DNAX-activating protein of 12 kDa impairs host defense in pneumococcal pneumonia.
OBJECTIVE
Streptococcus pneumoniae is the most common causative organism in community-acquired pneumonia responsible for millions of deaths every year. DNAX-activating protein of 12 kDa is an adaptor molecule for different myeloid expressed receptors involved in innate immunity.


METHODS
Animal study.


METHODS
University research laboratory.


METHODS
DNAX-activating protein of 12 kDa-deficient (dap12) and wild-type mice.


METHODS
Mice were intranasally infected with S. pneumoniae. In addition, ex vivo responsiveness of alveolar macrophages was examined.


RESULTS
dap12 alveolar macrophages released more tumor necrosis factor-α upon stimulation with S. pneumoniae and displayed increased phagocytosis of this pathogen compared with wild-type cells. After infection with S. pneumoniae via the airways, dap12 mice demonstrated reduced bacterial outgrowth in the lungs together with delayed dissemination to distant body sites relative to wild-type mice. This favorable response in dap12 mice was accompanied by reduced lung inflammation and an improved survival.


CONCLUSIONS
These data suggest that DNAX-activating protein of 12 kDa impairs host defense during pneumococcal pneumonia at the primary site of infection at least in part by inhibiting phagocytosis by alveolar macrophages.
1Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 3Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 4Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Tijmen J
TJ
Hommes
Arie J
AJ
Hoogendijk
Mark C
MC
Dessing
Cornelis
C
Van't Veer
Sandrine
S
Florquin
Alex F
AF
de Vos
Tom
T
van der Poll
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D007249:Inflammation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D013296:Streptococcus pneumoniae / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C484963:Tyrobp protein, mouse