Humanized nonobese diabetic-scid IL2rgammanull mice are susceptible to lethal Salmonella Typhi infection.
Salmonella enterica serovar Typhi, the cause of typhoid fever, is host-adapted to humans and unable to cause disease in mice. Here, we show that S. Typhi can replicate in vivo in nonobese diabetic (NOD)-scid IL2rgamma(null) mice engrafted with human hematopoietic stem cells (hu-SRC-SCID mice) to cause a lethal infection with pathological and inflammatory cytokine responses resembling human typhoid. In contrast, S. Typhi does not exhibit net replication or cause illness in nonengrafted or immunocompetent control animals. Screening of transposon pools in hu-SRC-SCID mice revealed both known and previously unknown Salmonella virulence determinants, including Salmonella Pathogenicity Islands 1, 2, 3, 4, and 6. Our observations indicate that the presence of human immune cells allows the in vivo replication of S. Typhi in mice. The hu-SRC-SCID mouse provides an unprecedented opportunity to gain insights into S. Typhi pathogenesis and devise strategies for the prevention of typhoid fever.
Libby
Stephen J
SJ
Departments of Laboratory Medicine and Microbiology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Brehm
Michael A
MA
Greiner
Dale L
DL
Shultz
Leonard D
LD
McClelland
Michael
M
Smith
Kelly D
KD
Cookson
Brad T
BT
Karlinsey
Joyce E
JE
Kinkel
Traci L
TL
Porwollik
Steffen
S
Canals
Rocio
R
Cummings
Lisa A
LA
Fang
Ferric C
FC
D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D012485:Salmonella typhi / Q000235:genetics / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014435:Typhoid Fever / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014774:Virulence / Q000235:genetics
D016207:Cytokines; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens