Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2002 Dec 24;99(26):16969-74.
doi: 10.1073/pnas.012669199. Epub 2002 Dec 11.

The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice

Jeremy S Brown  1 , Tracy Hussell, Sarah M Gilliland, David W Holden, James C Paton, Michael R Ehrenstein, Mark J Walport, Marina Botto
Affiliations

The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice

Jeremy S Brown et al. Proc Natl Acad Sci U S A. .

Abstract

The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.

PubMed Disclaimer

Figures

Fig 1.
Fig 1.
C3 deposition on the surface of S. pneumoniae strain D39. (A) Flow cytometry histogram for bacteria incubated with sera from wild-type (wt, gray line) or C3−/− mice (black line). (B) The proportion of bacteria positive for C3 after incubation for 20 min in sera from wild-type and complement-deficient mice. P values compared with wild-type sera are: for Bf−/−, P = 0.08; and for C1qa−/− or C4−/−, P < 0.002. (C) Intensity of C3 deposition on bacteria after incubation in sera from wild-type and complement-deficient mice for 20 min. P values compared with wild-type sera are: for Bf−/−, P = 0.009; for C1qa−/−, P = 0.0004; and for C4−/−, P = 0.96. For B and C, the data for each strain represent the mean of results obtained from four to five mice from a single experiment and are representative of results obtained from at least two separate experiments using sera from different mice. (Bars = SD.) (D–F) Examples of histograms of flow cytometry data for bacteria incubated with sera from complement-deficient mice (gray line) compared with bacteria incubated in sera from wild-type mice (black line).
Fig 2.
Fig 2.
Role of IgM in C3 deposition on S. pneumoniae. (A) An example of a flow cytometry histogram of C3 deposition on bacteria incubated with sera from wild-type (black line) and μs−/− (gray line) mice. (B) Time course of C3 deposition on D39 in sera from wild-type, C1qa−/−, and μs−/− mice. (Bars = SD.) Data are from a single experiment using pooled sera from three mice and are representative of two separate experiments using sera from different mice.
Fig 3.
Fig 3.
Survival curves for complement-deficient mice inoculated with S. pneumoniae. (A) i.n. inoculation with 1 × 106 cfu. For the differences between wild-type and C1qa−/− mice, P = 0.001; between wild-type and Bf−/− mice, P = 0.001; and between C1qa−/− and Bf−/− mice, P = 0.05. (B) i.n. inoculation with 4 × 105 cfu. For the differences between wild-type and C1qa−/− mice, P = 0.003; between wild-type and C3−/− mice, P = 0.001; and between C1qa−/− and C3−/− deficient mice, P = 0.05. (C) i.n. inoculation with 2 × 106 cfu. For the differences between wild-type or μs−/− and C1qa−/− or C4−/− mice, P = 0.001; between C1qa−/− and C4−/− mice, P = 0.96; and between μs−/− and wild-type mice, P = 0.01 (data pooled from two experiments). (D) i.p. inoculation with 2 × 103 cfu. For the differences between wild-type and C1qa−/−mice, P = 0.001; between wild-type and Bf−/− mice, P = 0.09; and between C1qa−/− and Bf−/− mice, P = 0.03. Duplicate experiments were performed for all i.n. comparisons and produced similar results.
Fig 4.
Fig 4.
Comparison of the recovery of S. pneumoniae cfu (expressed as log10) from the target organs of wild-type, C1qa−/−, and μs−/− mice 24 h after inoculation i.n. with 1 × 106 cfu. Each data point represents results from a separate mouse. (A) Total cfu in BAL fluid. (B) Bacterial cfu per ml of lung homogenate. (C) Bacterial cfu per ml of spleen homogenate. (D) Bacterial cfu per ml of blood. For the differences in cfu recovered from lungs, spleen, and blood at 24 h among wild-type, C1qa−/−, and μs−/− mice, P < 0.02. Similar results were obtained in duplicate experiments.
Fig 5.
Fig 5.
Clearance of S. pneumoniae from the blood and spleens of wild-type (gray bars) and C1qa−/− (hatched bars) mice inoculated i.v. with 1.5 × 106 cfu. Data are presented as median cfu per ml, with error bars representing the interquartile range. For the differences between wild-type and C1qa−/− mice for blood at 2 and 4 h, P = 0.02, and for the spleen at 4 h, P = 0.15. Similar results were obtained in duplicate experiments.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Lim W. S., Macfarlane, J. T., Boswell, T. C., Harrison, T. G., Rose, D., Leinonen, M. & Saikku, P. (2001) Thorax 56, 296-301. - PMC - PubMed
    1. Walport M. J. (2001) N. Engl. J. Med. 344, 1058-1066. - PubMed
    1. Alper C. A., Abramson, N., Johnston, R. B., Jr., Jandl, J. H. & Rosen, F. S. (1970) N. Engl. J. Med. 282, 350-354. - PubMed
    1. Gross G. N., Rehm, S. R. & Pierce, A. K. (1978) J. Clin. Invest. 62, 373-378. - PMC - PubMed
    1. Winkelstein J. A. (1981) Rev. Infect. Dis. 3, 289-298. - PubMed

Publication types

MeSH terms