 injection. In CD1KO, there was a delay in the kinetics, and increases in these cytokines were observed 60 h post Stx2 injection. These data suggest that NKT cells accelerate Stx2-induced pathology in mouse kidneys. To determine the mechanism by which NKT cells promote Stx2-associated disease, in vitro studies were performed using murine renal cells. We found that murine glomerular endothelial cells and podocytes express functional CD1d molecules and can present exogenous antigen to NKT cells. Moreover, we observed the direct interaction between Stx2 and the receptor Gb3 on the surface of mouse renal cells by 3D STORM-TIRF which provides single molecule imaging. Collectively, these data suggest that Stx2 binds to Gb3 on renal cells and leads to aberrant CD1d-mediated NKT cell activation. Therefore, strategies targeting NKT cells could have a significant impact on Stx2-associated renal pathology in STEC disease.
AB - Shiga toxin-producing Escherichia coli (STEC) is a leading cause of childhood renal disease Hemolytic Uremic Syndrome (HUS). The involvement of renal cytokines and chemokines is suspected to play a critical role in disease progression. In current article, we tested the hypothesis that NKT cells are involved in Stx2-induced pathology in vivo. To address this hypothesis we compared Stx2 toxicity in WT and CD1 knockout (KO) mice. In CD1KO mice, which lack natural killer T (NKT) cells, Stx2-induced pathologies such as weight loss, renal failure, and death were delayed. In WT mice, Stx2-specific selective increase in urinary albumin occurs in later time points, and this was also delayed in NKT cell deficient mice. NKT cell-associated cytokines such as IL-2, IL-4, IFN-γ, and IL-17 were detected in kidney lysates of Stx2-injected WT mice with the peak around 36 h after Stx2 injection. In CD1KO, there was a delay in the kinetics, and increases in these cytokines were observed 60 h post Stx2 injection. These data suggest that NKT cells accelerate Stx2-induced pathology in mouse kidneys. To determine the mechanism by which NKT cells promote Stx2-associated disease, in vitro studies were performed using murine renal cells. We found that murine glomerular endothelial cells and podocytes express functional CD1d molecules and can present exogenous antigen to NKT cells. Moreover, we observed the direct interaction between Stx2 and the receptor Gb3 on the surface of mouse renal cells by 3D STORM-TIRF which provides single molecule imaging. Collectively, these data suggest that Stx2 binds to Gb3 on renal cells and leads to aberrant CD1d-mediated NKT cell activation. Therefore, strategies targeting NKT cells could have a significant impact on Stx2-associated renal pathology in STEC disease.
KW - Cytokines
KW - Escherichia coli
KW - Hemolytic uremic syndrome
KW - Mouse models
KW - Natural killer T cell
KW - STORM-TIRF
KW - Shiga toxin
KW - Single molecule imaging
UR - http://www.scopus.com/inward/record.url?scp=84930938227&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930938227&partnerID=8YFLogxK
U2 - 10.3389/fmicb.2015.00262
DO - 10.3389/fmicb.2015.00262
M3 - Article
C2 - 25904903
AN - SCOPUS:84930938227
SN - 1664-302X
VL - 6
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
IS - APR
M1 - 262
ER -