The effect of complement depletion on lung clearance of bacteria.

Gross, Gary N.; Rehm, S R; Pierce, Alan K.

doi:10.1172/jci109138

Cited by 109 publications

(64 citation statements)

References 26 publications

(16 reference statements)

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“…The absence of a functional complement system has been associated with a paradoxical increase in inflammation in the lung during pneumonia in previous studies (5,6,19). In the current work, migration of neutrophils into the airway was unaffected by the absence of complement, and lung homogenate MPO activity was double that observed in normal mice.…”

Section: Discussionmentioning

confidence: 85%

“…The complement system also has been shown to be significant in the response to Pseudomonas pneumonia. Genetically C5-deficient mice exhibit impaired clearance of intrapulmonary P. aeruginosa (5). Although the formation of the membrane attack complex and subsequent complementmediated bacteriolysis may contribute to the role of C5, a need for the anaphylatoxin C5a has been demonstrated in C5a-receptor null mice challenged with intratracheal Pseudomonas (6).…”

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confidence: 99%

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Murine Complement Interactions withPseudomonas aeruginosaand Their Consequences During Pneumonia

Younger

Shankar-Sinha

Mickiewicz

et al. 2003

Am J Respir Cell Mol Biol

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Complement is necessary for defense against lung infection with Pseudomonas aeruginosa in mice. We studied in vitro interactions between complement and P. aeruginosa and in vivo effects of complement depletion to better understand this relationship. In vitro, P. aeruginosa strain UI-18 was resistant to killing by mouse serum. However, C3 opsonized the organism (via the alternative and mannose binding lectin [MBL] pathways), and C5 convertase activity on the bacterial surface was demonstrated. In vivo, compared with normal mice, complement-deficient mice experienced higher mortality and failed to sterilize their bronchoalveolar space within 24 h of inoculation. These changes did not seem to be a result of decreased inflammation because complementdeficient mice had normal neutrophil recruitment, greater lung myeloperoxidase content, and, by 24 h, a 35-fold higher level of the CXC chemokine KC. Lung static pressure-volume curves were abnormal in infected animals but were significantly more so in complement deficient mice. These data indicate that although P. aeruginosa is resistant to serum killing, C3 opsonization and C5 convertase assembly occur on its surface. This interaction in vivo plays a central role in host survival beyond just recruitment and activation of phagocytes and may serve to limit the inflammatory response to and tissue injury resulting from bacterial infection.Despite advances in diagnosis and treatment, Gram-negative pneumonia is a major health threat in the United States. As of 1999, pneumonia remained the fourth leading cause of death among hospitalized patients, behind the broad categories of cardiovascular disease, cerebrovascular disease, and malignancy (1). For patients developing nosocomial pneumonia, Pseudomonas aeruginosa is the most often identified etiologic organism, accounting for 21% of such infections in a recent survey (2). Well-recognized risk factors for infection with this organism include impaired host immunity, including malignancy; endotracheal intubation and mechanical ventilation; severe burns; and prolonged hospitalization (3).In mouse models of pneumonia, requirements for the cellular and humoral components of the innate immune system have been demonstrated in defense against P. aeruginosa. The NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript presence of neutrophils and the signaling apparatus needed to recruit them into the lung have been shown to be essential for survival during acute infection; native alveolar macrophages alone seem to be insufficient to defend against instilled bacteria (4). The complement system also has been shown to be significant in the response to Pseudomonas pneumonia. Genetically C5-deficient mice exhibit impaired clearance of intrapulmonary P. aeruginosa (5). Although the formation of the membrane attack complex and subsequent complementmediated bacteriolysis may contribute to the role of C5, a need for the anaphylatoxin C5a has been demonstrated in C5a-receptor null mice challenged with intratracheal Pseu...

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

Murine Complement Interactions withPseudomonas aeruginosaand Their Consequences During Pneumonia

Younger

Shankar-Sinha

Mickiewicz

et al. 2003

Am J Respir Cell Mol Biol

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“…Clinical data suggest the importance of complement for preventing infections with pyogenic bacteria (30), and experiments using animal models of disease and complement deficient mice has confirmed the essential role for complement for innate immunity to S. pneumoniae and other Gram-positive pathogens such as group B Streptococcus (5,8,31,32). Surprisingly, the classical pathway has been shown to be important for innate immunity to both S. pneumoniae and group B Streptococcus (5,8), suggesting that perhaps classical pathway-mediated complement activity is generally an important component of the innate immune response to streptococci and other extracellular pathogens.…”

Section: Discussionmentioning

confidence: 99%

Roles of the Alternative Complement Pathway and C1q during Innate Immunity to Streptococcus pyogenes

Yuste

Ali

Sriskandan

et al. 2006

The Journal of Immunology

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Complement is important for innate immunity to the common bacterial pathogen Streptococcus pyogenes, but the relative importance of the alternative and classical pathways has not been investigated. Using mice and human serum deficient in either C1q, the first component of the classical pathway, or factor B, an important component of the alternative pathway, we have investigated the role of both pathways for innate immunity to S. pyogenes. C3b deposition on four different strains of S. pyogenes was mainly dependent on factor B. As a consequence opsonophagocytosis of S. pyogenes was reduced in serum from factor B-deficient mice, and these mice were very susceptible to S. pyogenes infection. In contrast, C3b deposition was not dependent on C1q for two of the strains investigated, H372 and H305, yet opsonophagocytosis of all four S. pyogenes strains was impaired in serum deficient in C1q. Furthermore, infection in C1q-deficient mice with strain H372 resulted in a rapidly progressive disease associated with large numbers of bacteria in target organs. These results demonstrate the important role of the alternative pathway and C1q for innate immunity to S. pyogenes and suggest that C1q-mediated innate immunity to at least some strains of S. pyogenes may involve mechanisms that are independent of C3b on the bacteria.

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“…aeruginosa isolates and strains differ in resistance to complement-mediated lysis (5). The human complement system plays an important role in clearance of early pulmonary P. aeruginosa infection (6). Deposition of the complement component C3b at the bacterial surface is important for induction of host responses and elimination of the pathogen.…”

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confidence: 99%

Immune Evasion of the Human Pathogen Pseudomonas aeruginosa: Elongation Factor Tuf Is a Factor H and Plasminogen Binding Protein

Kunert

Losse

Gruszin

et al. 2007

The Journal of Immunology

205

189

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Pseudomonas aeruginosa is an opportunistic human pathogen that can cause a wide range of clinical symptoms and infections that are frequent in immunocompromised patients. In this study, we show that P. aeruginosa evades human complement attack by binding the human plasma regulators Factor H and Factor H-related protein-1 (FHR-1) to its surface. Factor H binds to intact bacteria via two sites that are located within short consensus repeat (SCR) domains 6–7 and 19–20, and FHR-1 binds within SCR domain 3–5. A P. aeruginosa Factor H binding protein was isolated using a Factor H affinity matrix, and was identified by mass spectrometry as the elongation factor Tuf. Factor H uses the same domains for binding to recombinant Tuf and to intact bacteria. Factor H bound to recombinant Tuf displayed cofactor activity for degradation of C3b. Similarly Factor H bound to intact P. aeruginosa showed complement regulatory activity and mediated C3b degradation. This acquired complement control was rather effective and acted in concert with endogenous proteases. Immunolocalization identified Tuf as a surface protein of P. aeruginosa. Tuf also bound plasminogen, and Tuf-bound plasminogen was converted by urokinase plasminogen activator to active plasmin. Thus, at the bacterial surface Tuf acts as a virulence factor and binds the human complement regulator Factor H and plasminogen. Acquisition of host effector proteins to the surface of the pathogen allows complement control and may facilitate tissue invasion.

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The effect of complement depletion on lung clearance of bacteria.

Cited by 109 publications

References 26 publications

Murine Complement Interactions withPseudomonas aeruginosaand Their Consequences During Pneumonia

Murine Complement Interactions withPseudomonas aeruginosaand Their Consequences During Pneumonia

Roles of the Alternative Complement Pathway and C1q during Innate Immunity to Streptococcus pyogenes

Immune Evasion of the Human Pathogen Pseudomonas aeruginosa: Elongation Factor Tuf Is a Factor H and Plasminogen Binding Protein

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