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Streptococcal disease and the host–parasite relationship
International Congress Series 1289 (2006) 9 – 13
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Streptococcal disease and the host–parasite relationship John D. Mathews * School of Population Health, University of Melbourne, 19 Earl St, Carlton North, 3054, Victoria, Australia
Abstract. Streptococcal evolution has been shaped by human history, social change and microbial selection. Streptococci with pathogenicity for people likely diversified within the last 5–10,000 years, jumping from animal hosts to infect the larger aggregations of people seen in towns and cities following the rise of agriculture. Streptococci are subject to continuing selection through changes in population immunity, hygiene, living conditions, medical interventions, and family size. Such selective effects can account, in part at least, for the virtual disappearance of scarlet fever, for changes in the prevalence and virulence of strains, and for the greatly reduced rates of rheumatic fever in affluent populations. In host populations of finite size which develop immunity, the distribution and survival of particular streptococcal strains is greatly influenced by competition from related strains, and by stochastic loss and turnover of multiple strains in small communities, as seen in child-care centres and Aboriginal settlements. Although multiple strains of GAS compete, they also help each other by boosting the immune response to shared T-cell epitopes, which can promote tissue inflammation and bacterial growth. This concept of multiple strain (multiple hit) sensitisation is applied also to help explain the age-specific incidence of RF and the explosive epidemics of RF seen in military camps in World War II. Ecological principles, such as those developed in this paper, could be more applied more deliberatively in the control of streptococcal diseases. D 2005 Published by Elsevier B.V. Keywords: Ecology; Evolution; Virulence; Scarlet fever; Rheumatic fever
1. Introduction The XVIth Lancefield Symposium honours the research tradition established by Rebecca Lancefield and reminds us all that streptococcal researchers around the world still * Tel./fax: +61 3 9347 2020. E-mail address: [email protected]. 0531-5131/ D 2005 Published by Elsevier B.V. doi:10.1016/j.ics.2005.11.003
10
J.D. Mathews / International Congress Series 1289 (2006) 9–13
benefit from her intellectual legacy. This paper draws upon the history of streptococcal disease, my own experience, and the wisdom of many colleagues. It applies epidemiological and ecological principles to complement the insights from genetic and molecular analyses of streptococcal disease. 2. Learning about streptococcal disease My own acquaintance with scarlet fever and rheumatic fever began as a student and intern, some 43 years ago, at the Fairfield Infectious Diseases Hospital in Melbourne [1]. We learnt to diagnose and treat RF just as it was disappearing. As a young medical student, I had also been greatly influenced by a prescient book, Natural History of Infectious Disease, a classic text exploring evolutionary and ecological principles in the host– parasite relationship, and applying them to diseases such as influenza, diphtheria and scarlet fever [2]. Macfarlane Burnet, its Australian author, was a world leader in immunology and microbiology, and Nobel Prize winner in 1960. He had a lasting influence on Australian medical research for people of my generation. In the mid-1960s, while working briefly in Papua New Guinea, I was challenged by high rates of GAS infection, RF and nephritis. Half a lifetime later, in 1985, I moved to the Northern Territory as Foundation Director of the Menzies School of Health Research [3], where we investigated the very high rates of streptococcal impetigo, acute nephritis, proteinuria, renal failure and RF in the Aboriginal population, and helped to introduce medical and educational interventions [3]. Aboriginal people still have age-specific mortality rates 3–8 fold greater than other Australians, reflecting poor living conditions in a harsh environment, poor nutrition, substance abuse, and the existential problems of a people caught between two very disparate cultures. Research at the Menzies School, summarised in a paper presented at the XIVth Lancefield meeting [4], raised many questions about the ecology of streptococcal disease that inform this paper. 3. The ecology and evolution of pathogenic streptococci If the host–parasite relationship is thought about just from the viewpoint of the human host, it will miss the insights about factors affecting survival of the pathogen. We need to remember that virulence towards the human host is beneficial to a microorganism only if it improves the latter’s survival. If virulence is disadvantageous, or can be made so by an intervention, then virulent strains will tend to be replaced by less virulent mutants or by pre-existing strains of lower virulence with which they are already in competition. 3.1. The decline of streptococcal disease in affluent countries The historical record for England and Wales, as cited by Denny [5], shows that scarlet fever mortality was declining long before the availability of antimicrobials. Rates peaked at 2400 per 100,000 in the 1860s. By the 1930s, mortality rates had already fallen some 50 fold. After sulphonamides and penicillin, scarlet fever has been rare. The dramatic historical decline in fatal infections with toxinogenic strains of GAS was arguably due to improved hygiene and isolation of patients with the most severe disease. The latter would have reduced transmission of the most virulent strains, thus favouring the transmission and preferential survival of less virulent GAS variants. In the shorter term, increasing
J.D. Mathews / International Congress Series 1289 (2006) 9–13
11
population immunity would also have contributed to the decline, but immunity alone would not explain the sustained fall in scarlet fever from generation to generation without a concomitant decrease in the virulence and prevalence of toxigenic strains. Although differential survival of children could have selected for greater host resistance, any such effect would be insignificant compared to streptococcal selection for reduced virulence over the time frame in question, simply because the human generation time is orders of magnitude greater than the streptococcal. Over longer time frames, as in those separating different groups of human ancestors (see Section 3.2), selection on host genotypes could have been more significant. Rheumatic fever incidence declined by about 100 fold over about 100 years in city populations of wealthy countries [5]. For Copenhagen, RF rates were over 200 per 100,000 from the 1860s to 1890, with a declining trend from 1900. By the 1960s the rate had declined to 10 per 100,000; 1980s rates in developed populations were around 1 per 100,000 [5]. RF rates stayed higher for longer than those for scarlet fever, perhaps because, even if the association of infection with RF had been recognised, there would have been almost no effect of any isolation of RF patients in limiting streptococcal spread in the population. The long-term decline in RF incidence is more plausibly attributed to improvements in living conditions and hygiene. In the years after WWII, treatment with penicillin in developed countries would have selected against those strains of GAS causing the most severe pharyngitis, giving a survival advantage to GAS strains causing fewer symptoms. Such later trends, together with changes in population immunity, could help to explain the decline of GAS serotypes that were most strongly associated with RF in earlier generations [6]. 3.2. Streptococcal ecology in indigenous populations today Rates of streptococcal disease are high amongst Aboriginal Australians, Pacific Islanders and other indigenous populations [3,4,7], reminiscent of high historical rates in European cities [5]. Today, Aboriginal people in remote Australia live in overcrowded housing with poor hygiene facilities, in settlements of several hundred people, rather than living their traditional hunter-gatherer lifestyle. Their current circumstances favour streptococcal cross-infection, with transmission of multiple strains of GAS within and between inter-connected Aboriginal settlements in a complex ecosystem. We previously reported [4] at least 13 different GAS strains in a single settlement at the same time, with high rates of strain turnover presumably due to the build-up of immunity, competition between strains, and introduction of new strains by people visiting from nearby settlements. Individual children acquired skin infections with a new strain in periods as short as 18 days, and each GAS strain was carried for a mean of 68 days unless treated. 3.3. Susceptibility of indigenous populations To what extent are high indigenous rates simply due to social disadvantage, and to what extent to greater susceptibility? When new infections were first introduced to indigenous peoples following European contact, they spread in dvirgin-soilT epidemics, with high mortality, often triggering depopulation, as in the Americas and Aboriginal Australia [8,9]. However, as the high impact of European infections in indigenous peoples persisted for generations beyond the population immunity induced by an initial epidemic, there is a
12
J.D. Mathews / International Congress Series 1289 (2006) 9–13
strong rationale, supported by limited empiric evidence [10,11], to suppose that indigenous susceptibility to European infections is partly genetic in origin. Susceptibility could reflect the small size of founder populations in Oceania and the Americas, with limited genetic diversity [11]. Alternatively, pre-historic indigenous populations would have been protected from selection by any agents such as GAS which had evolved after the indigenous ancestors had migrated to Australia, Oceania and the Americas, or by any agents unable to survive in hunter-gatherer groups. 3.4. Could pathogenic streptococci have survived in hunter-gatherer times? For human pathogens that induce protective immunity and clearance, there is a high probability of extinction in host populations of limited size, as the last carrier has to transmit to a new susceptible if the pathogen is to survive. For GAS as we know them today, we can assume a mean carriage-time of perhaps 10–16 weeks on the skin, and 2–6 weeks in the throat. On this basis, there would need to be an effective host population size of some 400 to give birth to enough new susceptibles to maintain GAS skin endemicity locally; for throat carriage alone the minimum population size to prevent stochastic loss would be some 2000. As hunter-gatherers in prehistoric times typically moved about in small groups of extended kin, and rarely came together in larger groups, it is unlikely that GAS, as we now know them, could have survived in their ecosystem. 3.5. Did streptococci diversify by exploiting new niches made available by agriculture? The phylogenetic tree of streptococci [12] shows the connections between lactobacilli, milk species such S. thermophilus, viridans species such as S. mutans and S. pneumoniae, pyogenic species able to infect animals, including S. agalacticae (group B) and group C and G species, as well as S. pyogenes (group A), the major human pathogen. We now know that streptococcal diversification has been greatly enriched by phage-mediated lateral gene transfer [13]. Its time frame is currently unknown, but there would have been major opportunities for streptococcal diversification to exploit new ecological niches over the last 5–10,000 years. In that time frame, agriculture provided increasing human exposure to herd animals, with opportunities for cross-species spread that could have led to greater virulence for human hosts. It also delivered milk, cereals and sugar, changing host diet and ecology. Agriculture ultimately supported the rise of towns and cities, and the larger and more sedentary human populations necessary to support pathogens such as GAS, and to enable gene transfer and strain diversification. 3.6. Can the diversity of GAS strains help to explain RF? GAS strains compete with each other directly at sites of colonisation, and indirectly when the humoral immune response of the host recognises previously encountered antigens [4]. Intriguingly, the puzzling age-distributions of pharyngeal carriage and of RF can be explained by supposing that GAS strains also bcooperateQ through the host response against shared T-cell antigens. The model proposes that T-cell sensitisation builds up with sequential exposures to different strains, promoting pharyngeal inflammation and increased density of GAS carriage by mid-childhood, and contributing to RF pathogenesis in susceptible children [4] (via mechanisms reviewed in the keynote paper by Dr. Cunningham). At later ages, humoral cross-immunity limits new infections in heavily exposed populations, accounting
J.D. Mathews / International Congress Series 1289 (2006) 9–13
13
for declining rates of RF in adult life. The quantitative model recovers the observed age distribution of RF, and explains why this is only weakly dependent on overall incidence. The model also implies that each GAS strain benefits from the presence of others, in partial compensation for the effects of competition. Thus RF can be seen as an incidental consequence of interaction between multiple GAS strains and host immunity. 3.7. Explosive epidemics of RF in military camps during world war II The idea that RF requires multiple sequential exposures to GAS (e.g. for priming, sensitisation and induction) can also help to explain the explosive epidemics of RF seen in US military camps when recruits were brought together from many parts of the country [5]. Groups of recruits from any one region would have included a few who were sensitised against their local GAS strains, but lacking in protective antibody against different strains brought into the camp by recruits from other parts of the USA. The mixing of regional populations in this way, together with the ready transmission of GAS in the overcrowded circumstances of the military camps, meant that many susceptible recruits, already sensitised, were exposed to novel strains very soon after entering the camp— triggering the explosive outbreaks of RF observed. 4. Final remarks Half a century on from Burnet’s book [2], our molecular understanding of streptococci is booming in a way he could barely have imagined. By applying ecological principles to think about the elective forces acting on the microorganism, we will make better sense of the molecular data, and devise better strategies for the control of streptococcal disease. References [1] W.K. Anderson, Fever Hospital, Melbourne University Press, 2002. [2] M. Burnet, Natural History of Infectious Disease, Cambridge University Press, 1953. [3] J.D. Mathews, The Menzies School of Health Research offers a new paradigm of cooperative research, Med. J. Aust. 169 (1998) 625 – 629. [4] J.D. Mathews, et al., Understanding streptococcal infections—molecular and modelling insights, in: D.R. Martin, J.R. Tagg (Eds.), Streptococci and Streptococcal Diseases—Entering the New Millenium, ESR, Porirua, 2000, pp. 35 – 40. [5] F.W. Denny, History of haemolytic streptococcus and associated diseases, in: D.L. Stevens, E.L. Kaplan (Eds.), Streptococcal Infections, OUP, New York, 2000, pp. 1 – 18. [6] R.R. Tanz, Why rheumatic fever has declined in the US over the past four decades, in: K.S. Sriprakash (Ed.), Abstracts of the XVIth Lancefield International Symposium on Streptococci and Streptococcal Disease, QIMR, Brisbane, 2005, p. 61. [7] J.R. Carapetis, M. McDonald, N.J. Wilson, Acute rheumatic fever, Lancet 366 (2005) 155 – 167. [8] S.J. Kunitz, Disease and social diversity, The European Impact on the Health of Non-Europeans, OUP, New York, 1994. [9] K.F. Kiple (Ed.), The Cambridge World History of Human Disease, Cambridge University Press, New York, 1993. [10] M.W. Turner, et al., Restricted polymorphism of the mannose-binding lectin gene of indigenous Australians, Hum. Mol. Genet. 9 (2000) 1481 – 1486. [11] L.L. Cavalli-Sforza, The human genome diversity project, Nat. Rev., Genet. 6 (2005) 333 – 340. [12] H. Tettelin, Streptococcal genomes provide food for thought, Nat. Biotechnol. 12 (2004) 1523 – 1524.
www.ics-elsevier.com
Streptococcal disease and the host–parasite relationship John D. Mathews * School of Population Health, University of Melbourne, 19 Earl St, Carlton North, 3054, Victoria, Australia
Abstract. Streptococcal evolution has been shaped by human history, social change and microbial selection. Streptococci with pathogenicity for people likely diversified within the last 5–10,000 years, jumping from animal hosts to infect the larger aggregations of people seen in towns and cities following the rise of agriculture. Streptococci are subject to continuing selection through changes in population immunity, hygiene, living conditions, medical interventions, and family size. Such selective effects can account, in part at least, for the virtual disappearance of scarlet fever, for changes in the prevalence and virulence of strains, and for the greatly reduced rates of rheumatic fever in affluent populations. In host populations of finite size which develop immunity, the distribution and survival of particular streptococcal strains is greatly influenced by competition from related strains, and by stochastic loss and turnover of multiple strains in small communities, as seen in child-care centres and Aboriginal settlements. Although multiple strains of GAS compete, they also help each other by boosting the immune response to shared T-cell epitopes, which can promote tissue inflammation and bacterial growth. This concept of multiple strain (multiple hit) sensitisation is applied also to help explain the age-specific incidence of RF and the explosive epidemics of RF seen in military camps in World War II. Ecological principles, such as those developed in this paper, could be more applied more deliberatively in the control of streptococcal diseases. D 2005 Published by Elsevier B.V. Keywords: Ecology; Evolution; Virulence; Scarlet fever; Rheumatic fever
1. Introduction The XVIth Lancefield Symposium honours the research tradition established by Rebecca Lancefield and reminds us all that streptococcal researchers around the world still * Tel./fax: +61 3 9347 2020. E-mail address: [email protected]. 0531-5131/ D 2005 Published by Elsevier B.V. doi:10.1016/j.ics.2005.11.003
10
J.D. Mathews / International Congress Series 1289 (2006) 9–13
benefit from her intellectual legacy. This paper draws upon the history of streptococcal disease, my own experience, and the wisdom of many colleagues. It applies epidemiological and ecological principles to complement the insights from genetic and molecular analyses of streptococcal disease. 2. Learning about streptococcal disease My own acquaintance with scarlet fever and rheumatic fever began as a student and intern, some 43 years ago, at the Fairfield Infectious Diseases Hospital in Melbourne [1]. We learnt to diagnose and treat RF just as it was disappearing. As a young medical student, I had also been greatly influenced by a prescient book, Natural History of Infectious Disease, a classic text exploring evolutionary and ecological principles in the host– parasite relationship, and applying them to diseases such as influenza, diphtheria and scarlet fever [2]. Macfarlane Burnet, its Australian author, was a world leader in immunology and microbiology, and Nobel Prize winner in 1960. He had a lasting influence on Australian medical research for people of my generation. In the mid-1960s, while working briefly in Papua New Guinea, I was challenged by high rates of GAS infection, RF and nephritis. Half a lifetime later, in 1985, I moved to the Northern Territory as Foundation Director of the Menzies School of Health Research [3], where we investigated the very high rates of streptococcal impetigo, acute nephritis, proteinuria, renal failure and RF in the Aboriginal population, and helped to introduce medical and educational interventions [3]. Aboriginal people still have age-specific mortality rates 3–8 fold greater than other Australians, reflecting poor living conditions in a harsh environment, poor nutrition, substance abuse, and the existential problems of a people caught between two very disparate cultures. Research at the Menzies School, summarised in a paper presented at the XIVth Lancefield meeting [4], raised many questions about the ecology of streptococcal disease that inform this paper. 3. The ecology and evolution of pathogenic streptococci If the host–parasite relationship is thought about just from the viewpoint of the human host, it will miss the insights about factors affecting survival of the pathogen. We need to remember that virulence towards the human host is beneficial to a microorganism only if it improves the latter’s survival. If virulence is disadvantageous, or can be made so by an intervention, then virulent strains will tend to be replaced by less virulent mutants or by pre-existing strains of lower virulence with which they are already in competition. 3.1. The decline of streptococcal disease in affluent countries The historical record for England and Wales, as cited by Denny [5], shows that scarlet fever mortality was declining long before the availability of antimicrobials. Rates peaked at 2400 per 100,000 in the 1860s. By the 1930s, mortality rates had already fallen some 50 fold. After sulphonamides and penicillin, scarlet fever has been rare. The dramatic historical decline in fatal infections with toxinogenic strains of GAS was arguably due to improved hygiene and isolation of patients with the most severe disease. The latter would have reduced transmission of the most virulent strains, thus favouring the transmission and preferential survival of less virulent GAS variants. In the shorter term, increasing
J.D. Mathews / International Congress Series 1289 (2006) 9–13
11
population immunity would also have contributed to the decline, but immunity alone would not explain the sustained fall in scarlet fever from generation to generation without a concomitant decrease in the virulence and prevalence of toxigenic strains. Although differential survival of children could have selected for greater host resistance, any such effect would be insignificant compared to streptococcal selection for reduced virulence over the time frame in question, simply because the human generation time is orders of magnitude greater than the streptococcal. Over longer time frames, as in those separating different groups of human ancestors (see Section 3.2), selection on host genotypes could have been more significant. Rheumatic fever incidence declined by about 100 fold over about 100 years in city populations of wealthy countries [5]. For Copenhagen, RF rates were over 200 per 100,000 from the 1860s to 1890, with a declining trend from 1900. By the 1960s the rate had declined to 10 per 100,000; 1980s rates in developed populations were around 1 per 100,000 [5]. RF rates stayed higher for longer than those for scarlet fever, perhaps because, even if the association of infection with RF had been recognised, there would have been almost no effect of any isolation of RF patients in limiting streptococcal spread in the population. The long-term decline in RF incidence is more plausibly attributed to improvements in living conditions and hygiene. In the years after WWII, treatment with penicillin in developed countries would have selected against those strains of GAS causing the most severe pharyngitis, giving a survival advantage to GAS strains causing fewer symptoms. Such later trends, together with changes in population immunity, could help to explain the decline of GAS serotypes that were most strongly associated with RF in earlier generations [6]. 3.2. Streptococcal ecology in indigenous populations today Rates of streptococcal disease are high amongst Aboriginal Australians, Pacific Islanders and other indigenous populations [3,4,7], reminiscent of high historical rates in European cities [5]. Today, Aboriginal people in remote Australia live in overcrowded housing with poor hygiene facilities, in settlements of several hundred people, rather than living their traditional hunter-gatherer lifestyle. Their current circumstances favour streptococcal cross-infection, with transmission of multiple strains of GAS within and between inter-connected Aboriginal settlements in a complex ecosystem. We previously reported [4] at least 13 different GAS strains in a single settlement at the same time, with high rates of strain turnover presumably due to the build-up of immunity, competition between strains, and introduction of new strains by people visiting from nearby settlements. Individual children acquired skin infections with a new strain in periods as short as 18 days, and each GAS strain was carried for a mean of 68 days unless treated. 3.3. Susceptibility of indigenous populations To what extent are high indigenous rates simply due to social disadvantage, and to what extent to greater susceptibility? When new infections were first introduced to indigenous peoples following European contact, they spread in dvirgin-soilT epidemics, with high mortality, often triggering depopulation, as in the Americas and Aboriginal Australia [8,9]. However, as the high impact of European infections in indigenous peoples persisted for generations beyond the population immunity induced by an initial epidemic, there is a
12
J.D. Mathews / International Congress Series 1289 (2006) 9–13
strong rationale, supported by limited empiric evidence [10,11], to suppose that indigenous susceptibility to European infections is partly genetic in origin. Susceptibility could reflect the small size of founder populations in Oceania and the Americas, with limited genetic diversity [11]. Alternatively, pre-historic indigenous populations would have been protected from selection by any agents such as GAS which had evolved after the indigenous ancestors had migrated to Australia, Oceania and the Americas, or by any agents unable to survive in hunter-gatherer groups. 3.4. Could pathogenic streptococci have survived in hunter-gatherer times? For human pathogens that induce protective immunity and clearance, there is a high probability of extinction in host populations of limited size, as the last carrier has to transmit to a new susceptible if the pathogen is to survive. For GAS as we know them today, we can assume a mean carriage-time of perhaps 10–16 weeks on the skin, and 2–6 weeks in the throat. On this basis, there would need to be an effective host population size of some 400 to give birth to enough new susceptibles to maintain GAS skin endemicity locally; for throat carriage alone the minimum population size to prevent stochastic loss would be some 2000. As hunter-gatherers in prehistoric times typically moved about in small groups of extended kin, and rarely came together in larger groups, it is unlikely that GAS, as we now know them, could have survived in their ecosystem. 3.5. Did streptococci diversify by exploiting new niches made available by agriculture? The phylogenetic tree of streptococci [12] shows the connections between lactobacilli, milk species such S. thermophilus, viridans species such as S. mutans and S. pneumoniae, pyogenic species able to infect animals, including S. agalacticae (group B) and group C and G species, as well as S. pyogenes (group A), the major human pathogen. We now know that streptococcal diversification has been greatly enriched by phage-mediated lateral gene transfer [13]. Its time frame is currently unknown, but there would have been major opportunities for streptococcal diversification to exploit new ecological niches over the last 5–10,000 years. In that time frame, agriculture provided increasing human exposure to herd animals, with opportunities for cross-species spread that could have led to greater virulence for human hosts. It also delivered milk, cereals and sugar, changing host diet and ecology. Agriculture ultimately supported the rise of towns and cities, and the larger and more sedentary human populations necessary to support pathogens such as GAS, and to enable gene transfer and strain diversification. 3.6. Can the diversity of GAS strains help to explain RF? GAS strains compete with each other directly at sites of colonisation, and indirectly when the humoral immune response of the host recognises previously encountered antigens [4]. Intriguingly, the puzzling age-distributions of pharyngeal carriage and of RF can be explained by supposing that GAS strains also bcooperateQ through the host response against shared T-cell antigens. The model proposes that T-cell sensitisation builds up with sequential exposures to different strains, promoting pharyngeal inflammation and increased density of GAS carriage by mid-childhood, and contributing to RF pathogenesis in susceptible children [4] (via mechanisms reviewed in the keynote paper by Dr. Cunningham). At later ages, humoral cross-immunity limits new infections in heavily exposed populations, accounting
J.D. Mathews / International Congress Series 1289 (2006) 9–13
13
for declining rates of RF in adult life. The quantitative model recovers the observed age distribution of RF, and explains why this is only weakly dependent on overall incidence. The model also implies that each GAS strain benefits from the presence of others, in partial compensation for the effects of competition. Thus RF can be seen as an incidental consequence of interaction between multiple GAS strains and host immunity. 3.7. Explosive epidemics of RF in military camps during world war II The idea that RF requires multiple sequential exposures to GAS (e.g. for priming, sensitisation and induction) can also help to explain the explosive epidemics of RF seen in US military camps when recruits were brought together from many parts of the country [5]. Groups of recruits from any one region would have included a few who were sensitised against their local GAS strains, but lacking in protective antibody against different strains brought into the camp by recruits from other parts of the USA. The mixing of regional populations in this way, together with the ready transmission of GAS in the overcrowded circumstances of the military camps, meant that many susceptible recruits, already sensitised, were exposed to novel strains very soon after entering the camp— triggering the explosive outbreaks of RF observed. 4. Final remarks Half a century on from Burnet’s book [2], our molecular understanding of streptococci is booming in a way he could barely have imagined. By applying ecological principles to think about the elective forces acting on the microorganism, we will make better sense of the molecular data, and devise better strategies for the control of streptococcal disease. References [1] W.K. Anderson, Fever Hospital, Melbourne University Press, 2002. [2] M. Burnet, Natural History of Infectious Disease, Cambridge University Press, 1953. [3] J.D. Mathews, The Menzies School of Health Research offers a new paradigm of cooperative research, Med. J. Aust. 169 (1998) 625 – 629. [4] J.D. Mathews, et al., Understanding streptococcal infections—molecular and modelling insights, in: D.R. Martin, J.R. Tagg (Eds.), Streptococci and Streptococcal Diseases—Entering the New Millenium, ESR, Porirua, 2000, pp. 35 – 40. [5] F.W. Denny, History of haemolytic streptococcus and associated diseases, in: D.L. Stevens, E.L. Kaplan (Eds.), Streptococcal Infections, OUP, New York, 2000, pp. 1 – 18. [6] R.R. Tanz, Why rheumatic fever has declined in the US over the past four decades, in: K.S. Sriprakash (Ed.), Abstracts of the XVIth Lancefield International Symposium on Streptococci and Streptococcal Disease, QIMR, Brisbane, 2005, p. 61. [7] J.R. Carapetis, M. McDonald, N.J. Wilson, Acute rheumatic fever, Lancet 366 (2005) 155 – 167. [8] S.J. Kunitz, Disease and social diversity, The European Impact on the Health of Non-Europeans, OUP, New York, 1994. [9] K.F. Kiple (Ed.), The Cambridge World History of Human Disease, Cambridge University Press, New York, 1993. [10] M.W. Turner, et al., Restricted polymorphism of the mannose-binding lectin gene of indigenous Australians, Hum. Mol. Genet. 9 (2000) 1481 – 1486. [11] L.L. Cavalli-Sforza, The human genome diversity project, Nat. Rev., Genet. 6 (2005) 333 – 340. [12] H. Tettelin, Streptococcal genomes provide food for thought, Nat. Biotechnol. 12 (2004) 1523 – 1524.