- Email: [email protected]
Rickettsia prowazekii, ribosomes and slow growth
OPINION
29 Gross, R. (1993) EMS Microbial. Rev. 104,301-326 30 Alex, L.A. and Simon, M.I. (1994) TrendsGenet.10,133-138 31 Bourret, R.B., Borkovich, K.A. and Simon, M.I. (1991) Annx Rev. Biochem. 60,401-441 32 Rood, J.I. and Wilkinson, R.G. (1975) 1. Bacterial.123,419-427
33 34 35 36
Imagawa, T. etal. (1981) &ken]. 24,13-21 Shim& T. et al. (1994) J. Bacterial. 176, 1616-1623 Lyristis, M. et al. (1994) Mol. Microbial.12, 761-777 Sloan, J. et al. (1992) Plasmid 27,207-219 37 Bannam, T.L. and Rood, J.1. (1993) Plusmid229,233-235
Rickettsiaprowazekii, ribosomes and slow growth Herbert H. Winkler
R
ickettsia prowazekii, the etio-
logical agent of louse-borne typhus, is a bacterium that can live only within the cytoplasm of a eukaryotic cel11e3.These rickettsiae are cousins of those that cause other arthropod-borne typhus and spotted fevers. Epidemic typhus is second only to malaria as an affliction of humankind throughout recorded history; however, little epidemic typhus is seen today. This is largely because of better public health and hygiene, and to some degree because it is socially and politically incorrect for any ‘nice’ country to have body lice infesting The rickettsiae, its population. members of the present-day alphapurple eubacteria, are an essential evolutionary model since they are the only known human bacterial pathogens that are obligate intracytoplasmic (free in the cytoplasm) parasites. This article considers the slow growth of R. prowazekii and the concentration of stable RNA in this, and other, slowly growing organisms. Evolutionary advantages of slow growth
With a generation time of about lOh, R. prowazekii still grows almost twice as fast as Mycobacterium tuberculosis. But we are not looking for the champion of slow growth. Even the familiar Escherichia coli, when conditions are very poor, can have a generation time of many hours - much longer than the 20min that aficionados of speed and exponential explosiveness enthuse about. The crucial difference
Some bacteria, such as Rickettsia prowuzekii, grow slowly, not with anticipation of a future feast, but because it is evolutionarily advantageous to do so. This creates apparent paradoxes for understanding their physiology and biochemistry. These rickettsiae have a ribosome concentration higher than expected if these ribosomes support translation at rates comparable to those in Escherichia coli. H.H. Winkler is in the Laboratory of Molecular Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA. tel: +1 334 460 6108, fax: +I 334 460 7269, e-mail: [email protected]
is that R. prowazekii (and M. tuberculosis) grows slowly without the opportunity ever to grow fast; this is not the common bacteriological paradigm of feast and famine. The pathogenicity of rickettsial disease is not caused by the elaboration of any special toxins, but is caused by the growth of the rickettsiae and the response of the host cell to its increased occupation. In epidemic typhus, a single R. prowazekii organism enters the cytoplasm of the host cell and grows by binary fission until there are many hundreds of rickettsiae in the cell. As a result of this rickettsial burden, the cell bursts, releasing the rickettsiae, which in turn will infect other cells. This intracytoplasmic growth results in the destruction of the endothelial cells lining the capillaries of the host. 0
TRENDS
When an individual succumbs to epidemic typhus, the millions of rickettsiae growing within the cytoplasm of the host are doomed to lose their habitat and die because these rickettsiae have no route to another host. Transmission of rickettsial diseases is always by an arthropod vector (lice, fleas, mites and ticks). The vector for epidemic typhus, the human body louse, will feed only on living humans. Thus, the survival of these rickettsiae depends on a louse obtaining at least one rickettsia in its bloodmeal on the infected host so that the rickettsia can grow within the cells of the louse and be transmitted eventually to another human host. Clearly, the evolutionary success of R. prowazekii as a species depends on the success of rickettsial transmission; a common theme in parasitology, but one that is rarely voiced in bacteriology. The success of transmission is, in turn, related to the longevity and vigor of the infected person, and the concentration of rickettsiae in the blood. To obtain the highest level of rickettsiae in the blood and at the same time to preserve the life of the host for as long as possible, every cell that bursts must release the maximum number of rickettsiae. A high concentration of intracytoplasmic rickettsiae is hypothesized to be necessary for the escape of the rickettsiae from the host cell because the phospholipase A activity of the entire intracytoplasmic rickettsial mass is needed to overcome the ability of the host cell to repair the damage to its plasma membrane4.
1995 Elsevier Science Ltd
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MAY
1995
OPINION
To obtain this maximal growth yield and to minimize the rate of host-cell destruction requires a finely tuned rickettsial metabolism. However, the rickettsia is not totally master of its own fate: it must use the hostcell metabolism to obtain many of the nutrients that it needs to grow. These nutrients can be relatively complex: uridine Y-diphosphoglucase is taken up by rickettsiae, rather than glucose, and uridine Y-monophosphate, rather than uridine. If R. prowazekii, like a free-living bacterium, were to abscond as rapidly as it could with every nutrient molecule available in its environment, then the metabolism of the host cell would suffer. If, early in infection, the rickettsiae were to ignore the metabolic needs of the host cell and maximize their own growth rate, their growth yield would be compromised by the exhaustion of the nutrients that they require in the host cytoplasm. Rickettsiae do not have to maximize growth rates to compete with other bacterial species colonizing the same niche. To be successful, rickettsiae need to take their time and provide minimal trauma to the host and, thus, maximize the rickettsial yield per infected host cell. Rickettsiae have no hesitation in eventually killing not only the infected host cell, but also the host. Mechanistic paradoxes of slow growth I have speculated on why rickettsiae grow slowly, but what is the mechanism? The biochemical basis of slow growth is not known. The ‘shift-down’ growth of organisms that normally grow rapidly is not relevant to this problem: such organisms have not evolved to optimize slow growth, they are growing slowly with the hope and promise of better times ahead. It would be hoped that clues would come from investigations of very slowly growing, free-living bacteria (for example, M. tuberculosis) with which experiments could be done more easily; but, to the best of my knowledge, these questions have not been asked with such organisms. The biochemistry of slow growth is difficult to understand. For example, I and my colleagues found
TRENDS
recently that in R. prowazekii, growing in an apparently unrestrained and close to logarithmic fashion within the host cell, the mRNA turns over rapidly with a half-life of about 15min (Ref. 5). This presents a paradox: the labile mRNA says ‘use me or lose me’, while the growth rate forbids its use, suggesting a terribly unattractive, futile cycle of synthesis and degradation. However, the cost of such useless synthesis might not be as high as it would be thought because R. prowazekii has a transport system to obtain ATP from the host-cell cytoplasm6. Alternatively, to avoid this waste of mRNA, transcription might be very slow or have remarkable temporal control. Limitations on growth What does limit the rate of rickettsial growth? Is the limitation an intrinsic property of an unusually slow rickettsial enzyme or transport system, or are we unaware of nutrients that are needed by the rickettsiae and are limiting in the seemingly very rich host-cell cytoplasm? I and my colleagues have demonstrated that the limitation is not likely to be the ribosome concentration: R. prowazekii growing with a generation time of 10 h has a concentration of ribosomes that is similar to that in E. coli growing with a generation time of 4Omin (Ref. 7). (To control for the difficulties in measuring rRNA in very small rickettsial samples, the rRNA of E. coli was measured in an identical fashion.) Thus, rickettsiae have enough ribosomes (assuming that the rickettsial ribosomes are of as high a quality as are those of E. coli ) to make protein tenfold faster than they can use it. It would appear that, at least relative to E. coli, rickettsiae have ‘extra’ ribosomes. Excess ribosomes In contrast to the paucity of information on ribosome concentration in slowly growing bacteria, variations in the number of rRNA genes have been more widely investigated. While E. coli has seven copies of the genes for rRNA and Bacillus subtilis has ten, interestingly, R. prowazekii has only a single copy of the gene for 16 S rRNA and a single copy of the unlinked 23 S rRNA-
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encoding gene. Other slowly growing organisms also have few copies of these geness-12, and there does seem to be a good correlation between growing slowly and having a low number of rRNA genes. However, the concentration of ribosomes has not been determined except for the rickettsiae and, clearly, the number of genes cannot predict the concentration of ribosomes. To explain these ‘extra’ ribosomes it could be hypothesized that: (1) a large fraction of the rickettsial ribosomes are in reserve ready to seize the moment when better times come, or (2) many of the rickettsial ribosomes are defective or unassembled. These are the usual explanations for the extra ribosomes in slowly growing E. coP3J4. But, in contrast to E. coli, with rickettsiae this is normal growth rather than shift-down or imposed nutrientlimitation experiments. Rickettsia prowazekii should have learned that, for them, growing within the stable conditions of the eukaryotic cytoplasm over hundreds of millions of years, there are no better times. One hypothesis is that the rickettsial ribosomes are just as active and efficient as are those of E. coli, but that there is a very high protein turnover. However, the protein turnover rate in R. prowazekii has been measured, and rickettsial proteins are as stable as are those of E. coli’. Thus, perhaps the most attractive scenario is that rickettsiae really need all these ribosomes because they synthesize protein slowly. This slowness could be caused by a low concentration or poor efficiency (both relative to E. coli) of any component that is involved in any stage of translation. Assuming that protein concentrations in R. prowazekii and .in E. coli are similar, rickettsiae could synthesize all the protein they need if all their ribosomes worked at 2 amino acids s-l, eightfold slower than those of E. coli. Unfortunately, at this time I know of no way to do the definitive experiment, that is, to measure the chaingrowth rate per ribosome in these obligate intracellular parasites. Conclusions The biosynthesis of ribosomes, which are a large part of the mass
5
MAY
1995
OPINION
Questions *Are the ribosomes of Rickettsia prowazekii arranged in a polyribosome structure? l Would (1) the growth of R. prowazekii in the cells of the flying squirrel, and (2) the growth of spotted-fevergroup rickettsiae in ticks, showthe same ribosomal and growth patterns that f?. prowazekii presents in humans and lice? l Does the lack of a maximum rickettsial growth yield per cell and the prominent cell-to-cell spread seen in studies of Rickettsia rickettsiicorrelate with the exquisite adaptation of these rickettsiae to the tick that is both vector and host? l Do free-living slowly growing bacteria, such as Mycobacterium tuberculosis, have a paradoxically rapid turnover of mRNA and could the chain-growth rate per ribosome be measured in such organisms?
of a bacterium, is a major commitment of the resources of the organism. I cannot explain why having fewer ribosomes that work better is not evolutionarily advantageous for the rickettsiae. Are these considerations of ribosome excess, and other paradoxes of slow growth, general features of those bacteria that are evolutionarily adapted to slow growth? If so, then perhaps these unexplored, but fundamental, features
of microbial physiology could be more easily and thoroughly investigated in free-living slow-growing bacteria. Acknowledgement This work was supported by grant AI-15035 from NIH.
References 1 Winkler, H.H. (1990) Anntc. Rev. Microbial. 44,131-153
2 Winkier, H.H. and Turco, J. (1988) Curr. Top. Microbial. Immtrnol. 138,81-107 3 Walker, D.H., ed. (1988) Biology of Rickettsial Diseases, CRC Press 4 Winkler, H.H. and Daugherty, R.M. (1989) Ifect. Immun. 57,36-40 5 Cai, J. and Winkler, H.H. (1993) J. Bacterial. 175,5725-5727 6 Winkler, H.H. (1976) J. Biol. Cbem. 251,389-396 7 Pang, H. and Winkler, H.H. (1994) Mol. Microbial. 12, 115-120 8 Amikam, D., Glaser, G. and Razin, S. (1984) 1. Bacterial. 158,376-378 9 Sela, S., Clark-Curtiss, J.E. and Bercovier, H. (1989) 1. Bacterial. 171, 70-73 10 Hofman, J.D., Lau, R.H. and Doolittle, W.F. (1979) Nticleic Acids Res. 7,1321-1333 11 Neumann, H. et al. (1983) Mol. Genet. 192,66-72 12 Bercovier, H., Kafri, 0. and Sela, S. (1986) Biochem. Biophys. Res. Conzmun. 136,1136-1141 13 Jensen, K.F. and Pedersen, S. (1990) Microbial. Rev. 54,89-100 14 Koch, A.L. (1971) Adv. Microb. Physiol. 6,147-217
Recognition and control of neisserial infection bv antibody and complement d
Gary A. Jarvis efense against disseminated neisserial infection depends on recognition of the bacterial surface by intibody and complement. Individuals with inherited deficiencies in the terminal complement components CS-C9, which are critical for neisserial lysis, are strikingly susceptible to systemic neisserial disease and have recurrent, disseminated neisserial infections, despite having an intact, complement-dependent, opsonophagocytic effector system’. The low incidence in these individuals of bacteremia caused by other organisms that routinely disseminate into the bloodstream, such as Huemophilus infltrenzae, strongly suggests that there is a unique relationship between the neisserial cell surface and the complement cascade. This review addresses selected aspects of
3 1
Immunity to neisserial infection involves complex interactions between antibody, complement and bacterial cell-surface molecules. N&se& species express polysaccharide and glycolipid membrane components, which downregulate complement activation. The pathogenic potential of Neisseria depends on evasion of the complement cascade. G.A. Jarvis is in the Center for Immunochemistry, Dept of Laboratory Medicine, University of California and Veterans Administration Medical Center/l 11 Wl, 4150 Clement Street, San Francisco, CA 94121, USA. tel: +l 415 221 4810 x2303, fax: +1 415 221 7542, e-mail: [email protected]
the molecular basis for the resistance of pathogenic Neisseriu to complement-dependent immune lysis.
Activation of the complement cascade Complement activation proceeds through a series of limited proteolytic steps in one of two pathways, the classical pathway or the alternative pathway2. Activation of the classical pathway is initiated by the interaction of the complement component Clq with the Fc regions of immunoglobulin G (IgG) and IgM molecules within immune complexes; activation of the alternative pathway is largely independent of antibody. C3 is critical because it links the two pathways of complement activation and is the source of fragments that act as opsonins. C3 binds covalently either to hydroxyl groups via an ester linkage or to primary amino groups via an amide bond through a reactive intramolecular thioester in the C3d
0 1995 Elsevier Science Ltd TRENDS
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MAY
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29 Gross, R. (1993) EMS Microbial. Rev. 104,301-326 30 Alex, L.A. and Simon, M.I. (1994) TrendsGenet.10,133-138 31 Bourret, R.B., Borkovich, K.A. and Simon, M.I. (1991) Annx Rev. Biochem. 60,401-441 32 Rood, J.I. and Wilkinson, R.G. (1975) 1. Bacterial.123,419-427
33 34 35 36
Imagawa, T. etal. (1981) &ken]. 24,13-21 Shim& T. et al. (1994) J. Bacterial. 176, 1616-1623 Lyristis, M. et al. (1994) Mol. Microbial.12, 761-777 Sloan, J. et al. (1992) Plasmid 27,207-219 37 Bannam, T.L. and Rood, J.1. (1993) Plusmid229,233-235
Rickettsiaprowazekii, ribosomes and slow growth Herbert H. Winkler
R
ickettsia prowazekii, the etio-
logical agent of louse-borne typhus, is a bacterium that can live only within the cytoplasm of a eukaryotic cel11e3.These rickettsiae are cousins of those that cause other arthropod-borne typhus and spotted fevers. Epidemic typhus is second only to malaria as an affliction of humankind throughout recorded history; however, little epidemic typhus is seen today. This is largely because of better public health and hygiene, and to some degree because it is socially and politically incorrect for any ‘nice’ country to have body lice infesting The rickettsiae, its population. members of the present-day alphapurple eubacteria, are an essential evolutionary model since they are the only known human bacterial pathogens that are obligate intracytoplasmic (free in the cytoplasm) parasites. This article considers the slow growth of R. prowazekii and the concentration of stable RNA in this, and other, slowly growing organisms. Evolutionary advantages of slow growth
With a generation time of about lOh, R. prowazekii still grows almost twice as fast as Mycobacterium tuberculosis. But we are not looking for the champion of slow growth. Even the familiar Escherichia coli, when conditions are very poor, can have a generation time of many hours - much longer than the 20min that aficionados of speed and exponential explosiveness enthuse about. The crucial difference
Some bacteria, such as Rickettsia prowuzekii, grow slowly, not with anticipation of a future feast, but because it is evolutionarily advantageous to do so. This creates apparent paradoxes for understanding their physiology and biochemistry. These rickettsiae have a ribosome concentration higher than expected if these ribosomes support translation at rates comparable to those in Escherichia coli. H.H. Winkler is in the Laboratory of Molecular Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA. tel: +1 334 460 6108, fax: +I 334 460 7269, e-mail: [email protected]
is that R. prowazekii (and M. tuberculosis) grows slowly without the opportunity ever to grow fast; this is not the common bacteriological paradigm of feast and famine. The pathogenicity of rickettsial disease is not caused by the elaboration of any special toxins, but is caused by the growth of the rickettsiae and the response of the host cell to its increased occupation. In epidemic typhus, a single R. prowazekii organism enters the cytoplasm of the host cell and grows by binary fission until there are many hundreds of rickettsiae in the cell. As a result of this rickettsial burden, the cell bursts, releasing the rickettsiae, which in turn will infect other cells. This intracytoplasmic growth results in the destruction of the endothelial cells lining the capillaries of the host. 0
TRENDS
When an individual succumbs to epidemic typhus, the millions of rickettsiae growing within the cytoplasm of the host are doomed to lose their habitat and die because these rickettsiae have no route to another host. Transmission of rickettsial diseases is always by an arthropod vector (lice, fleas, mites and ticks). The vector for epidemic typhus, the human body louse, will feed only on living humans. Thus, the survival of these rickettsiae depends on a louse obtaining at least one rickettsia in its bloodmeal on the infected host so that the rickettsia can grow within the cells of the louse and be transmitted eventually to another human host. Clearly, the evolutionary success of R. prowazekii as a species depends on the success of rickettsial transmission; a common theme in parasitology, but one that is rarely voiced in bacteriology. The success of transmission is, in turn, related to the longevity and vigor of the infected person, and the concentration of rickettsiae in the blood. To obtain the highest level of rickettsiae in the blood and at the same time to preserve the life of the host for as long as possible, every cell that bursts must release the maximum number of rickettsiae. A high concentration of intracytoplasmic rickettsiae is hypothesized to be necessary for the escape of the rickettsiae from the host cell because the phospholipase A activity of the entire intracytoplasmic rickettsial mass is needed to overcome the ability of the host cell to repair the damage to its plasma membrane4.
1995 Elsevier Science Ltd
IN MICROBIOLOGY
196
VOL.
3
No.
5
MAY
1995
OPINION
To obtain this maximal growth yield and to minimize the rate of host-cell destruction requires a finely tuned rickettsial metabolism. However, the rickettsia is not totally master of its own fate: it must use the hostcell metabolism to obtain many of the nutrients that it needs to grow. These nutrients can be relatively complex: uridine Y-diphosphoglucase is taken up by rickettsiae, rather than glucose, and uridine Y-monophosphate, rather than uridine. If R. prowazekii, like a free-living bacterium, were to abscond as rapidly as it could with every nutrient molecule available in its environment, then the metabolism of the host cell would suffer. If, early in infection, the rickettsiae were to ignore the metabolic needs of the host cell and maximize their own growth rate, their growth yield would be compromised by the exhaustion of the nutrients that they require in the host cytoplasm. Rickettsiae do not have to maximize growth rates to compete with other bacterial species colonizing the same niche. To be successful, rickettsiae need to take their time and provide minimal trauma to the host and, thus, maximize the rickettsial yield per infected host cell. Rickettsiae have no hesitation in eventually killing not only the infected host cell, but also the host. Mechanistic paradoxes of slow growth I have speculated on why rickettsiae grow slowly, but what is the mechanism? The biochemical basis of slow growth is not known. The ‘shift-down’ growth of organisms that normally grow rapidly is not relevant to this problem: such organisms have not evolved to optimize slow growth, they are growing slowly with the hope and promise of better times ahead. It would be hoped that clues would come from investigations of very slowly growing, free-living bacteria (for example, M. tuberculosis) with which experiments could be done more easily; but, to the best of my knowledge, these questions have not been asked with such organisms. The biochemistry of slow growth is difficult to understand. For example, I and my colleagues found
TRENDS
recently that in R. prowazekii, growing in an apparently unrestrained and close to logarithmic fashion within the host cell, the mRNA turns over rapidly with a half-life of about 15min (Ref. 5). This presents a paradox: the labile mRNA says ‘use me or lose me’, while the growth rate forbids its use, suggesting a terribly unattractive, futile cycle of synthesis and degradation. However, the cost of such useless synthesis might not be as high as it would be thought because R. prowazekii has a transport system to obtain ATP from the host-cell cytoplasm6. Alternatively, to avoid this waste of mRNA, transcription might be very slow or have remarkable temporal control. Limitations on growth What does limit the rate of rickettsial growth? Is the limitation an intrinsic property of an unusually slow rickettsial enzyme or transport system, or are we unaware of nutrients that are needed by the rickettsiae and are limiting in the seemingly very rich host-cell cytoplasm? I and my colleagues have demonstrated that the limitation is not likely to be the ribosome concentration: R. prowazekii growing with a generation time of 10 h has a concentration of ribosomes that is similar to that in E. coli growing with a generation time of 4Omin (Ref. 7). (To control for the difficulties in measuring rRNA in very small rickettsial samples, the rRNA of E. coli was measured in an identical fashion.) Thus, rickettsiae have enough ribosomes (assuming that the rickettsial ribosomes are of as high a quality as are those of E. coli ) to make protein tenfold faster than they can use it. It would appear that, at least relative to E. coli, rickettsiae have ‘extra’ ribosomes. Excess ribosomes In contrast to the paucity of information on ribosome concentration in slowly growing bacteria, variations in the number of rRNA genes have been more widely investigated. While E. coli has seven copies of the genes for rRNA and Bacillus subtilis has ten, interestingly, R. prowazekii has only a single copy of the gene for 16 S rRNA and a single copy of the unlinked 23 S rRNA-
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encoding gene. Other slowly growing organisms also have few copies of these geness-12, and there does seem to be a good correlation between growing slowly and having a low number of rRNA genes. However, the concentration of ribosomes has not been determined except for the rickettsiae and, clearly, the number of genes cannot predict the concentration of ribosomes. To explain these ‘extra’ ribosomes it could be hypothesized that: (1) a large fraction of the rickettsial ribosomes are in reserve ready to seize the moment when better times come, or (2) many of the rickettsial ribosomes are defective or unassembled. These are the usual explanations for the extra ribosomes in slowly growing E. coP3J4. But, in contrast to E. coli, with rickettsiae this is normal growth rather than shift-down or imposed nutrientlimitation experiments. Rickettsia prowazekii should have learned that, for them, growing within the stable conditions of the eukaryotic cytoplasm over hundreds of millions of years, there are no better times. One hypothesis is that the rickettsial ribosomes are just as active and efficient as are those of E. coli, but that there is a very high protein turnover. However, the protein turnover rate in R. prowazekii has been measured, and rickettsial proteins are as stable as are those of E. coli’. Thus, perhaps the most attractive scenario is that rickettsiae really need all these ribosomes because they synthesize protein slowly. This slowness could be caused by a low concentration or poor efficiency (both relative to E. coli) of any component that is involved in any stage of translation. Assuming that protein concentrations in R. prowazekii and .in E. coli are similar, rickettsiae could synthesize all the protein they need if all their ribosomes worked at 2 amino acids s-l, eightfold slower than those of E. coli. Unfortunately, at this time I know of no way to do the definitive experiment, that is, to measure the chaingrowth rate per ribosome in these obligate intracellular parasites. Conclusions The biosynthesis of ribosomes, which are a large part of the mass
5
MAY
1995
OPINION
Questions *Are the ribosomes of Rickettsia prowazekii arranged in a polyribosome structure? l Would (1) the growth of R. prowazekii in the cells of the flying squirrel, and (2) the growth of spotted-fevergroup rickettsiae in ticks, showthe same ribosomal and growth patterns that f?. prowazekii presents in humans and lice? l Does the lack of a maximum rickettsial growth yield per cell and the prominent cell-to-cell spread seen in studies of Rickettsia rickettsiicorrelate with the exquisite adaptation of these rickettsiae to the tick that is both vector and host? l Do free-living slowly growing bacteria, such as Mycobacterium tuberculosis, have a paradoxically rapid turnover of mRNA and could the chain-growth rate per ribosome be measured in such organisms?
of a bacterium, is a major commitment of the resources of the organism. I cannot explain why having fewer ribosomes that work better is not evolutionarily advantageous for the rickettsiae. Are these considerations of ribosome excess, and other paradoxes of slow growth, general features of those bacteria that are evolutionarily adapted to slow growth? If so, then perhaps these unexplored, but fundamental, features
of microbial physiology could be more easily and thoroughly investigated in free-living slow-growing bacteria. Acknowledgement This work was supported by grant AI-15035 from NIH.
References 1 Winkler, H.H. (1990) Anntc. Rev. Microbial. 44,131-153
2 Winkier, H.H. and Turco, J. (1988) Curr. Top. Microbial. Immtrnol. 138,81-107 3 Walker, D.H., ed. (1988) Biology of Rickettsial Diseases, CRC Press 4 Winkler, H.H. and Daugherty, R.M. (1989) Ifect. Immun. 57,36-40 5 Cai, J. and Winkler, H.H. (1993) J. Bacterial. 175,5725-5727 6 Winkler, H.H. (1976) J. Biol. Cbem. 251,389-396 7 Pang, H. and Winkler, H.H. (1994) Mol. Microbial. 12, 115-120 8 Amikam, D., Glaser, G. and Razin, S. (1984) 1. Bacterial. 158,376-378 9 Sela, S., Clark-Curtiss, J.E. and Bercovier, H. (1989) 1. Bacterial. 171, 70-73 10 Hofman, J.D., Lau, R.H. and Doolittle, W.F. (1979) Nticleic Acids Res. 7,1321-1333 11 Neumann, H. et al. (1983) Mol. Genet. 192,66-72 12 Bercovier, H., Kafri, 0. and Sela, S. (1986) Biochem. Biophys. Res. Conzmun. 136,1136-1141 13 Jensen, K.F. and Pedersen, S. (1990) Microbial. Rev. 54,89-100 14 Koch, A.L. (1971) Adv. Microb. Physiol. 6,147-217
Recognition and control of neisserial infection bv antibody and complement d
Gary A. Jarvis efense against disseminated neisserial infection depends on recognition of the bacterial surface by intibody and complement. Individuals with inherited deficiencies in the terminal complement components CS-C9, which are critical for neisserial lysis, are strikingly susceptible to systemic neisserial disease and have recurrent, disseminated neisserial infections, despite having an intact, complement-dependent, opsonophagocytic effector system’. The low incidence in these individuals of bacteremia caused by other organisms that routinely disseminate into the bloodstream, such as Huemophilus infltrenzae, strongly suggests that there is a unique relationship between the neisserial cell surface and the complement cascade. This review addresses selected aspects of
3 1
Immunity to neisserial infection involves complex interactions between antibody, complement and bacterial cell-surface molecules. N&se& species express polysaccharide and glycolipid membrane components, which downregulate complement activation. The pathogenic potential of Neisseria depends on evasion of the complement cascade. G.A. Jarvis is in the Center for Immunochemistry, Dept of Laboratory Medicine, University of California and Veterans Administration Medical Center/l 11 Wl, 4150 Clement Street, San Francisco, CA 94121, USA. tel: +l 415 221 4810 x2303, fax: +1 415 221 7542, e-mail: [email protected]
the molecular basis for the resistance of pathogenic Neisseriu to complement-dependent immune lysis.
Activation of the complement cascade Complement activation proceeds through a series of limited proteolytic steps in one of two pathways, the classical pathway or the alternative pathway2. Activation of the classical pathway is initiated by the interaction of the complement component Clq with the Fc regions of immunoglobulin G (IgG) and IgM molecules within immune complexes; activation of the alternative pathway is largely independent of antibody. C3 is critical because it links the two pathways of complement activation and is the source of fragments that act as opsonins. C3 binds covalently either to hydroxyl groups via an ester linkage or to primary amino groups via an amide bond through a reactive intramolecular thioester in the C3d
0 1995 Elsevier Science Ltd TRENDS
IN MICROBIOLOGY
198
VOL..
3
No.
5
MAY
199.5