TY - JOUR
T1 - Perforin and Granzymes Have Distinct Roles in Defensive Immunity and Immunopathology
AU - van Dommelen, Serani L.H.
AU - Sumaria, Nital
AU - Schreiber, Robert D.
AU - Scalzo, Anthony A.
AU - Smyth, Mark J.
AU - Degli-Esposti, Mariapia A.
N1 - Funding Information:
The authors are grateful to S. Griffiths, S. Ross, and staff in the Animal Facilities at the Peter MacCallum and the University of Western Australia for their support with animal breeding and maintenance and G.R. Hill from the Queensland Institute of Medical Research for valuable advice and discussions. G. Brizard is acknowledged for her technical help with some aspects of the project. This work was supported by grants and fellowships from the NHMRC Australia (to A.A.S., M.A.D.-E., and M.J.S), grants from the NIH and the Ludwig Institute for Cancer Research (to R.D.S), and a Wellcome Trust Overseas Senior Research Fellowship in Biomedical Science (to M.A.D.-E.).
PY - 2006/11
Y1 - 2006/11
N2 - Successful control of viral infection requires the host to eliminate the infecting pathogen without causing overt immunopathology. Here we showed that perforin (Prf1) and granzymes (Gzms) have distinct roles in defensive immunity and immunopathology in a well-established model of viral infection. Both Prf1 and Gzms drastically affected the outcome of murine cytomegalovirus (MCMV) infection. Viral titres increased markedly in both Prf1-/- and Gzma-/-Gzmb-/- mice, but Gzma-/-Gzmb-/- mice recovered and survived infection, whereas Prf1-/- mice did not. Indeed, infected Prf1-deficient hosts developed a fatal hemophagocytic lymphohistiocytosis (HLH)-like syndrome. This distinction in outcome depended on accumulation of mononuclear cells and T cells in infected Prf1-/- mice. Importantly, blocking experiments that clearly identified tumor necrosis factor-α (TNF-α) as the principal contributor to the lethality observed in infected Prf1-/- mice provided support for the clinical potential of such an approach in HLH patients whose disease is triggered by viral infection.
AB - Successful control of viral infection requires the host to eliminate the infecting pathogen without causing overt immunopathology. Here we showed that perforin (Prf1) and granzymes (Gzms) have distinct roles in defensive immunity and immunopathology in a well-established model of viral infection. Both Prf1 and Gzms drastically affected the outcome of murine cytomegalovirus (MCMV) infection. Viral titres increased markedly in both Prf1-/- and Gzma-/-Gzmb-/- mice, but Gzma-/-Gzmb-/- mice recovered and survived infection, whereas Prf1-/- mice did not. Indeed, infected Prf1-deficient hosts developed a fatal hemophagocytic lymphohistiocytosis (HLH)-like syndrome. This distinction in outcome depended on accumulation of mononuclear cells and T cells in infected Prf1-/- mice. Importantly, blocking experiments that clearly identified tumor necrosis factor-α (TNF-α) as the principal contributor to the lethality observed in infected Prf1-/- mice provided support for the clinical potential of such an approach in HLH patients whose disease is triggered by viral infection.
KW - CELLIMMUNO
KW - MICROBIO
UR - http://www.scopus.com/inward/record.url?scp=33846238173&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2006.09.010
DO - 10.1016/j.immuni.2006.09.010
M3 - Article
C2 - 17088087
AN - SCOPUS:33846238173
SN - 1074-7613
VL - 25
SP - 835
EP - 848
JO - Immunity
JF - Immunity
IS - 5
ER -