IL-12/23p40-dependent clearance of Anaplasma phagocytophilum in the murine model of human anaplasmosis.
Human anaplasmosis is an emerging infectious disease transmitted by ticks that can be potentially fatal in the immunocompromised and the elderly. The mechanisms of defense against the causative agent, Anaplasma phagocytophilum, are not completely understood; however, interferon (IFN)-gamma plays an important role in pathogen clearance. Here, we show that IFN-gamma is regulated through an early IL-12/23p40-dependent mechanism. Interleukin (IL)-12/23p40 is regulated in macrophages and dendritic cells after activation by microbial agonists and cytokines and constitutes a subunit of IL-12 and IL-23. IL-12/23p40-deficient mice displayed an increased A. phagocytophilum burden, accelerated thrombocytopenia and increased neutrophil numbers in the spleen at day 6 postinfection. Infection of MyD88- and mitogen-activated kinase kinase 3 (MKK3)-deficient mice suggested that the early susceptibility due to IL-12/23p40 deficiency was not dependent on signaling through MyD88 or MKK3. The lack of IL-12/23p40 reduced IFN-gamma production in both CD4(+) and CD8(+) T cells although the effect was more pronounced in CD4(+) T cells. Our data suggest that the immune response against A. phagocytophilum is a multifactorial and cooperative process. The IL-12/23p40 subunit drives the CD4(+) Th1 immune response in the early phase of infection and IL-12/23p40-independent mechanisms ultimately contribute to pathogen elimination from the host.
Pedra
Joao H F
JH
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Tao
Jian
J
Sutterwala
Fayyaz S
FS
Sukumaran
Bindu
B
Berliner
Nancy
N
Bockenstedt
Linda K
LK
Flavell
Richard A
RA
Yin
Zhinan
Z
Fikrig
Erol
E
D041081:Anaplasma phagocytophilum; D000712:Anaplasmosis / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000502:physiology*; D007958:Leukocyte Count; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000502:physiology; D009504:Neutrophils; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D013921:Thrombocytopenia / Q000382:microbiology
D053762:Interleukin-12 Subunit p40; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D007371:Interferon-gamma; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse