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1.
Sci Rep ; 6: 30239, 2016 07 22.
Article in English | MEDLINE | ID: mdl-27444648

ABSTRACT

Terminal complement membrane attack complex (MAC) formation is induced initially by C5b, followed by the sequential condensation of the C6, C7, C8. Polymerization of C9 to the C5b-8 complex forms the C5b-9 (or MAC). The C5b-9 forms lytic or non lytic pores in the cell membrane destroys membrane integrity. The biological functionalities of MAC has been previously investigated by using either the mice deficient in C5 and C6, or MAC's regulator CD59. However, there is no available C9 deficient mice (mC9(-/-)) for directly dissecting the role of C5b-9 in the pathogenesis of human diseases. Further, since C5b-7 and C5b-8 complexes form non lytic pore, it may also plays biological functionality. To better understand the role of terminal complement cascades, here we report a successful generation of mC9(-/-). We demonstrated that lack of C9 attenuates anti-erythrocyte antibody-mediated hemolysis or LPS-induced acute shock. Further, the rescuing effect on the acute shock correlates with the less release of IL-1ß in mC9(-/-), which is associated with suppression of MAC-mediated inflammasome activation in mC9(-/-). Taken together, these results not only confirm the critical role of C5b-9 in complement-mediated hemolysis and but also highlight the critical role of C5b-9 in inflammasome activation.


Subject(s)
Complement C5b/genetics , Complement C9/genetics , Complement Membrane Attack Complex/genetics , Inflammation/genetics , Shock/genetics , Animals , Antibodies/immunology , Antibodies/metabolism , Cell Membrane/genetics , Cell Membrane/metabolism , Complement C5b/immunology , Complement C9/immunology , Complement Membrane Attack Complex/chemistry , Complement Membrane Attack Complex/immunology , Complement System Proteins/genetics , Complement System Proteins/immunology , Complement System Proteins/metabolism , Erythrocytes/immunology , Erythrocytes/metabolism , Hemolysis/immunology , Humans , Inflammasomes/genetics , Inflammasomes/immunology , Inflammation/chemically induced , Inflammation/immunology , Inflammation/pathology , Lipopolysaccharides/toxicity , Mice , Mice, Knockout , Shock/chemically induced , Shock/immunology , Shock/physiopathology
2.
J Immunol ; 193(10): 5099-107, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25297874

ABSTRACT

Listeria monocytogenes is a major cause of mortality resulting from food poisoning in the United States. In mice, C5 has been genetically linked to host resistance to listeriosis. Despite this genetic association, it remains poorly understood how C5 and its activation products, C5a and C5b, confer host protection to this Gram-positive intracellular bacterium. In this article, we show in a systemic infection model that the major receptor for C5a, C5aR1, is required for a normal robust host immune response against L. monocytogenes. In comparison with wild-type mice, C5aR1(-/-) mice had reduced survival and increased bacterial burden in their livers and spleens. Infected C5aR1(-/-) mice exhibited a dramatic reduction in all major subsets of splenocytes, which was associated with elevated caspase-3 activity and increased TUNEL staining. Because type 1 IFN has been reported to impede the host response to L. monocytogenes through the promotion of splenocyte death, we examined the effect of C5aR1 on type 1 IFN expression in vivo. Indeed, serum levels of IFN-α and IFN-ß were significantly elevated in L. monocytogenes-infected C5aR1(-/-) mice. Similarly, the expression of TRAIL, a type 1 IFN target gene and a proapoptotic factor, was elevated in NK cells isolated from infected C5aR1(-/-) mice. Treatment of C5aR1(-/-) mice with a type 1 IFNR blocking Ab resulted in near-complete rescue of L. monocytogenes-induced mortality. Thus, these findings reveal a critical role for C5aR1 in host defense against L. monocytogenes through the suppression of type 1 IFN expression.


Subject(s)
Interferon-alpha/genetics , Interferon-beta/genetics , Listeria monocytogenes/immunology , Listeriosis/immunology , Spleen/immunology , Anaphylatoxins/immunology , Animals , Antibodies/pharmacology , Apoptosis , Bacterial Load , Caspase 3/genetics , Caspase 3/immunology , Complement C5a/genetics , Complement C5a/immunology , Complement C5b/genetics , Complement C5b/immunology , Gene Expression , Interferon-alpha/immunology , Interferon-beta/immunology , Listeriosis/drug therapy , Listeriosis/microbiology , Listeriosis/mortality , Liver/immunology , Liver/microbiology , Liver/pathology , Lymphocytes/immunology , Lymphocytes/microbiology , Lymphocytes/pathology , Male , Mice , Mice, Knockout , Receptor, Anaphylatoxin C5a/genetics , Receptor, Anaphylatoxin C5a/immunology , Receptors, Interferon/antagonists & inhibitors , Receptors, Interferon/genetics , Receptors, Interferon/immunology , Spleen/microbiology , Spleen/pathology , Survival Analysis , TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/immunology
3.
PLoS Pathog ; 10(9): e1004412, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25254972

ABSTRACT

During evolution, herpesviruses have developed numerous, and often very ingenious, strategies to counteract efficient host immunity. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) eludes host immunity by undergoing a dormant stage, called latency wherein it expresses a minimal number of viral proteins to evade host immune activation. Here, we show that during latency, KSHV hijacks the complement pathway to promote cell survival. We detected strong deposition of complement membrane attack complex C5b-9 and the complement component C3 activated product C3b on Kaposi's sarcoma spindle tumor cells, and on human endothelial cells latently infected by KSHV, TIME-KSHV and TIVE-LTC, but not on their respective uninfected control cells, TIME and TIVE. We further showed that complement activation in latently KSHV-infected cells was mediated by the alternative complement pathway through down-regulation of cell surface complement regulatory proteins CD55 and CD59. Interestingly, complement activation caused minimal cell death but promoted the survival of latently KSHV-infected cells grown in medium depleted of growth factors. We found that complement activation increased STAT3 tyrosine phosphorylation (Y705) of KSHV-infected cells, which was required for the enhanced cell survival. Furthermore, overexpression of either CD55 or CD59 in latently KSHV-infected cells was sufficient to inhibit complement activation, prevent STAT3 Y705 phosphorylation and abolish the enhanced survival of cells cultured in growth factor-depleted condition. Together, these results demonstrate a novel mechanism by which an oncogenic virus subverts and exploits the host innate immune system to promote viral persistent infection.


Subject(s)
Apoptosis/immunology , Complement C3b/metabolism , Complement C5b/metabolism , Herpesvirus 8, Human/physiology , Sarcoma, Kaposi/virology , Virus Latency , Blotting, Western , Cell Proliferation , Cells, Cultured , Complement C3b/genetics , Complement C5b/genetics , Endothelium, Vascular/immunology , Endothelium, Vascular/pathology , Endothelium, Vascular/virology , Flow Cytometry , Fluorescent Antibody Technique , Human Umbilical Vein Endothelial Cells/immunology , Human Umbilical Vein Endothelial Cells/pathology , Human Umbilical Vein Endothelial Cells/virology , Humans , Inflammation/immunology , Inflammation/pathology , Inflammation/virology , Neovascularization, Pathologic , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Sarcoma, Kaposi/immunology , Sarcoma, Kaposi/pathology , Viral Proteins/genetics , Viral Proteins/immunology , Viral Proteins/metabolism
4.
Neurobiol Dis ; 26(3): 497-511, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17412602

ABSTRACT

We investigated the involvement of the complement cascade during epileptogenesis in a rat model of temporal lobe epilepsy (TLE), and in the chronic epileptic phase in both experimental as well as human TLE. Previous rat gene expression analysis using microarrays indicated prominent activation of the classical complement pathway which peaked at 1 week after SE in CA3 and entorhinal cortex. Increased expression of C1q, C3 and C4 was confirmed in CA3 tissue using quantitative PCR at 1 day, 1 week and 3-4 months after status epilepticus (SE). Upregulation of C1q and C3d protein expression was confirmed mainly to be present in microglia and in a few hippocampal neurons. In human TLE with hippocampal sclerosis, astroglial, microglial and neuronal (5/8 cases) expression of C1q, C3c and C3d was observed particularly within regions where neuronal cell loss occurs. The membrane attack protein complex (C5b-C9) was predominantly detected in activated microglial cells. The persistence of complement activation could contribute to a sustained inflammatory response and could destabilize neuronal networks involved.


Subject(s)
Complement System Proteins/immunology , Encephalitis/immunology , Epilepsy, Temporal Lobe/immunology , Gliosis/immunology , Hippocampus/immunology , Up-Regulation/immunology , Adolescent , Adult , Aged , Animals , Astrocytes/immunology , Astrocytes/metabolism , Complement C1q/genetics , Complement C1q/immunology , Complement C1q/metabolism , Complement C3c/genetics , Complement C3c/immunology , Complement C3c/metabolism , Complement C3d/genetics , Complement C3d/immunology , Complement C3d/metabolism , Complement C5b/genetics , Complement C5b/immunology , Complement C5b/metabolism , Complement System Proteins/genetics , Complement System Proteins/metabolism , Disease Models, Animal , Encephalitis/genetics , Encephalitis/physiopathology , Epilepsy, Temporal Lobe/genetics , Epilepsy, Temporal Lobe/physiopathology , Female , Gliosis/genetics , Gliosis/physiopathology , Hippocampus/pathology , Hippocampus/physiopathology , Humans , Male , Microglia/immunology , Microglia/metabolism , Middle Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Status Epilepticus/genetics , Status Epilepticus/immunology , Status Epilepticus/physiopathology , Up-Regulation/genetics
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