Co-infection of Mycobacterium tuberculosis and Mycobacterium leprae in human archaeological samples: a possible explanation for the historical decline of leprosy

Both leprosy and tuberculosis were prevalent in Europe during the first millennium but thereafter leprosy declined. It is not known why this occurred, but one suggestion is that cross-immunity protected tuberculosis patients from leprosy. To investigate any relationship between the two diseases, selected archaeological samples, dating from the Roman period to the thirteenth century, were examined for both Mycobacterium leprae and Mycobacterium tuberculosis DNA, using PCR. The work was carried out and verified in geographically separate and independent laboratories. Several specimens with palaeopathological signs of leprosy were found to contain DNA from both pathogens, indicating that these diseases coexisted in the past. We suggest that the immunological changes found in multi-bacillary leprosy, in association with the socio-economic impact on those suffering from the disease, led to increased mortality from tuberculosis and therefore to the historical decline in leprosy.     

The SIRC model and influenza A

We develop a simple ordinary differential equation model to study the epidemiological consequences of the drift mechanism for influenza A viruses. Improving over the classical SIR approach, we introduce a fourth class (C) for the cross-immune individuals in the population, i.e., those that recovered after being infected by different strains of the same viral subtype in the past years. The SIRC model predicts that the prevalence of a virus is maximum for an intermediate value of R(0), the basic reproduction number. Via a bifurcation analysis of the model, we discuss the effect of seasonality on the epidemiological regimes. For realistic parameter values, the model exhibits a rich variety of behaviors, including chaos and multi-stable periodic outbreaks. Comparison with empirical evidence shows that the simulated regimes are qualitatively and quantitatively consistent with reality, both for tropical and temperate countries. We find that the basins of attraction of coexisting cycles can be fractal sets, thus predictability can in some cases become problematic even theoretically. In accordance with previous studies, we find that increasing cross-immunity tends to complicate the dynamics of the system.     

A General HIV Incidence Inference Scheme Based on Likelihood of Individual Level Data and a Population Renewal Equation

We derive a new method to estimate the age specific incidence of an infection with a differential mortality, using individual level infection status data from successive surveys. The method consists of a) an SI-type model to express the incidence rate in terms of the prevalence and its derivatives as well as the difference in mortality rate, and b) a maximum likelihood approach to estimate the prevalence and its derivatives. Estimates can in principle be obtained for any chosen age and time, and no particular assumptions are made about the epidemiological or demographic context. This is in contrast with earlier methods for estimating incidence from prevalence data, which work with aggregated data, and the aggregated effect of demographic and epidemiological rates over the time interval between prevalence surveys. Numerical simulation of HIV epidemics, under the presumption of known excess mortality due to infection, shows improved control of bias and variance, compared to previous methods. Our analysis motivates for a) effort to be applied to obtain accurate estimates of excess mortality rates as a function of age and time among HIV infected individuals and b) use of individual level rather than aggregated data in order to estimate HIV incidence rates at times between two prevalence surveys.     

Genetic evidence that culling increases badger movement: implications for the spread of bovine tuberculosis

The Eurasian badger (Meles meles) has been implicated in the transmission of bovine tuberculosis (TB, caused by Mycobacterium bovis) to cattle. However, evidence suggests that attempts to reduce the spread of TB among cattle in Britain by culling badgers have mixed effects. A large-scale field experiment (the randomized badger culling trial, RBCT) showed that widespread proactive badger culling reduced the incidence of TB in cattle within culled areas but that TB incidence increased in adjoining areas. Additionally, localized reactive badger culling increased the incidence of TB in cattle. It has been suggested that culling-induced perturbation of badger social structure may increase individual movements and elevate the risk of disease transmission between badgers and cattle. Field studies support this hypothesis, by demonstrating increases in badger group ranges and the prevalence of TB infection in badgers following culling. However, more evidence on the effect of culling on badger movements is needed in order to predict the epidemiological consequences of this control strategy. Here, analysis of the genetic signatures of badger populations in the RBCT revealed increased dispersal following culling. While standard tests provided evidence for greater dispersal after culling, a novel method indicated that this was due to medium- and long-distance dispersal, in addition to previously reported increases in home-range size. Our results also indicated that, on average, badgers infected with M. bovis moved significantly farther than did uninfected badgers. A disease control strategy that included culling would need to take account of the potentially negative epidemiological consequences of increased badger dispersal.     

Consanguinity and susceptibility to infectious diseases in humans

Studies of animal populations suggest that low genetic heterozygosity is an important risk factor for infection by a diverse range of pathogens, but relatively little research has looked to see whether similar patterns exist in humans. We have used microsatellite genome screen data for tuberculosis (TB), hepatitis and leprosy to test the hypothesis that inbreeding depression increases risk of infection. Our results indicate that inbred individuals are more common among our infected cases for TB and hepatitis, but only in populations where consanguineous marriages are common. No effect was found either for leprosy, which is thought to be oligogenic, or for hepatitis in Italy where consanguineous marriages are rare. Our results suggest that consanguinity is an important risk factor in susceptibility to infectious diseases in humans.     

Implications of partial immunity on the prospects for tuberculosis control by post-exposure interventions

One-third of the world population (approximately 2 billion individuals) is currently infected with Mycobacterium tuberculosis, the vast majority harboring a latent infection. As the risk of reactivation is around 10% in a lifetime, it follows that 200 million of these will eventually develop active pulmonary disease. Only therapeutic or post-exposure interventions can tame this vast reservoir of infection. Treatment of latent infections can reduce the risk of reactivation, and there is accumulating evidence that combination with post-exposure vaccines can reduce the risk of reinfection. Here we develop mathematical models to explore the potential of these post-exposure interventions to control tuberculosis on a global scale. Intensive programs targeting recent infections appear generally effective, but the benefit is potentially greater in intermediate prevalence scenarios. Extending these strategies to longer-term persistent infections appears more beneficial where prevalence is low. Finally, we consider that susceptibility to reinfection is altered by therapy, and explore its epidemiological consequences. When we assume that therapy reduces susceptibility to subsequent reinfection, catastrophic dynamics are observed. Thus, a bipolar outcome is obtained, where either small or large reductions in prevalence levels result, depending on the rate of detection and treatment of latent infections. By contrast, increased susceptibility after therapy may induce an increase in disease prevalence and does not lead to catastrophic dynamics. These potential outcomes are silent unless a widespread intervention is implemented.     

Evaluating the influence of epidemiological parameters and host ecology on the spread of phocine distemper virus through populations of harbour seals

Background

Outbreaks of phocine distemper virus (PDV) in Europe during 1988 and 2002 were responsible for the death of around 23,000 and 30,000 harbour seals, respectively. These epidemics, particularly the one in 2002, provided an unusual opportunity to estimate epidemic parameters for a wildlife disease. There were marked regional differences in the values of some parameters both within and between epidemics.

Methodology and Principal Findings

We used an individual-based model of seal movement that allowed us to incorporate realistic representations of space, time and animal behaviour into a traditional epidemiological modelling framework. We explored the potential influence of a range of ecological (foraging trip duration, time of epidemic onset, population size) and epidemiological (length of infectious period, contact rate between infectious and susceptible individuals, case mortality) parameters on four readily-measurable epidemic characteristics (number of dead individuals, duration of epidemic, peak mortality date and prevalence) and on the probability that an epidemic would occur in a particular region. We analysed the outputs as if they were the results of a series of virtual experiments, using Generalised Linear Modelling. All six variables had a significant effect on the probability that an epidemic would be recognised as an unusual mortality event by human observers.

Conclusions

Regional and temporal variation in contact rate was the most likely cause of the observed differences between the two epidemics. This variation could be a consequence of differences in the way individuals divide their time between land and sea at different times of the year.     

Mycobacterium tuberculosis Complex Enhances Susceptibility of CD4 T Cells to HIV through a TLR2-Mediated Pathway

Among HIV-infected individuals, co-infection with Mycobacterium tuberculosis is associated with faster progression to AIDS. We investigated the hypothesis that M. bovis BCG and M. tuberculosis (Mtb complex) could enhance susceptibility of CD4+ cells to HIV infection. Peripheral blood mononuclear cells (PBMCs) collected from healthy donors were stimulated with M. bovis BCG, M. tuberculosis CDC1551 and M. smegmatis MC(2)155, and stimulated CD4+ cells were infected with R5-and X4-tropic single replication-competent pseudovirus. CD4+ cells stimulated with Mtb complex showed enhanced infection with R5- and X4-tropic HIV, compared to unstimulated cells or cells stimulated with M. smegmatis (p<0.01). Treatment with TLR2 siRNA reversed the increased susceptibility of CD4+ cells with R5- and X4-tropic virus induced by Mtb complex. These findings suggest that TB infection and/or BCG vaccination may be a risk factor for HIV acquisition.     

The effect of intrinsic stochasticity on transmitted HIV drug resistance patterns

Estimates of transmitted HIV drug-resistance prevalence vary widely among and within epidemiological surveys. Interpretation of trends from available survey data is therefore difficult. Because the emergence of drug-resistance involves small populations of infected drug-resistant individuals, the role of stochasticity (chance events) is likely to be important. The question addressed here is: how much variability in transmitted HIV drug-resistance prevalence patterns arises due to intrinsic stochasticity alone, i.e., if all starting conditions in the different epidemics surveyed were identical? This ‘thought experiment’ gives insight into the minimum expected variabilities within and among epidemics. A simple stochastic mathematical model was implemented. Our results show that stochasticity alone can generate a significant degree of variability and that this depends on the size and variation of the pool of new infections when drug treatment is first introduced. The variability in transmitted drug-resistance prevalence within an epidemic (i.e., the temporal variability) is large when the annual pool of all new infections is small (fewer than 200, typical of the HIV epidemics in Central European and Scandinavian countries) but diminishes rapidly as that pool grows. Epidemiological surveys involving hundreds of new infections annually are therefore needed to allow meaningful interpretation of temporal trends in transmitted drug-resistance prevalence within individual epidemics. The stochastic variability among epidemics shows a similar dependence on the pool of new infections if treatment is introduced after endemic equilibrium is established, but can persist even when there are more than 10,000 new infections annually if drug therapy is introduced earlier. Stochastic models may therefore have an important role to play in interpreting differences in transmitted drug-resistance prevalence trends among epidemiological surveys.     

Of mice and men: asymmetric interactions between Bordetella pathogen species

In a recent experiment, we found that mice previously infected with Bordetella pertussis were not protected against a later infection with Bordetella parapertussis, while primary infection with B. parapertussis conferred cross-protection. This challenges the common assumption made in most mathematical models for pathogenic strain dynamics that cross-immunity between strains is symmetric. Here we investigate the potential consequences of this pattern on the circulation of the two pathogens in human populations. To match the empirical dominance of B. pertussis, we made the additional assumption that B. parapertussis pays a cost in terms of reduced fitness. We begin by exploring the range of parameter values that allow the coexistence of the two pathogens, with or without vaccination. We then track the dynamics of the system following the introduction of anti-pertussis vaccination. Our results suggest that (1) in order for B. pertussis to be more prevalent than B. parapertussis, the former must have a strong competitive advantage, possibly in the form of higher infectivity, and (2) because of asymmetric cross-immunity, the introduction of anti-pertussis vaccination should have little effect on the absolute prevalence of B. parapertussis. We discuss the evidence supporting these predictions, and the potential relevance of this model for other pathogens.     

The epidemiology of human immunodeficiency virus in South Africa

We review the epidemiology of human immunodeficiency virus (HIV) in South Africa where the prevalence of HIV infection is among the highest in the world. The epidemic reached South Africa relatively recently but the prevalence of infection has increased rapidly and there are significant differences among provinces. Although few 15-year-old people are infected the prevalence increases rapidly with age thereafter, especially among women. The prevalence of herpes simplex virus type 2 exceeds that of HIV and curable sexually transmitted infections are common. 'Circular migration' may help to explain the high rates and rapid spread of HIV in the region. The incidence of tuberculosis has increased dramatically as a result of the HIV epidemic. Antiretroviral therapy for the prevention of vertical transmission has been shown to be effective in local conditions but transmission through breast-feeding remains problematical. While some epidemiological models have been developed, much more needs to be done in this regard in order to plan, coordinate and evaluate an effective response to the epidemic. We conclude by discussing some of the research that is needed and steps that could be taken to reduce the continued spread of the infection.     

Health newscasts for increasing influenza vaccination coverage: an inductive reasoning game approach

Both pandemic and seasonal influenza are receiving more attention from mass media than ever before. Topics such as epidemic severity and vaccination are changing the way in which we perceive the utility of disease prevention. Voluntary influenza vaccination has been recently modeled using inductive reasoning games. It has thus been found that severe epidemics may occur because individuals do not vaccinate and, instead, attempt to benefit from the immunity of their peers. Such epidemics could be prevented by voluntary vaccination if incentives were offered. However, a key assumption has been that individuals make vaccination decisions based on whether there was an epidemic each influenza season; no other epidemiological information is available to them. In this work, we relax this assumption and investigate the consequences of making more informed vaccination decisions while no incentives are offered. We obtain three major results. First, individuals will not cooperate enough to constantly prevent influenza epidemics through voluntary vaccination no matter how much they learned about influenza epidemiology. Second, broadcasting epidemiological information richer than whether an epidemic occurred may stabilize the vaccination coverage and suppress severe influenza epidemics. Third, the stable vaccination coverage follows the trend of the perceived benefit of vaccination. However, increasing the amount of epidemiological information released to the public may either increase or decrease the perceived benefit of vaccination. We discuss three scenarios where individuals know, in addition to whether there was an epidemic, (i) the incidence, (ii) the vaccination coverage and (iii) both the incidence and the vaccination coverage, every influenza season. We show that broadcasting both the incidence and the vaccination coverage could yield either better or worse vaccination coverage than broadcasting each piece of information on its own.     

Tracking the dynamics of pathogen interactions: modeling ecological and immune-mediated processes in a two-pathogen single-host system

Traditionally, epidemiological studies have focused on understanding the dynamics of a single pathogen, assuming no interactions with other pathogens. Recently, a large body of work has begun to explore the effects of immune-mediated interactions, arising from cross-immunity and antibody-dependent enhancement, between related pathogen strains. In addition, ecological processes such as a temporary period of convalescence and pathogen-induced mortality have led to the concept of ecological interference between unrelated diseases. There remains, however, the need for a systematic study of both immunological and ecological processes within a single framework. In this paper, we develop a general two-pathogen single-host model of pathogen interactions that simultaneously incorporates these mechanisms. We are then able to mechanistically explore how immunoecological processes mediate interactions between diseases for a pool of susceptible individuals. We show that the precise nature of the interaction can induce either competitive or cooperative associations between pathogens. Understanding the dynamic implications of multi-pathogen associations has potentially important public health consequences. Such a framework may be especially helpful in disentangling the effects of partially cross-immunizing infections that affect populations with a pre-disposition towards immunosuppression such as children and the elderly.     

Reduced blood parasite prevalence with age in the Seychelles Warbler: selective mortality or suppression of infection?

Avian malaria can affect survival and reproduction of their hosts. Two patterns commonly observed in birds are that females have a higher prevalence of malaria than do males and that prevalence decreases with age. The mechanisms behind these patterns remain unclear. However, most studies on blood parasite infections are based on cross-sectional analyses of prevalence, ignoring malaria related mortality and individual changes in infection. Here, we analyse both within-individual changes in malaria prevalence and long-term survival consequences of infection in the Seychelles Warbler (Acrocephalus sechellensis). Adults were less likely to be infected than juveniles but, contrary to broad patterns previously reported in birds, females were less likely to be infected than males. We show by screening individual birds in two subsequent years that the decline with age is a result both of individual suppression of infection and selective mortality. Birds that were infected early in life had a lower survival rate compared to uninfected birds, but among those that survived to be screened twice the proportion of infected birds had also decreased. Uninfected birds did not become infected later in life. Males were found to be more infected than females in this species possibly because, unlike most birds, males are the dispersing sex and the cost of dispersal may have to be traded against immunity. Infected males took longer to suppress their infection than did females. We conclude that these infections are indeed costly, and that age-related patterns in blood parasite prevalence are influenced both by suppression and selective mortality.     

Characterizing the symmetric equilibrium of multi-strain host-pathogen systems in the presence of cross immunity

We investigate the population dynamics of host-pathogen systems in which the pathogen has a potentially arbitrary number of antigenically distinct strains interacting via cross-immunity. The interior equilibrium configuration of the symmetric multiple strain SIR model with cross-immunity is characterized. We develop an efficient iterative method for numerically solving the equilibrium equation together with a number of informative analytical approximations to the full solution. Equilibrium properties are studied as a function of the number of strains, reproduction number, infectious period, and cross immunity profile. We establish that the prevalence in the system increases monotonically with the number of strains and the reduction in cross immunity. Moreover, we demonstrate the existence of a phase transition separating high prevalence and low prevalence parameter regions, with the critical point being defined by R₀1, where is the level of cross-immunity and R₀ is the reproduction number. Above the threshold, prevalence saturates with increasing numbers of strains as a result of the inclusion of prohibition of co-infection in the model. Below the threshold, prevalence saturates much more rapidly as the number of strains increases - indicating that when cross-protection is sufficiently intense, the selective advantage for a pathogen to increase its diversity is substantially less than in the threshold region. Similarly, there is limited benefit to increased transmissibility (or decreased cross-immunity) both for the high and low diversity pathogen systems compared with systems at the threshold R₀1 where small increase in transmissibility can result in significant increase in prevalence.     

Epidemiological models of Mycobacterium tuberculosis complex infections

The resurgence of tuberculosis in the 1990s and the emergence of drug-resistant tuberculosis in the first decade of the 21st century increased the importance of epidemiological models for the disease. Due to slow progression of tuberculosis, the transmission dynamics and its long-term effects can often be better observed and predicted using simulations of epidemiological models. This study provides a review of earlier study on modeling different aspects of tuberculosis dynamics. The models simulate tuberculosis transmission dynamics, treatment, drug resistance, control strategies for increasing compliance to treatment, HIV/TB co-infection, and patient groups. The models are based on various mathematical systems, such as systems of ordinary differential equations, simulation models, and Markov Chain Monte Carlo methods. The inferences from the models are justified by case studies and statistical analysis of TB patient datasets.     

Immunological serotype interactions and their effect on the epidemiological pattern of dengue

Long-term epidemiological data reveal multi-annual fluctuations in the incidence of dengue fever and dengue haemorrhagic fever, as well as complex cyclical behaviour in the dynamics of the four serotypes of the dengue virus. It has previously been proposed that these patterns are due to the phenomenon of the so-called antibody-dependent enhancement (ADE) among dengue serotypes, whereby viral replication is increased during secondary infection with a heterologous serotype; however, recent studies have implied that this positive reinforcement cannot account for the temporal patterns of dengue and that some form of cross-immunity or external forcing is necessary. Here, we show that ADE alone can produce the observed periodicities and desynchronized oscillations of individual serotypes if its effects are decomposed into its two possible manifestations: enhancement of susceptibility to secondary infections and increased transmissibility from individuals suffering from secondary infections. This decomposition not only lowers the level of enhancement necessary for realistic disease patterns but also reduces the risk of stochastic extinction. Furthermore, our analyses reveal a time-lagged correlation between serotype dynamics and disease incidence rates, which could have important implications for understanding the irregular pattern of dengue epidemics.     

Longitudinal study of tuberculosis outcomes among immunologically naive Aché natives of Paraguay

This study documents the course of a tuberculosis epidemic in an immunologically naive group of South American Indians within fewer than 20 years after first sustained contact with outsiders. Groups of Northern Aché (ah-CHAY) of eastern Paraguay were contacted and settled on reservations between 1971-1979. Not surprisingly, the Aché are very susceptible to tuberculosis, and the epidemiological characteristics of the disease are quite different from those of populations that have had tuberculosis for centuries. Within 6 years of the first detected case of tuberculosis among the Aché, the prevalence rate of active tuberculosis cases reached 18.2%, and of infected cases among adults, 64.6%, some of the highest rates ever reported for any human group. Remarkably, males and females are equally likely to have been diagnosed with active tuberculosis, Aché children between birth and 5 years of age are least vulnerable to tuberculosis, high nutritional and socioeconomic status do not decrease the risk of disease or infection, and children immunized with BCG are less responsive to tuberculin challenge than are other children. Moreover, similar to the Yanomam?, but unlike populations of European or African descent, a high percentage of Aché with active disease test negative on tuberculin challenge tests (purified protein derivative; PPD). These differences may be due to a high prevalence of diminished cell-mediated immunity, and T-helper 2 dominance. We also hypothesize that these immunological characteristics, low genetic diversity, hostile intergroup interactions, and behavioral noncompliance to treatment protocols together contribute to the high rates of active disease observed. Existing tuberculosis control programs are poorly equipped to handle the impact of these causal complexities on the course of recent tuberculosis epidemics that have quickly spread throughout native communities of Latin America during the last decade.     

Influence of age structure of plant populations on damping-off epidemics

Summary Germination synchrony may facilitate damping-off epidemics by creating a high density of uniformly susceptible individuals. We tested the hypothesis that synchronous germination causes increased seed and seedling mortality from damping-off in two legume species attacked by the fungal pathogen, Pythium aphanidermatum. Glycine max exhibited rapid, synchronous germination compared to its progenitor, G. soja, and suffered greater mortality from both pre-and postemergent damping-off in controlled environment experiments. However, when mixed-aged populations of G. max were created experimentally by staggering planting times, a significant increase in damping-off mortality occurred. In G. soja, which typically has mixed-aged populations due to asynchronous germination, experimental populations with an even-aged distribution also suffered increased damping-off mortality. Hence, the relationship between population age structure and damping-off mortality was species-specific. We propose that species differences in the duration of individual seedling susceptibility to disbase interact with population age structure to control the cutcome of damping-off epidemics.