TNF is important for pathogen control and limits brain damage in murine cerebral listeriosis.
Cerebral listeriosis is a life-threatening disease. However, little is known about the bacterial virulence factors responsible for the severe course of disease and the factors of the immune system contributing to the control of Listeria monocytogenes (LM) or even to the damage of the brain. To analyze the importance of the actA gene of LM, which mediates cell-to-cell spread of intracellular LM, the function of TNF in murine cerebral listeriosis was studied. C57BL/6 mice survived an intracerebral (i.c.) infection with actA-deficient LM, but succumbed to infection with wild-type (WT) LM. Upon infection with actA-deficient LM, macrophages and microglial cells rapidly, and later LM-specific CD4 and CD8 T cells, produced TNF. In contrast to WT mice, TNF-deficient animals succumbed to the infection within 4 days due to failure of control of LM. Histology identified a more severe meningoencephalitis, brain edema, and neuronal damage, but a reduced inducible NO synthase expression in TNF-deficient mice. Reciprocal bone marrow chimeras between WT and TNF-deficient mice revealed that hematogenously derived TNF was essential for survival, whereas TNF produced by brain-resident cells was less important. Death of TNF-deficient mice could be prevented by LM-specific T cells induced by an active immunization before i.c. infection. However, brain pathology and inflammation of immunized TNF-deficient mice were still more severe. In conclusion, these findings identify a crucial role of TNF for the i.c. control of LM and survival of cerebral listeriosis, whereas TNF was not responsible for the destruction of brain tissue.
Virna
Simona
S
Institut für Medizinische Mikrobiologie und Hygiene, Fakultät für klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany.
Deckert
Martina
M
Lütjen
Sonja
S
Soltek
Sabine
S
Foulds
Kathryn E
KE
Shen
Hao
H
Körner
Heinrich
H
Sedgwick
Jonathon D
JD
Schlüter
Dirk
D
D000199:Actins / Q000235:genetics; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D007276:Injections, Intraventricular; D008089:Listeria monocytogenes / Q000235:genetics* / Q000472:pathogenicity*; D008565:Membrane Proteins / Q000235:genetics; D008584:Meningitis, Listeria / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D037521:Virulence Factors
D000199:Actins; D001426:Bacterial Proteins; D008565:Membrane Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; C072980:actA protein, Listeria monocytogenes