Strains of Neisseria gonorrhoeae with mosaic penA genes bearing novel point mutations in penA hav... more Strains of Neisseria gonorrhoeae with mosaic penA genes bearing novel point mutations in penA have been isolated from ceftriaxone treatment failures. Such isolates exhibit significantly higher MIC values to third-generation cephalosporins. Here we report the in vitro isolation of two mutants with elevated MICs to cephalosporins. The first possesses a point mutation in the transpeptidase region of the mosaic penA gene, and the second contains an insertion mutation in pilQ.
Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal ... more Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.
Timely and accurate information about the onset of malaria epidemics is essential for effective c... more Timely and accurate information about the onset of malaria epidemics is essential for effective control activities in epidemic-prone regions. Early warning methods that provide earlier alerts (usually by the use of weather variables) may permit control measures to interrupt transmission earlier in the epidemic, perhaps at the expense of some level of accuracy. Expected case numbers were modeled using a Poisson regression with lagged weather factors in a 4th-degree polynomial distributed lag model. For each week, the numbers of malaria cases were predicted using coefficients obtained using all years except that for which the prediction was being made. The effectiveness of alerts generated by the prediction system was compared against that of alerts based on observed cases. The usefulness of the prediction system was evaluated in cold and hot districts. The system predicts the overall pattern of cases well, yet underestimates the height of the largest peaks. Relative to alerts trigger...
Prior influenza infection is a risk factor for invasive meningococcal disease. Quantifying the fr... more Prior influenza infection is a risk factor for invasive meningococcal disease. Quantifying the fraction of meningococcal disease attributable to influenza could improve understanding of viral-bacterial interaction and indicate additional health benefits to influenza immunization. A time series analysis of the association of influenza and meningococcal disease using hospitalizations in 9 states from 1989-2009 included in the State Inpatient Databases from the Agency for Healthcare Research and Quality and the proportion of positive influenza tests by subtype reported to the Centers for Disease Control. The model accounts for the autocorrelation of meningococcal disease and influenza between weeks, temporal trends, co-circulating respiratory syncytial virus, and seasonality. The influenza-subtype-attributable fraction was estimated using the model coefficients. We analyzed the synchrony of seasonal peaks in hospitalizations for influenza, respiratory syncytial virus, and meningococcal...
Infections have long been thought to exert natural selection on humans. Infectious disease resist... more Infections have long been thought to exert natural selection on humans. Infectious disease resistance is frequently invoked as a mechanism shaping human genetic diversity, but such hypotheses have rarely been quantitatively evaluated with direct measures of disease-related mortality. Enhancement of genetically deter- mined resistance to tuberculosis by natural selection has been proposed as a factor explaining the decline of tuberculosis
Proceedings of The National Academy of Sciences, 2005
Acquired immunity to Streptococcus pneumoniae (pneumococcus) has long been assumed to depend on t... more Acquired immunity to Streptococcus pneumoniae (pneumococcus) has long been assumed to depend on the presence of anticapsular antibodies. We found, however, that colonization with live pneumococci of serotypes 6B, 7F, or 14 protected mice against recolonization by any of the serotypes and that protection from acquisition of a heterologous or homologous strain did not depend on anticapsular antibody. Further, intranasal
Widespread use of conjugate vaccines against Streptococcus pneumoniae, by reducing carriage of S.... more Widespread use of conjugate vaccines against Streptococcus pneumoniae, by reducing carriage of S. pneumoniae serotypes included in the vaccine, may result in an increase in nasopharyngeal carriage of - and disease from - nonvaccine serotypes of the same species. Mathematical models predict that the extent of such replacement will depend positively on the degree to which carriage of vaccine-type S. pneumoniae inhibits acquisition of nonvaccine-type pneumococci, and may depend negatively on the inhibition of vaccine-type pneumococci by nonvaccine-type pneumococci. We used a mouse model of intranasal carriage of pneumococci to test whether such inhibition occurs between different pneumococcal strains. Mice carrying a streptomycin-resistant derivative of S. pneumoniae BG9163 (serotype 6B) as a resident strain showed reduced levels of colonization when challenged intranasally by optochin-resistant derivatives of the same strain and of a serotype 23F pneumococcus, BG8826. Inhibition could be overcome by increasing the dose of the challenge strain. Carriage of optochin-resistant BG9163 did not inhibit acquisition of the streptomycin-resistant variant. Colonization by a challenge strain did not significantly affect the level of colonization with the resident strain. These results provide evidence that is consistent with several hitherto untested assumptions of mathematical models of serotype replacement and suggest that a biological mechanism exists that could account for serotype replacement that is observed in clinical trials. The findings provide a basis for further studies of in vivo interactions between strains of S. pneumoniae.
Antimicrobial resistance is a growing problem in nearly every infectious disease, but the extent ... more Antimicrobial resistance is a growing problem in nearly every infectious disease, but the extent and rate of increase of the problem varies widely with different pathogen-drug combinations. The rate of increase of resistance depends primarily on the availability of resistant variants and the intensity of selection imposed by antimicrobial treatment (appropriately measured). Declines in resistance following antimicrobial control measures are typically faster in hospital-acquired infections than in community-acquired ones, probably owing to the dependence in the latter case on the fitness cost of resistance. Open questions and approaches for testing the hypotheses proposed here are outlined.
The fitness of most pathogenic microorganisms depends on transmission from host to host. This req... more The fitness of most pathogenic microorganisms depends on transmission from host to host. This requires adaptation for dissemination, translocation and survival between hosts, as well as for colonization. A complex relationship exists between these components of microbial fitness and virulence. Understanding this relationship has important implications for research and public health.
... In contrast to the effect of the parasite on host fecundity, the relationship between equi-li... more ... In contrast to the effect of the parasite on host fecundity, the relationship between equi-libriumhost ... In an earlier publication, this parasite was re-ferred to as Tuzetia sp. ... to the new jars because transmission from a "spore bank" could influence the host-parasite dy-namics (Ebert ...
Competition through cross-reacting host immune responses, a form of apparent competition, is a ma... more Competition through cross-reacting host immune responses, a form of apparent competition, is a major driver of pathogen evolution and diversity. Most models of pathogens have focused on intraspecific interactions to explain observed patterns. Two recent experiments suggested that Haemophilus influenzae, a common nasopharyngeal colonizer of humans, might alter the immune environment in a way that favors otherwise less fit serotypes of another common pathogen, pneumococcus. Using a computational model, we demonstrate that H. influenzae, if it consistently raises the fitness of the less fit serotypes, can strongly promote pneumococcal diversity. However, the effects of H. influenzae are so sensitive to the prevalence of H. influenzae that this species is unlikely to be the main driver of serotype coexistence. Interactions that significantly affect diversity could furthermore be extremely difficult to detect through co-occurrence analysis alone. These results suggest that small differences in strains' adaptations to different immunological regimes, which are shaped by coinfections with other pathogens, can have dramatic effects on strain dynamics and patterns of phenotypic variation. Studies of microbial communities might therefore benefit from the use of varied approaches to infer the presence of indirect interactions.
Infection with herpes simplex virus type 2 (HSV-2) currently affects approximately 22% of adult A... more Infection with herpes simplex virus type 2 (HSV-2) currently affects approximately 22% of adult Americans and increased markedly in prevalence between the late 1970s and early 1990s. Although some estimates of the costs of prevalent disease due to HSV-2 are available, selection of interventions to prevent HSV-2 infection, as well as evaluation of their potential cost-effectiveness, should take into account projected future costs that will result if the epidemic is left unchecked. The goal was to estimate the future health and economic consequences attributable to the HSV-2 epidemic in the absence of interventions to slow the epidemic. A mathematical model was constructed to project future increases in HSV-2 seroprevalence in the United States. The probability of heterosexual transmission of HSV-2 was estimated from cross-sectional estimates of infection prevalence reported by the National Health and Nutrition Examination Survey (NHANES). Per-infection expected costs were calculated on the basis of data obtained from the published medical literature. RESULTS Without intervention, the prevalence of HSV-2 infection among individuals aged 15 to 39 years was projected to increase to 39% among men and 49% among women by 2025. Annual incidence was projected to increase steadily between 2000 and 2025, from 9 to 26 infections per 1,000 men and from 12 to 32 infections per 1,000 women in this age group. The cost of incident infections in the year 2000 were estimated to be $1.8 billion; the cost of incident infections was predicted to rise to $2.5 billion by 2015 and $2.7 billion by 2025. The projected cumulative cost of incident HSV-2 infections occurring over the next 25 years was estimated to be $61 billion; at a 3% discount rate, this sum has a present value of $43 billion. The costs of incident HSV-2 infection in the United States are substantial and can be expected to increase as both the incidence and prevalence of this disease increase in the first half of the century. The level of resource allocation for HSV-2 prevention strategies should reflect the economic benefits that would result from control of this epidemic.
Over 90 capsular serotypes of Streptococcus pneumoniae, a common nasopharyngeal colonizer and maj... more Over 90 capsular serotypes of Streptococcus pneumoniae, a common nasopharyngeal colonizer and major cause of pneumonia, bacteremia, and meningitis, are known. It is unclear why some serotypes can persist at all: They are more easily cleared from carriage and compete poorly in vivo. Serotype-specific immune responses, which could promote diversity in principle, are weak enough to allow repeated colonizations by the same type. We show that weak serotype-specific immunity and an acquired response not specific to the capsule can together reproduce observed diversity. Serotype-specific immunity stabilizes competition, and acquired immunity to noncapsular antigens reduces fitness differences. Our model can be used to explain the effects of pneumococcal vaccination and indicates general factors that regulate the diversity of pathogens.
Strains of Neisseria gonorrhoeae with mosaic penA genes bearing novel point mutations in penA hav... more Strains of Neisseria gonorrhoeae with mosaic penA genes bearing novel point mutations in penA have been isolated from ceftriaxone treatment failures. Such isolates exhibit significantly higher MIC values to third-generation cephalosporins. Here we report the in vitro isolation of two mutants with elevated MICs to cephalosporins. The first possesses a point mutation in the transpeptidase region of the mosaic penA gene, and the second contains an insertion mutation in pilQ.
Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal ... more Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.
Timely and accurate information about the onset of malaria epidemics is essential for effective c... more Timely and accurate information about the onset of malaria epidemics is essential for effective control activities in epidemic-prone regions. Early warning methods that provide earlier alerts (usually by the use of weather variables) may permit control measures to interrupt transmission earlier in the epidemic, perhaps at the expense of some level of accuracy. Expected case numbers were modeled using a Poisson regression with lagged weather factors in a 4th-degree polynomial distributed lag model. For each week, the numbers of malaria cases were predicted using coefficients obtained using all years except that for which the prediction was being made. The effectiveness of alerts generated by the prediction system was compared against that of alerts based on observed cases. The usefulness of the prediction system was evaluated in cold and hot districts. The system predicts the overall pattern of cases well, yet underestimates the height of the largest peaks. Relative to alerts trigger...
Prior influenza infection is a risk factor for invasive meningococcal disease. Quantifying the fr... more Prior influenza infection is a risk factor for invasive meningococcal disease. Quantifying the fraction of meningococcal disease attributable to influenza could improve understanding of viral-bacterial interaction and indicate additional health benefits to influenza immunization. A time series analysis of the association of influenza and meningococcal disease using hospitalizations in 9 states from 1989-2009 included in the State Inpatient Databases from the Agency for Healthcare Research and Quality and the proportion of positive influenza tests by subtype reported to the Centers for Disease Control. The model accounts for the autocorrelation of meningococcal disease and influenza between weeks, temporal trends, co-circulating respiratory syncytial virus, and seasonality. The influenza-subtype-attributable fraction was estimated using the model coefficients. We analyzed the synchrony of seasonal peaks in hospitalizations for influenza, respiratory syncytial virus, and meningococcal...
Infections have long been thought to exert natural selection on humans. Infectious disease resist... more Infections have long been thought to exert natural selection on humans. Infectious disease resistance is frequently invoked as a mechanism shaping human genetic diversity, but such hypotheses have rarely been quantitatively evaluated with direct measures of disease-related mortality. Enhancement of genetically deter- mined resistance to tuberculosis by natural selection has been proposed as a factor explaining the decline of tuberculosis
Proceedings of The National Academy of Sciences, 2005
Acquired immunity to Streptococcus pneumoniae (pneumococcus) has long been assumed to depend on t... more Acquired immunity to Streptococcus pneumoniae (pneumococcus) has long been assumed to depend on the presence of anticapsular antibodies. We found, however, that colonization with live pneumococci of serotypes 6B, 7F, or 14 protected mice against recolonization by any of the serotypes and that protection from acquisition of a heterologous or homologous strain did not depend on anticapsular antibody. Further, intranasal
Widespread use of conjugate vaccines against Streptococcus pneumoniae, by reducing carriage of S.... more Widespread use of conjugate vaccines against Streptococcus pneumoniae, by reducing carriage of S. pneumoniae serotypes included in the vaccine, may result in an increase in nasopharyngeal carriage of - and disease from - nonvaccine serotypes of the same species. Mathematical models predict that the extent of such replacement will depend positively on the degree to which carriage of vaccine-type S. pneumoniae inhibits acquisition of nonvaccine-type pneumococci, and may depend negatively on the inhibition of vaccine-type pneumococci by nonvaccine-type pneumococci. We used a mouse model of intranasal carriage of pneumococci to test whether such inhibition occurs between different pneumococcal strains. Mice carrying a streptomycin-resistant derivative of S. pneumoniae BG9163 (serotype 6B) as a resident strain showed reduced levels of colonization when challenged intranasally by optochin-resistant derivatives of the same strain and of a serotype 23F pneumococcus, BG8826. Inhibition could be overcome by increasing the dose of the challenge strain. Carriage of optochin-resistant BG9163 did not inhibit acquisition of the streptomycin-resistant variant. Colonization by a challenge strain did not significantly affect the level of colonization with the resident strain. These results provide evidence that is consistent with several hitherto untested assumptions of mathematical models of serotype replacement and suggest that a biological mechanism exists that could account for serotype replacement that is observed in clinical trials. The findings provide a basis for further studies of in vivo interactions between strains of S. pneumoniae.
Antimicrobial resistance is a growing problem in nearly every infectious disease, but the extent ... more Antimicrobial resistance is a growing problem in nearly every infectious disease, but the extent and rate of increase of the problem varies widely with different pathogen-drug combinations. The rate of increase of resistance depends primarily on the availability of resistant variants and the intensity of selection imposed by antimicrobial treatment (appropriately measured). Declines in resistance following antimicrobial control measures are typically faster in hospital-acquired infections than in community-acquired ones, probably owing to the dependence in the latter case on the fitness cost of resistance. Open questions and approaches for testing the hypotheses proposed here are outlined.
The fitness of most pathogenic microorganisms depends on transmission from host to host. This req... more The fitness of most pathogenic microorganisms depends on transmission from host to host. This requires adaptation for dissemination, translocation and survival between hosts, as well as for colonization. A complex relationship exists between these components of microbial fitness and virulence. Understanding this relationship has important implications for research and public health.
... In contrast to the effect of the parasite on host fecundity, the relationship between equi-li... more ... In contrast to the effect of the parasite on host fecundity, the relationship between equi-libriumhost ... In an earlier publication, this parasite was re-ferred to as Tuzetia sp. ... to the new jars because transmission from a "spore bank" could influence the host-parasite dy-namics (Ebert ...
Competition through cross-reacting host immune responses, a form of apparent competition, is a ma... more Competition through cross-reacting host immune responses, a form of apparent competition, is a major driver of pathogen evolution and diversity. Most models of pathogens have focused on intraspecific interactions to explain observed patterns. Two recent experiments suggested that Haemophilus influenzae, a common nasopharyngeal colonizer of humans, might alter the immune environment in a way that favors otherwise less fit serotypes of another common pathogen, pneumococcus. Using a computational model, we demonstrate that H. influenzae, if it consistently raises the fitness of the less fit serotypes, can strongly promote pneumococcal diversity. However, the effects of H. influenzae are so sensitive to the prevalence of H. influenzae that this species is unlikely to be the main driver of serotype coexistence. Interactions that significantly affect diversity could furthermore be extremely difficult to detect through co-occurrence analysis alone. These results suggest that small differences in strains' adaptations to different immunological regimes, which are shaped by coinfections with other pathogens, can have dramatic effects on strain dynamics and patterns of phenotypic variation. Studies of microbial communities might therefore benefit from the use of varied approaches to infer the presence of indirect interactions.
Infection with herpes simplex virus type 2 (HSV-2) currently affects approximately 22% of adult A... more Infection with herpes simplex virus type 2 (HSV-2) currently affects approximately 22% of adult Americans and increased markedly in prevalence between the late 1970s and early 1990s. Although some estimates of the costs of prevalent disease due to HSV-2 are available, selection of interventions to prevent HSV-2 infection, as well as evaluation of their potential cost-effectiveness, should take into account projected future costs that will result if the epidemic is left unchecked. The goal was to estimate the future health and economic consequences attributable to the HSV-2 epidemic in the absence of interventions to slow the epidemic. A mathematical model was constructed to project future increases in HSV-2 seroprevalence in the United States. The probability of heterosexual transmission of HSV-2 was estimated from cross-sectional estimates of infection prevalence reported by the National Health and Nutrition Examination Survey (NHANES). Per-infection expected costs were calculated on the basis of data obtained from the published medical literature. RESULTS Without intervention, the prevalence of HSV-2 infection among individuals aged 15 to 39 years was projected to increase to 39% among men and 49% among women by 2025. Annual incidence was projected to increase steadily between 2000 and 2025, from 9 to 26 infections per 1,000 men and from 12 to 32 infections per 1,000 women in this age group. The cost of incident infections in the year 2000 were estimated to be $1.8 billion; the cost of incident infections was predicted to rise to $2.5 billion by 2015 and $2.7 billion by 2025. The projected cumulative cost of incident HSV-2 infections occurring over the next 25 years was estimated to be $61 billion; at a 3% discount rate, this sum has a present value of $43 billion. The costs of incident HSV-2 infection in the United States are substantial and can be expected to increase as both the incidence and prevalence of this disease increase in the first half of the century. The level of resource allocation for HSV-2 prevention strategies should reflect the economic benefits that would result from control of this epidemic.
Over 90 capsular serotypes of Streptococcus pneumoniae, a common nasopharyngeal colonizer and maj... more Over 90 capsular serotypes of Streptococcus pneumoniae, a common nasopharyngeal colonizer and major cause of pneumonia, bacteremia, and meningitis, are known. It is unclear why some serotypes can persist at all: They are more easily cleared from carriage and compete poorly in vivo. Serotype-specific immune responses, which could promote diversity in principle, are weak enough to allow repeated colonizations by the same type. We show that weak serotype-specific immunity and an acquired response not specific to the capsule can together reproduce observed diversity. Serotype-specific immunity stabilizes competition, and acquired immunity to noncapsular antigens reduces fitness differences. Our model can be used to explain the effects of pneumococcal vaccination and indicates general factors that regulate the diversity of pathogens.
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Papers by Marc Lipsitch