An intact complement system dampens cornea inflammation during acute primary HSV-1 infection

AbstractCorneal transparency is an essential characteristic necessary for normal vision. In response to microbial infection, the integrity of the cornea can become compromised as a result of the inflammatory response and the ensuing tissue pathology including neovascularization (NV) and collagen lamellae destruction. We have previously found complement activation contributes to cornea pathology-specifically, denervation in response to HSV-1 infection. Therefore, we investigated whether the complement system also played a role in HSV-1-mediated neovascularization. Using wild type (WT) and complement component 3 deficient (C3 KO) mice infected with HSV-1, we found corneal NV was accelerated associated with an increase in inflammatory monocytes (CD11b+CCR2+CD115+/−Ly6G−Ly6Chigh), macrophages (CD11b+CCR2+CD115+Ly6G−Ly6Chigh) and a subpopulation of granulocytes/neutrophils (CD11b+CCR2−CD115+Ly6G+Ly6Clow). There were also increases in select pro-inflammatory and pro-angiogenic factors including IL-1α, matrix metalloproteinases (MMP)-2, MMP-3, MMP-8, CXCL1, CCL2, and VEGF-A that coincided with increased inflammation, neovascularization, and corneal opacity in the C3 KO mice. The difference in inflammation between WT and C3 KO mice was not driven by changes in virus titer. However, viral antigen clearance was hindered in C3 KO mouse corneas suggesting the complement system has a dynamic regulatory role within the cornea once an inflammatory cascade is initiated by HSV-1.

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Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis

mBio ◽

10.1128/mbio.01753-18 ◽

2018 ◽

Vol 9 (5) ◽

Cited By ~ 224

Author(s):

Lisa E. Gralinski ◽

Timothy P. Sheahan ◽

Thomas E. Morrison ◽

Vineet D. Menachery ◽

Kara Jensen ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Host Defense ◽

Complement System ◽

Complement Activation ◽

Fungal Infections ◽

Central Component ◽

Lung Pathology ◽

Inflammatory Monocytes ◽

The Complement System

ABSTRACT Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3–/–), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3–/– mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3–/– mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3–/– mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic. IMPORTANCE The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection.

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COMPLEMENT SYSTEM AS A MARKER OF IMMUNE DYSFUNCTION IN CHILDREN AUTISM SPECTRUM DISORDERS

Medical Immunology (Russia) ◽

10.15789/1563-0625-2019-4-773-780 ◽

2019 ◽

Vol 21 (4) ◽

pp. 773-780

Author(s):

E. G. Cheremnykh ◽

P. A. Ivanov ◽

M. I. Factor ◽

E. Yu. Chikina ◽

S. G. Nikitina ◽

...

Keyword(s):

Autism Spectrum Disorders ◽

Immune System ◽

Complement System ◽

Functional Activity ◽

Autism Spectrum ◽

Autistic Spectrum ◽

Healthy Donors ◽

Spectrum Disorders ◽

The Difference ◽

The Complement System

It is known that functional activity of complement system depends not only on balance and concentration of components participating in formation of the system end products, but also on levels of inhibitory activities. Numerous relations with hemostasis also substantially contribute to general level of complement system activity. Changes in complement system functioning are inevitable during chronic diseases accompanied with immune system dysregulation. All mental diseases tend to be chronic and are they aggravated by patients’ immune system changes. Autism spectrum disorders in children is a group of mental disorders. Immune system dysregulation is usually detected in such patients, manifesting as excessive susceptibility to viral and bacterial infections. Therefore, the level of its functional activity is diagnostically and prognostically significant in this pathology, since the complement system is a key element of immune system.We have evaluated functional activity of complement system in patients with autistic spectrum disorders, using the method which was developed earlier. It is based on the reaction of the protozoa (Tetrahymena pyriformis) which are both targets and activators for the complement system. The complement system capacity (cSC) was used as the main parameter of complement evaluation. The half-time of protozoa survival (T50) was defined using the BioLat device for each serum specimen added at four concentrations (1/20, 1/40, 1/80, 1/160 dilution). The complement capacity was calculated as the area enclosed by influence curve of the reciprocals of T50 and the serum dilution. According to Mann–Whitney U test, the difference between patients’ and healthy volunteers’ groups was established as Z = 4.43 (by T50 at 1/160 dilution), p < 0.001 and by cSCas Z = 5.8, p < 0.001. cSC was calculated from the results obtained at each serum concentration measured. The difference between the two groups according to Mann–Whitney U test appeared to be more significant than the difference according to T50. Therefore, cSC was taken as the main characteristic of complement system function.The contribution of hemostasis plasma components to complement system functional activity level was estimated by determination of complement capacity in plasma and serum of each blood sample from 6 patients with autism spectrum disorders and 5 healthy donors. All healthy donors showed small difference between plasma and serum complement capacity, and their complement activity was higher in plasma. In patients’ group, the complement capacity levels in plasma and serum differed significantly. The cSC levels of two patients were higher in serum than in plasma, and the cSC levels of three other patients were significantly higher in plasma than in serum. Differential involvement of coagulation into the complement system activation may be indicative for the immune system dysfunction which is observed in patients with autistic spectrum disorders of different etiology.

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Modulation of the Complement system by Zingiberacea Aframomum Melegueta in mice-induced Schizophrenia

JOURNAL OF RESEARCH AND REVIEW IN SCIENCE ◽

10.36108/jrrslasu/1202.80.0140 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Thona Wusu

Keyword(s):

Aqueous Extract ◽

Complement System ◽

Economic Effect ◽

Complement Component ◽

Dependent Manner ◽

C Reactive Protein ◽

Phytochemical Content ◽

Reactive Protein ◽

The Complement System ◽

Complement Component 3

Introduction: Schizophrenia is a severe mental disorder among nationalities of the world, which has a substantial social and economic effect. Scientific therapeutic drugs have proved abortive due to adverse effects. Aim: The study investigated the repression of the complement system by aqueous extract of alligator pepper on schizophrenia. Methods: Male mice were induced with schizophrenia using ketamine and dexamethasone; the mice were treated with aqueous extract of alligator pepper (200mg/ml and 400mg/ml) respectively for ten days. After which their brain was removed, and analysed for dopamine. Blood samples was collected from the animal and plasma was used to determine the level of complement component (3 and 4), and C-reactive protein spectrophotometrically. Phytochemical content of the aqueous extract was also done spectrophotometrically, and characterization was confirmed using FTIR. Result: The alligator plant extract constituent includes flavonoids, tannins, saponin, steroids, phlabotannis, terpenoids, and cardiac glycoside. With a tannins having a concentration of 1292.6 µg/ml and 726.8µg/ml, phenol had a concentration of 221.7 µg/ml and 94.2 µg/ml and flavonoids had a concentration of 105.3 µg/ml and 100.0 µg/ml at 200mg/ml and 400mg/ml plant concentration respectively. The alligator pepper reversed the effect of ketamine and dexamethasone induced schizophrenia by decreasing the level of C-reactive protein , complement component (3 and 4) and dopamine significantly (<0.0001) in a dose dependent manner, in all the groups compared to the control. Conclusion: The high phenolic and flavonoids content in alligator pepper may be responsible for the antipsychotic property of alligator pepper. Thus, probable natural therapy for schizophrenia.

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The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.693118 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chiara Agostinis ◽

Sonia Zorzet ◽

Andrea Balduit ◽

Gabriella Zito ◽

Alessandro Mangogna ◽

...

Keyword(s):

Complement System ◽

Immune Escape ◽

Immune Surveillance ◽

Complement Component ◽

Wild Type ◽

Local Synthesis ◽

Knock Out ◽

Complement Component C3 ◽

Knock Out Mice ◽

The Complement System

The complement system is a major component of humoral innate immunity, acting as a first line of defense against microbes via opsonization and lysis of pathogens. However, novel roles of the complement system in inflammatory and immunological processes, including in cancer, are emerging. Endometriosis (EM), a benign disease characterized by ectopic endometrial implants, shows certain unique features of cancer, such as the capacity to invade surrounding tissues, and in severe cases, metastatic properties. A defective immune surveillance against autologous tissue deposited in the peritoneal cavity allows immune escape for endometriotic lesions. There is evidence that the glandular epithelial cells found in endometriotic implants produce and secrete the complement component C3. Here, we show, using immunofluorescence and RT-qPCR, the presence of locally synthesized C3 in the ectopic endometriotic tissue, but not in the eutopic tissue. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse into the peritoneum of recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. Peritoneal washings from the wild type mice with EM showed more degranulated mast cells compared to C3 knock-out mice, consistent with higher C3a levels in the peritoneal fluid of EM patients. We provide evidence that C3a participates in an auto-amplifying loop leading to mast cell infiltration and activation, which is pathogenic in EM. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts.

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Role of the Classical Pathway of Complement Activation in Experimentally Induced Polymicrobial Peritonitis

Infection and Immunity ◽

10.1128/iai.69.12.7304-7309.2001 ◽

2001 ◽

Vol 69 (12) ◽

pp. 7304-7309 ◽

Cited By ~ 26

Author(s):

Ilhan Celik ◽

Cordula Stover ◽

Marina Botto ◽

Steffen Thiel ◽

Sotiria Tzima ◽

...

Keyword(s):

Complement System ◽

Complement Activation ◽

Immune Defense ◽

Classical Pathway ◽

Complement Factor ◽

Wild Type ◽

Factor B ◽

The Complement System ◽

Deficient Mice

ABSTRACT The complement system and the natural antibody repertoire provide a critical first-line defense against infection. The binding of natural antibodies to microbial surfaces opsonizes invading microorganisms and activates complement via the classical pathway. Both defense systems cooperate within the innate immune response. We studied the role of the complement system in the host defense against experimental polymicrobial peritonitis using mice lacking either C1q or factor B and C2. The C1q-deficient mice lacked the classical pathway of complement activation. The factor B- and C2-deficient mice were known to lack the classical and alternative pathways, and we demonstrate here that these mice also lacked the lectin pathway of complement activation. Using inoculum doses adjusted to cause 42% mortality in the wild-type strain, none of the mice deficient in the three activation routes of complement (factor B and C2 deficient) survived (mortality of 100%). Mortality in mice deficient only in the classical pathway of complement activation (C1q deficient) was 83%. Application of further dilutions of the polymicrobial inoculum showed a dose-dependent decrease of mortality in wild-type controls, whereas no changes in mortality were observed in the two gene-targeted strains. These results demonstrate that the classical activation pathway is required for an effective antimicrobial immune defense in polymicrobial peritonitis and that, in the infection model used, the remaining antibody-independent complement activation routes (alternative and lectin pathways) provide a supporting line of defense to gain residual protection in classical pathway deficiency.

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Complement factor H contributes to mortality in humans and mice with bacterial meningitis

Journal of Neuroinflammation ◽

10.1186/s12974-019-1675-1 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 4

Author(s):

E. Soemirien Kasanmoentalib ◽

Mercedes Valls Serón ◽

Joo Yeon Engelen-Lee ◽

Michael W. Tanck ◽

Richard B. Pouw ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Bacterial Meningitis ◽

Mouse Model ◽

Adjuvant Treatment ◽

Complement System ◽

Pneumococcal Meningitis ◽

Factor H ◽

Complement Factor ◽

Wild Type ◽

The Complement System

Abstract Background The complement system is a vital component of the inflammatory response occurring during bacterial meningitis. Blocking the complement system was shown to improve the outcome of experimental pneumococcal meningitis. Complement factor H (FH) is a complement regulatory protein inhibiting alternative pathway activation but is also exploited by the pneumococcus to prevent complement activation on its surface conferring serum resistance. Methods In a nationwide prospective cohort study of 1009 episodes with community-acquired bacterial meningitis, we analyzed whether genetic variations in CFH influenced FH cerebrospinal fluid levels and/or disease severity. Subsequently, we analyzed the role of FH in our pneumococcal meningitis mouse model using FH knock-out (Cfh−/−) mice and wild-type (wt) mice. Finally, we tested whether adjuvant treatment with human FH (hFH) improved outcome in a randomized investigator blinded trial in a pneumococcal meningitis mouse model. Results We found the major allele (G) of single nucleotide polymorphism in CFH (rs6677604) to be associated with low FH cerebrospinal fluid concentration and increased mortality. In patients and mice with bacterial meningitis, FH concentrations were elevated during disease and Cfh−/− mice with pneumococcal meningitis had increased mortality compared to wild-type mice due to C3 depletion. Adjuvant treatment of wild-type mice with purified human FH led to complement inhibition but also increased bacterial outgrowth which resulted in similar disease outcomes. Conclusion Low FH levels contribute to mortality in pneumococcal meningitis but adjuvant treatment with FH at a clinically relevant time point is not beneficial.

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Complement Contributes to Inflammatory Tissue Destruction in a Mouse Model of Ross River Virus-Induced Disease

Journal of Virology ◽

10.1128/jvi.02799-06 ◽

2007 ◽

Vol 81 (10) ◽

pp. 5132-5143 ◽

Cited By ~ 72

Author(s):

Thomas E. Morrison ◽

Robert J. Fraser ◽

Paul N. Smith ◽

Suresh Mahalingam ◽

Mark T. Heise

Keyword(s):

Skeletal Muscle ◽

Muscle Tissue ◽

Complement System ◽

Complement Activation ◽

Skeletal Muscle Tissue ◽

Central Component ◽

Ross River Virus ◽

Wild Type ◽

Inflammatory Infiltrates ◽

The Complement System

ABSTRACT Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus, are mosquito-borne viruses that cause significant human disease worldwide, including explosive epidemics that can result in thousands to millions of infected individuals. Similar to infection of humans, infection of C57BL/6 mice with RRV results in severe monocytic inflammation of bone, joint, and skeletal muscle tissues. We demonstrate here that the complement system, an important component of the innate immune response, enhances the severity of RRV-induced disease in mice. Complement activation products were detected in the inflamed tissues and in the serum of RRV-infected wild-type mice. Furthermore, mice deficient in C3 (C3−/−), the central component of the complement system, developed much less severe disease signs than did wild-type mice. Complement-mediated chemotaxis is essential for many inflammatory arthritides; however, RRV-infected wild-type and C3−/− mice had similar numbers and composition of inflammatory infiltrates within hind limb skeletal muscle tissue. Despite similar inflammatory infiltrates, RRV-infected C3−/− mice exhibited far less severe destruction of skeletal muscle tissue. In addition to these studies, complement activation was also detected in synovial fluid from RRV-infected patients. Taken together, these findings indicate that complement activation occurs in the tissues of humans and mice infected with RRV and suggest that complement plays an essential role in the effector phase, but not the inductive phase, of RRV-induced arthritis and myositis.

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The alternative pathway of complement is activated in the glomeruli and tubulointerstitium of mice with adriamycin nephropathy

AJP Renal Physiology ◽

10.1152/ajprenal.00403.2006 ◽

2007 ◽

Vol 293 (2) ◽

pp. F555-F564 ◽

Cited By ~ 30

Author(s):

Amanda M. Lenderink ◽

Katharine Liegel ◽

Danica Ljubanović ◽

Kathrin E. Coleman ◽

Gary S. Gilkeson ◽

...

Keyword(s):

Renal Disease ◽

Complement System ◽

Complement Activation ◽

Alternative Pathway ◽

Host Cells ◽

Renal Tubules ◽

Wild Type ◽

Tubulointerstitial Injury ◽

Factor B ◽

The Complement System

The complement system effectively identifies and clears invasive pathogens as well as injured host cells. Uncontrolled complement activation can also contribute to tissue injury, however, and inhibition of this system may ameliorate many types of inflammatory injury. Several studies have demonstrated that the filtration of complement proteins into the renal tubules, as occurs during proteinuric renal disease, causes tubular inflammation and injury. In the present study, we tested the hypothesis that activation of the complement system in the urinary space requires an intact alternative pathway. Using a model of adriamycin-induced renal injury, which induces injury resembling focal segmental glomerulosclerosis, we examined whether mice deficient in factor B would be protected from the development of progressive tubulointerstitial injury. Complement activation was attenuated in the glomeruli and tubulointerstitium of mice with congenital deficiency of factor B ( fB−/−) compared with wild-type controls, demonstrating that complement activation does occur through the alternative pathway. Deficiency in factor B did not significantly protect the mice from tubulointerstitial injury. However, treatment of wild-type mice with an inhibitory monoclonal antibody to factor B did delay the development of renal failure. These results demonstrate that complement activation in this nonimmune complex-mediated model of progressive renal disease requires an intact alternative pathway.

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Modulation of Mouse Endotoxic Fever by Complement

Infection and Immunity ◽

10.1128/iai.70.5.2519-2525.2002 ◽

2002 ◽

Vol 70 (5) ◽

pp. 2519-2525 ◽

Cited By ~ 21

Author(s):

S. Li ◽

V. M. Holers ◽

S. A. Boackle ◽

C. M. Blatteis

Keyword(s):

Escherichia Coli ◽

Complement System ◽

Guinea Pigs ◽

Critical Role ◽

Complement Cascade ◽

Wild Type ◽

Febrile Response ◽

Gene Deletions ◽

The Core ◽

The Complement System

ABSTRACT It was recently reported that the complement system may be critically involved in the febrile response of guinea pigs to systemic, particularly intraperitoneally (i.p.) injected, lipopolysaccharides (LPS). The present study was designed to identify which component(s) of the complement cascade may be specifically critical. To this end, we used mice with C3, C5, and CR2 gene deletions. To assess preliminarily the suitability of mice for such a study, we replicated our earlier studies with guinea pigs. Thus, to verify initially whether complement is similarly involved in the febrile response of wild-type (C57BL/6J) mice to i.p. LPS (Escherichia coli, 1 μg/mouse), we depleted complement with cobra venom factor (CVF; 7 U/mouse, intravenously [i.v.]). These animals did not develop fever, whereas the core temperature (T c) of CVF vehicle-treated controls rose ∼1°C by 80 min postinjection and then gradually abated over the following 2.5 h, confirming the involvement of complement in fever production after i.p. LPS injection and the suitability of this species for these studies. C3- and C5-sufficient (C3+/+ and C5+/+) mice also developed 1°C fevers within 80 min after i.p. LPS (1 or 2 μg/mouse) injection. These fevers were totally prevented by CVF (10 U/mouse, i.v.) pretreatment. C3- and C5-deficient (C3−/− and C5−/−) mice were also unable to develop T c rises after i.p. LPS. Both CR2+/+ and CR2−/− mice responded normally to i.p. LPS (1 μg/mouse). These data indicate that C5, but not C3d acting through CR2, may play a critical role in the febrile response of mice to i.p. LPS.

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Absence of Macrophage Inflammatory Protein-1α Prevents the Development of Blinding Herpes Stromal Keratitis

Journal of Virology ◽

10.1128/jvi.72.5.3705-3710.1998 ◽

1998 ◽

Vol 72 (5) ◽

pp. 3705-3710 ◽

Cited By ~ 71

Author(s):

Terrence M. Tumpey ◽

Hao Cheng ◽

Donald N. Cook ◽

Oliver Smithies ◽

John E. Oakes ◽

...

Keyword(s):

T Cell ◽

Interleukin 2 ◽

Corneal Opacity ◽

Wild Type ◽

Virus Growth ◽

Inflammatory Protein ◽

Stromal Keratitis ◽

The Mean ◽

Macrophage Inflammatory Protein ◽

Hsv 1

ABSTRACT Prior studies in our laboratory have suggested that the CC chemokine macrophage inflammatory protein-1α (MIP-1α) may be an important mediator in the blinding ocular inflammation which develops following herpes simplex virus type 1 (HSV-1) infection of the murine cornea. To directly test this hypothesis, MIP-1α-deficient (−/−) mice and their wild-type (+/+) counterparts were infected topically on the scarified cornea with 2.5 × 105 PFU of HSV-1 strain RE and subsequently graded for corneal opacity. Four weeks postinfection (p.i.), the mean corneal opacity score of −/− mice was 1.1 ± 0.3 while that of the +/+ mice was 3.7 ± 0.5. No detectable infiltrating CD4+ T cells were seen histologically at 14 or 21 days p.i. in −/− animals, whereas the mean CD4+ T-cell count per field (36 fields counted) in +/+ hosts was 26 ± 2 (P < 0.001). In addition, neutrophil counts in the −/− mouse corneas were reduced by >80% in comparison to the wild-type controls. At 2 weeks p.i., no interleukin-2 or gamma interferon could be detected in six of seven −/− mice, whereas both T-cell cytokines were readily demonstrable in +/+ mouse corneas. Also, MIP-2 and monocyte chemoattractant protein-1 protein levels were significantly lower in MIP-1α −/− mouse corneas than in +/+ host corneas, suggesting that MIP-1α directly, or more likely indirectly, influences the expression of other chemokines. Interestingly, despite the paucity of infiltrating cells, HSV-1 clearance from the eyes of −/− mice was not significantly different from that observed in +/+ hosts. We conclude that MIP-1α is not needed to control virus growth in the cornea but is essential for the development of severe stromal keratitis.

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