TY - JOUR
T1 - Variation in hemolysin A expression between uropathogenic Escherichia coli isolates determines NLRP3-dependent vs. -independent macrophage cell death and host colonization
AU - Murthy, Ambika M. V.
AU - Sullivan, Matthew J.
AU - Nhu, Nguyen Thi Khanh
AU - Lo, Alvin W.
AU - Phan, Minh-Duy
AU - Peters, Kate M.
AU - Boucher, Dave
AU - Schroder, Kate
AU - Beatson, Scott A.
AU - Ulett, Glen C.
AU - Schembri, Mark A.
AU - Sweet, Matthew J.
N1 - Funding Information: The authors thank Rodney Welch (University of Wisconsin, Madison, WI, USA) for providing the hemolysin A antibody, Avril Robertson (The University of Queensland) for providing MCC950, and the Australian Red Cross Blood Service for providing buffy coats that were used to isolate monocytes in these studies. This work was supported by Project Grants GNT1068593 and GNT1129273 from the National Health and Medical Research Council of Australia (NHMRC). D.B. was supported by a University of Queensland Postdoctoral Fellowship; K.S. was supported by an NHMRC Career Development Fellowship (GNT1141131); S.A.B. is supported by an NHMRC Career Development Fellowship (GNT1090456); and MJ.S. and M.A.S. were supported by NHMRC Senior Research Fellowships (GNT1107914, GNT1106930). The authors declare no conflicts of interest.
PY - 2019/6
Y1 - 2019/6
N2 - Uropathogenic Escherichia coli (UPEC) is the major cause of urinary tract infections (UTIs). The multidrug-resistant E. coli sequence type 131 (ST131) clone is a serious threat to human health, yet its effects on immune responses are not well understood. Here we screened a panel of ST131 isolates, finding that only strains expressing the toxin hemolysin A (HlyA) killed primary human macrophages and triggered maturation of the inflammasome-dependent cytokine IL-1β. Using a representative strain, the requirement for the hlyA gene in these responses was confirmed. We also observed considerable heterogeneity in levels of cell death initiated by different HlyA+ve ST131 isolates, and this correlated with secreted HlyA levels. Investigation into the biological significance of this variation revealed that an ST131 strain producing low levels of HlyA initiated cell death that was partly dependent on the nod-like receptor family pyrin domain–containing 3 (NLRP3) inflammasome, with this response being associated with a host-protective role in a mouse UTI model. When the same ST131 strain was engineered to overexpress high HlyA levels, macrophage cell death occurred even when NLRP3 function was abrogated, and bladder colonization was significantly increased. Thus, variation in HlyA expression in UPEC affects mechanisms by which macrophages die, as well as host susceptibility vs. resistance to colonization.—Murthy, A. M. V., Sullivan, M. J., Nhu, N. T. K., Lo, A. W., Phan, M.-D., Peters, K. M., Boucher, D., Schroder, K., Beatson, S. A., Ulett, G. C., Schembri, M. A., Sweet, M. J. Variation in hemolysin A expression between uropathogenic Escherichia coli isolates determines NLRP3-dependent vs. -independent macrophage cell death and host colonization. FASEB J. 33, 7437–7450 (2019). www.fasebj.org.
AB - Uropathogenic Escherichia coli (UPEC) is the major cause of urinary tract infections (UTIs). The multidrug-resistant E. coli sequence type 131 (ST131) clone is a serious threat to human health, yet its effects on immune responses are not well understood. Here we screened a panel of ST131 isolates, finding that only strains expressing the toxin hemolysin A (HlyA) killed primary human macrophages and triggered maturation of the inflammasome-dependent cytokine IL-1β. Using a representative strain, the requirement for the hlyA gene in these responses was confirmed. We also observed considerable heterogeneity in levels of cell death initiated by different HlyA+ve ST131 isolates, and this correlated with secreted HlyA levels. Investigation into the biological significance of this variation revealed that an ST131 strain producing low levels of HlyA initiated cell death that was partly dependent on the nod-like receptor family pyrin domain–containing 3 (NLRP3) inflammasome, with this response being associated with a host-protective role in a mouse UTI model. When the same ST131 strain was engineered to overexpress high HlyA levels, macrophage cell death occurred even when NLRP3 function was abrogated, and bladder colonization was significantly increased. Thus, variation in HlyA expression in UPEC affects mechanisms by which macrophages die, as well as host susceptibility vs. resistance to colonization.—Murthy, A. M. V., Sullivan, M. J., Nhu, N. T. K., Lo, A. W., Phan, M.-D., Peters, K. M., Boucher, D., Schroder, K., Beatson, S. A., Ulett, G. C., Schembri, M. A., Sweet, M. J. Variation in hemolysin A expression between uropathogenic Escherichia coli isolates determines NLRP3-dependent vs. -independent macrophage cell death and host colonization. FASEB J. 33, 7437–7450 (2019). www.fasebj.org.
KW - inflammasome
KW - ST131
KW - UPEC
KW - UTI
KW - α-hemolysin
UR - http://www.scopus.com/inward/record.url?scp=85067267902&partnerID=8YFLogxK
U2 - 10.1096/fj.201802100R
DO - 10.1096/fj.201802100R
M3 - Article
C2 - 30869997
AN - SCOPUS:85067267902
VL - 33
SP - 7437
EP - 7450
JO - The FASEB Journal
JF - The FASEB Journal
SN - 0892-6638
IS - 6
ER -
