Immune responses to Pneumocystis murina are robust in healthy mice but largely absent in CD40 ligand-deficient mice.
Pneumocystis is a pathogen of immunocompromised hosts but can also infect healthy hosts, in whom infection is rapidly controlled and cleared. Microarray methods were used to examine differential gene expression in the lungs of C57BL/6 and CD40 ligand knockout (CD40L-KO) mice over time following exposure to Pneumocystis murina. Immunocompetent C57BL/6 mice, which control and clear infection efficiently, showed a robust response to infection characterized by the up-regulation of 349 primarily immune response-associated genes. Temporal changes in the expression of these genes identified an early (Week 2), primarily innate response, which waned before the infection was controlled; this was followed by primarily adaptive immune responses that peaked at Week 5, which coincided with clearance of the infection. In conjunction with the latter, there was an increased expression of B cell-associated (Ig) genes at Week 6 that persisted through 11 weeks. In contrast, CD40L-KO mice, which are highly susceptible to developing severe Pneumocystis pneumonia, showed essentially no up-regulation of immune response-associated genes at Days 35-75. Immunohistochemical staining supported these observations by demonstrating an increase in CD4+, CD68+, and CD19+ cells in C57BL/6 but not CD40L-KO mice. Thus, the healthy host demonstrates a robust, biphasic response to infection by Pneumocystis; CD40L is an essential upstream regulator of the adaptive immune responses that efficiently control infection and prevent development of progressive pneumonia.
Hernandez-Novoa
Beatriz
B
Critical Care Medicine Department, National Institutes of Health Clinical Center, NIH, Building 10, Room 2C145, MSC 1662, Bethesda, MD 20892-1662, USA.
Bishop
Lisa
L
Logun
Carolea
C
Munson
Peter J
PJ
Elnekave
Eldad
E
Rangel
Zoila G
ZG
Barb
Jennifer
J
Danner
Robert L
RL
Kovacs
Joseph A
JA
D000818:Animals; D023201:CD40 Ligand / Q000172:deficiency* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011010:Pneumocystis / Q000276:immunology*; D016720:Pneumocystis Infections / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D023201:CD40 Ligand