I. THE INNATE IMMUNE SYSTEM
E. THE COMPLEMENT SYSTEM
4. Ways in which Microorganisms can Resist Body Defenses by Circumventing the Complement Pathways
The overall purpose of this Learning Object is:
1) to introduce mechanisms certain microbes use to circumvent the complement pathways; and
2) to give several examples of microbes that utilize such mechanisms.
Innate immunity refers to antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to an antigen (def). This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection.
Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPS and include LPS from the gram-negative cell wall, peptidoglycan and lipotechoic acids from the gram-positive cell wall, the sugar mannose (a terminal sugar common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial and viral unmethylated CpG DNA, bacterial flagellin, the amino acid N-formylmethionine found in bacterial proteins, double-stranded and single-stranded RNA from viruses, and glucans from fungal cell walls. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also act as PAMPS. (Because all microbes, not just pathogenic microbes, possess PAMPs, pathogen-associated molecular patterns are sometimes referred to as microbe-associated molecular patterns or MAMPs.)
Most body defense cells have pattern-recognition receptors for these common PAMPSand so there is an immediate response against the invading microorganism. Pathogen-associated molecular patterns can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathways. In all, the innate immune system is thought to recognize approximately 103 of these microbial molecular patterns.
The innate immune responses do not improve with repeated exposure to a given infection and involve the following:
Examples of innate immunity include anatomical barriers, mechanical removal, bacterial antagonism, pattern-recognition receptors, antigen-nonspecific defense chemicals, the complement pathways, phagocytosis, inflammation, and fever.
We will now take a closer look at the 3 pathways of the complement system.
The complement system refers to a series of proteins circulating in the blood and bathing the fluids surrounding tissues. The proteins circulate in an inactive form, but in response to the recognition of molecular components of microorganism, they become sequentially actived, working in a cascade where in the binding of one protein promotes the binding of the next protein in the cascade.
There are 3 complement pathways that make up the complement system: the classical complement pathway, the lectin pathway, and the alternative complement pathway.
E. THE COMPLEMENT SYSTEM
4. Ways in which Microorganisms can Resist Body Defenses by Circumventing the Complement Pathways
Bacterial capsules can interfere with the complement pathways in a number of ways.
- Some capsules prevent the formation of C3 convertase, an early enzyme in the complement pathways. Without this enzyme, the opsonins C3b and C4b, as well as the other beneficial proteins are not produced.
- Other capsules, rich in sialic acid, a common component of host cell glycoprotein, have an affinity for serum protein H, a complement regulatory protein that degrades C3b. (Serum protein H is what normally prevents C3b from binding to host glycoproteins.)
- Some capsules simply cover the C3b that does bind to the bacterial surface and prevent the C3b receptor on phagocytes from making contact with the C3b (see Fig. 1). This is seen with the capsule of Streptococcus pneumoniae.
Microbes can circumvent the complement pathways in a variety of ways including the following:
- An outer membrane molecule of Neisseria gonorrhoeae (inf) called Opa and the M-protein of Streptococcus pyogenes (inf) allow these bacteria to be more resistant to phagocytic engulfment. The M-protein of S. pyogenes (inf), for example, binds factor H of the complement pathway and this leads to the degradation of the opsonin C3b by factor I and the formation of C3 convertase.
- S. pyogenes also produces a protease that cleaves the complement protein C5a.
- A Yersinia protein degrades C3b and C5a.
- Serum lysis refers to the lysis of gram-negative bacteria by the complement protein complex known as the Membrane Attack Complex or MAC. The pores introduced into the outer membrane and possibly the cytoplasmic membrane of gram-negative bacteria my MAC results in their lysis. The LPS of the cell wall is the principle target for complement in gram-negative bacteria by activating the alternative complement pathway (def) and serving as a binding site for C3b as well as the site for formation of MAC (see Fig. 3). Some gram-negative bacteria, such as Salmonella (inf), lengthen the LPS O-polysaccharide side chain and this prevents the MAC lysis of the bacterium (see Fig. 4).
- Some gram-negative bacteria attach sialic acid from host cells to the LPS O antigen (see Fig. 2) and this prevents the formation of the complement enzyme C3 convertase that is needed for the eventual formation of all the beneficial complement proteins such as C3b, C5a, nd MAC. Blood-invasive strains of Neisseria gonorrhoeae (inf), as well as Bordetella pertussis (inf) and Haemophilus influenzae (inf) are examples of Gram-negative bacteria that are able to alter their LPS in this maner.
- Neisseria meningitidis (inf) and Group B Streptococcus (inf), on the other hand, produces capsular polysaccharides composed of sialic acid and as mentioned above, sialic acid prevents MAC lysis.
- Streptococcus pneumoniae activates the classical complement pathway (def), but resists C3b opsonization, and complement causes further inflammation in the lungs.
- Escherichia coli produces a C1q binding protein that inhibits the formation of the first enzyme of the classical complement pathway. The first enzyme requires the joining of three complement proteins C1q, C1r, and C1s. The C1q binding protein of E. coli ties up the C1q.
- Staphylococcus aureus produces a protein called Staphylococcal complement inhibitor that binds and inhibits the C3 convertase enzyme needed for all three complement pathways.
- In addition, some viruses adsorb to complement receptors on body cells to begin their life cycle. The Epstein-Barr virus (EBV), for example, adsorbs to CR2 complement receptors found on B-lymphocytes and epithelial cells.
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