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Strategies HomeCOMPLEMENT MODULATION STRATEGIES:
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OVERVIEW:
Microorganisms use a wide variety of strategies to evade the effects of host complement activation. One strategy is to avoid activating complement in the first place. It is thought, for example that schistosomes avoid activating complement by acquiring sialic acid from their hosts. As explained earlier, the presence of sialic acid reduces binding of the C3b fragments that initiate the alternative pathway.
Another type of evasion used by many pathogens is resistance to MAC-induced lysis. Gram-positive bacteria, for example, are not lysed because their thick outer layer does not allow the MAC access to the more vulnerable cytoplasmic membrane. Certain E. Coli and Salmonella strains also avoid complement lysis. In these organisms, the alternative complement pathway is activated but only by the lipopolysaccharides with the longest O side chains. Thus, the MAC is formed far from the susceptible membrane.
Other microbes actually utilize complement receptors to facilitate their pathogenic effects on the host. The parasite Leishmania, for example, possesses C3-like epitopes which mediate its attachment to host macrophages. Once inside, these protozoans replicate and eventually destroy the cells which they infected.
While the aforementioned types of complement evasion are indeed numerous and interesting, the goal of the rest of this page is to examine the mechanisms by which pathogens actually modulate the immune system for their own benefit. The organisms discussed below mediate these effects primarily by utilizing molecules which mimic the complement control proteins discussed on the Complement control protein page. HIV uses a slightly different modulatory technique, incorporating host complement regulatory proteins into its outer membrane as it buds from host cells. But more on this later....
HERPES VIRUSES:
Herpes Simplex:
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Adapted From http://www.uct.ac.za/depts/mmi/stannard/emimages.html |
The most well-characterized complement-regulating herpes virus protein is Glycoprotein C (gC) of herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). HSV viruses are responsible for cold sores and genital herpes in humans. Different studies have shown that both gC-1 and gC-2, as the respective gC proteins are called, offer protection against viral neutralization mediated by complement. (McNeary et al, 1987; Harris et al., 1990) In a study of the immune evasion properties of gC-1, two HSV strains which had mutations in the gC gene were compared with normal HSV in their susceptibility to complement-mediated neutralization. Whereas normal viruses had a half- life of one hour in the presence of complement, mutant strains had a half-life of around 2 minutes. Since the complement utilized in the study lacked antibody, it was demonstrated that gC offers resistance to antibody-independent complement neutralization. The authors therefore suggested that gC plays a role early in HSV infection, before the development of antibodies. (Friedman, et al., 1996)
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Adapted from http://www.bocklabs.wisc.edu/Herpesvirus.html |
An early study showed that gC-1 causes the dissociation of the alternative pathway C3 convertase, C3bBb, into its component parts. (Fries et al., 1986). More recently, it was shown that gC-1 destabilizes the convertase by inhibiting the binding of properdin to C3b. (Hung et al., 1994) Later analysis suggested that the two molecules do not bind to the same site on C3b; rather, the gC-1 inhibition of properdin is thought to be due to steric hindrance; ie. it just gets in the way. (Kostavasili et al., 1997) Whereas both gCs bind to complement protein C3b when they are either expressed on transfected cells (Seidel-Dugan et al., 1988) or when in purified form (Eisenberg et al., 1987), gC-2 does not block the C3b/properdin interaction. (Hung et al., 1994)
A recent finding is that both gC-1 and gC-2 bind to native C3. This is in contrast to host complement control molecules such as factor H, MCP, CR1, and DAF, which all interact with C3b but not with the whole molecule, C3. Thus, the gC molecules are not analogues of the host complement control proteins. (Kostavasili et al., 1997)
To summarize: gC-1 is thought to mediate its inhibition of complement via blocking the binding of properdin to C3b of the C3 convertase. The mechanism by which gC-2 achieves complement neutralization is less clear and is under current investigation. Both molecules also may disrupt complement activation via binding to C3.
Most of the studies to date have only assessed the actions of the gC proteins in in vitro systems, ie. not in actual living organisms. Since gC proteins also have other important functions in the life cycle of the virus, such as mediating cell attachment, mutant strains which lack gC cannot be studied in vivo until mutant lines are developed which don't interfere with their other functions. (Ward and Roizman, 1998)
Other Herpes Viruses:
For more information on EBV immune-evasion
strategies, click here.
For information on the immune evasion strategies of another
Herpes virus, click to our Case Study:
Cytomegalovirus page.
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Adapted from The Big Picture Book of Viruses at: http://www.tulane.edu/~dmsander/Big_Virology/ |
VACCINIA VIRUS:
The vaccinia virus is a member of the poxvirus family of viruses. These viruses are large DNA viruses with double-stranded DNA genomes. Other members of the poxvirus family include cowpox virus, monkeypox virus, and the variola virus - the microbe that causes smallpox. Vaccinia virus is of particular interest to those studying vaccine development because vaccination with this virus has led to the worldwide eradication of smallpox. Vaccinia virus is also of interest to many researchers because of its suitability as an expression vector.
Vaccinia virus utilizes a number of different immune evasion strategies, and its evasion of host complement activation is particularly well-characterized. The major secretory protein of the virus is 35-kD in size and contains four SCRs, which is the repeating unit found in human complement control proteins. This vaccinia virus complement control protein, or VCP, structurally most resembles the human C4b-binding Protein but has sequence homology to many of the other human complement control proteins as well. (Kotwal and Moss, 1988)
In many ways, however, the VCP differs from C4b-BP. While VCP inhibits the classical complement pathway via binding to C4b (Kotwal et al., 1990), it also inactivates the alternative complement pathway by binding to C3b and accelerates the decay of the C3 convertases of both the classical and alternative pathways. (McKenzie et al, 1992) While VCP does have cofactor activity for factor I most resembling soluble CR1, the interaction of VCP with C3 is different from all the other factor I cofactors yet examined. (Sahu et al., 1998)
It is thought that VCP functions to protect vaccinia-infected cells and free virus particles from complement-mediated neutralization. Support for this posited function comes from both in vitro and in vivo studies. One study showed that VCP prevented antibody-dependent complement-enhanced neutralization of virus. Using mutant vaccinia that did not express VCP, this study also clearly demonstrated the importance of VCP for virulence in vivo. Guinea pigs infected with the attenuated virus had smaller skin lesions than those that were infected by normal vacinia virus. (Isaacs et al., 1992)
Further in vivo support for the role of VCP in evasion of the host immune system comes from studies of cowpox virus (CPV). Since rodents are the primary reservoir for CPV and don't naturally acquire the vaccinia virus, studying the effects of CPV on mice gives a more accurate portrayal of the course of natural infection of poxviruses. Cowpox virus encodes a protein that is a highly conserved homologue of VCP, called the inflammation modulatory protein (IMP). In experiments where mice were injected with either normal CPV or mutant CPV that lacked the IMP gene, the mutant-infected mice showed greater local tissue damage than did the mice infected with normal CPV. (Miller et al., 1997) At first glance, this might not make sense. Shouldn't we expect the virus which lacked an important protein to cause less damage than the normal virus? This would perhaps be true if the virus was mediating the damage directly. However, in its attempt to clear the virus, it is the inflammatory response of the mouse that actually damages tissue. The viral IMP down-regulates the inflammatory response to protect surrounding host tissue, thus permitting host cells to support its own growth. Since IMP and VCP are so closely related, it is speculated that VCP may play a similar role in modulating host inflammatory response via its interactions with the complement system.
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Adapted from University of Queensland, Dept. of Parasitology at: www.uq.oz.au/parasitology |
TRYPANOSOMA CRUZI:
T. cruzi is a protozoan parasite indigenous to S. America that causes Chagas Disease in humans. In the infectious, trypomastigote stage of the T. cruzi life cycle, this single-celled organism expresses a 160 kDa glycoprotein, labeled gp160. This glycoprotein was found to have complement regulatory activity. Specifically, the membrane-bound gp160 inhibits complement activation by binding to the complement pathway component C3b and thus blocking the formation of the alternative pathway C3 convertase. Analysis has demonstrated that gp160 closely resembles the human complement control protein, Decay Accelerating Factor (DAF). (Norris et al., 1991) A second trypomastigote protein, between 87-93 kDa in size also inhibits the formation of the alternative pathway C3 convertase (Joiner et al, 1988) This protein also closely resembles human DAF both functionally and genetically, and was thus termed trypomastigote decay accelerating factor (T-DAF).
These proteins are developmentally regulated. While both are found in the trypomastigote form, neither are expressed in the insect-infecting epimastigote form. Thus, the insect forms are susceptible to the alternative complement pathway. It is thought that the human-infecting trypomastigote form requires this protein to avoid complement-mediated destruction prior to infecting human cells where they further evade immune recognition. In summary, infectious T. Cruzi trypomastigotes use a complement-modulation mechanism as a stopgap prior to gaining the immune-protected shelter of the inside of a human cell.
Click to learn more about T.
cruzi from the Brown
University Bio 160 Trypanosomiasis website.
HUMAN IMMUNODEFICIENCY VIRUS (HIV):
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Adapted from http://www.ncbi.nlm.nih.gov/ICTVdb/Images/ |
Human immunodeficiency virus, or HIV, is the virus that causes AIDS. It is a member of the retrovirus family of viruses. These viruses contain RNA and an enzyme called reverse transcriptase which turns the RNA into DNA once the virus has gained entrance to a susceptible cell. In HIV, once the DNA has been created, it can insert itself into the host DNA and either take over the cell machinery to create numerous copies of itself or remain quiescent for an indefinite period of time.
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Budding HIV Virion |
In active HIV infection, the virus makes numerous copies of itself. Once created, the virions bud off from the host cell, taking host membrane proteins with them as they go. Included among the proteins incorporated into the HIV membrane is host Decay accelerating factor (DAF). (Marschang et al., 1995) The host complement regulatory molecule CD59 is acquired by budding virions as well. (Saifuddin et al., 1995) These two molecules, it shall be recalled, are responsible for the dissociation of the C3 convertase and inhibition of MAC formation, respectively.
 HIV Diagram |
Showing Important Viral Proteins |
Adapted from http://osms.otago.ac.nz/bur_AIDS.htm |
These host-derived proteins offer some protection to HIV; however, the acquisition of host DAF can only partially explain the measured resistance of HIV to complement-mediated lysis. It turns out that the human complement regulator factor H is even more crucial for HIV's resistance. Factor H is not a membrane-bound protein, so HIV does not acquire it during cell budding. Rather, one of its two major surface glycoproteins, gp41 (the other is gp120), binds to serum factor H (Pinter et al, 1995). The crucial importance of this interaction in mediating HIV resistance to complement is underscored by the finding that antibodies specific to the factor H binding region on gp41 allowed for efficient complement-mediated lysis. (Stoiber et al, 1996) This finding and others which demonstrate interactions between HIV surface proteins and complement regulatory molecules (Stoiber et al, 1995) are potentially important because they suggest a particular HIV vaccine strategy. [See my next section, Implications for Vaccine Development.]
Lest the situation seem overly simple, HIV interacts with the complement system in a variety of other ways as well. For example, like many other pathogens, HIV binds to certain complement receptors and uses them to gain entry to cells. The full interaction of HIV with the human complement system remains to be elucidated.
Click here to learn more about HIV from the Brown University Bio 160 HIV
Website
OTHER PATHOGENS:
The following is a grab-bag of some other microbes which modulate the host complement system:
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Adapted from http://www.wisc.edu/botany/fungi/jan99.html |
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Adapted from http://www.pfizer.com/rd/microbes/ |
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