Mice lacking myeloid differentiation factor 88 display profound defects in host resistance and immune responses to Mycobacterium avium infection not exhibited by Toll-like receptor 2 (TLR2)- and TLR4-deficient animals.
To assess the role of Toll-like receptor (TLR) signaling in host resistance to Mycobacterium avium infection, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88), as well as TLR2(-/-) and TLR4(-/-) animals, were infected with a virulent strain of M. avium, and bacterial burdens and immune responses were compared with those in wild-type (WT) animals. MyD88(-/-) mice failed to control acute and chronic M. avium growth and succumbed 9-14 wk postinfection. Infected TLR2(-/-) mice also showed increased susceptibility, but displayed longer survival and lower bacterial burdens than MyD88(-/-) animals, while TLR4(-/-) mice were indistinguishable from their WT counterparts. Histopathological examination of MyD88(-/-) mice revealed massive destruction of lung tissue not present in WT, TLR2(-/-), or TLR4(-/-) mice. In addition, MyD88(-/-) and TLR2(-/-), but not TLR4(-/-), mice displayed marked reductions in hepatic neutrophil infiltration during the first 2 h of infection. Although both MyD88(-/-) and TLR2(-/-) macrophages showed profound defects in IL-6, TNF, and IL-12p40 responses to M. avium stimulation in vitro, in vivo TNF and IL-12p40 mRNA induction was impaired only in infected MyD88(-/-) mice. Similarly, MyD88(-/-) mice displayed a profound defect in IFN-gamma response that was not evident in TLR2(-/-) or TLR4(-/-) mice or in animals deficient in IL-18. These findings indicate that resistance to mycobacterial infection is regulated by multiple MyD88-dependent signals in addition to those previously attributed to TLR2 or TLR4, and that these undefined elements play a major role in determining bacterial induced proinflammatory as well as IFN-gamma responses.
Feng
Carl G
CG
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-8003, USA. cfeng@niaid.nih.gov
Scanga
Charles A
CA
Collazo-Custodio
Carmen M
CM
Cheever
Allen W
AW
Hieny
Sara
S
Caspar
Patricia
P
Sher
Alan
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009162:Mycobacterium avium / Q000254:growth & development / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014375:Tuberculoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D007371:Interferon-gamma