Multi-sectorial research is paramount for preventing and controlling emerging infectious diseases.

The social, economic and political consequences of emerging infectious disease (EID) may escape the sphere in which they first arise. In recent years, many EIDs have revealed the close links between human, animal and plant health, highlighting the need for multi-scale, multisectorial EID management. Human beings play a dual role in EID because they can promote their development through numerous human-environment interfaces and expanding international trade. On the other hand, their ability to analyze, interpret and act on the determinants of EID allows them to access the expertise necessary to control these EIDs. This expertise must be constantly adapted to remain relevant as the EID evolves, particularly in its virulence or transmission channels. Flexibility should become an inherent part of the expertise-based decision-making process even if it means going backwards. A certain degree of transparency and feedback to citizens is necessary for the acceptability of political decisions basing on expertise. A key step in the management of EID is the appropriate management of the early signal of infectious emergence. This step combines multidisciplinary skills allowing access to the best pathway for containing EID by implementing early countermeasures adapted to the situation. New digital technologies could significantly improve this early detection phase. Finally, experts have a fundamental role to play because they are located at the interface between operational actors and decision-makers, which allows multidirectional feedback, ideally in real time, between professional actors and decision makers. To combat current and future EIDs, expertise should be based on a multi-sectorial approach, promotion of collegiality and continuously adaptation to the evolving nature of EIDs.

Need for integrative thinking to fight against emerging infectious diseases. Proceedings of the 5th seminar on emerging infectious diseases, March 22, 2016 - current trends and proposals.

We present here the proceedings of the 5th seminar on emerging infectious diseases, held in Paris on March 22nd, 2016, with seven priority proposals that can be outlined as follows: encourage research on the prediction, screening and early detection of new risks of infection; develop research and surveillance concerning transmission of pathogens between animals and humans, with their reinforcement in particular in intertropical areas ("hot-spots") via public support; pursue aid development and support in these areas of prevention and training for local health personnel, and foster risk awareness in the population; ensure adapted patient care in order to promote adherence to treatment and to epidemic propagation reduction measures; develop greater awareness and better education among politicians and healthcare providers, in order to ensure more adapted response to new types of crises; modify the logic of governance, drawing from all available modes of communication and incorporating new information-sharing tools; develop economic research on the fight against emerging infectious diseases, taking into account specific driving factors in order to create a balance between preventive and curative approaches.

Disease ecology, health and the environment: a framework to account for ecological and socio-economic drivers in the control of neglected tropical diseases.

Reducing the burden of neglected tropical diseases (NTDs) is one of the key strategic targets advanced by the Sustainable Development Goals. Despite the unprecedented effort deployed for NTD elimination in the past decade, their control, mainly through drug administration, remains particularly challenging: persistent poverty and repeated exposure to pathogens embedded in the environment limit the efficacy of strategies focused exclusively on human treatment or medical care. Here, we present a simple modelling framework to illustrate the relative role of ecological and socio-economic drivers of environmentally transmitted parasites and pathogens. Through the analysis of system dynamics, we show that periodic drug treatments that lead to the elimination of directly transmitted diseases may fail to do so in the case of human pathogens with an environmental reservoir. Control of environmentally transmitted diseases can be more effective when human treatment is complemented with interventions targeting the environmental reservoir of the pathogen. We present mechanisms through which the environment can influence the dynamics of poverty via disease feedbacks. For illustration, we present the case studies of Buruli ulcer and schistosomiasis, two devastating waterborne NTDs for which control is particularly challenging.This article is part of the themed issue 'Conservation, biodiversity and infectious disease: scientific evidence and policy implications'.

[Paradoxical reactions and responses during antibiotic treatment for Mycobacterium ulcerans infection (Buruli ulcer). Four cases from French Guiana]. / Réponses et réactions paradoxales au cours du traitement médicamenteux de l'infection à Mycobacterium ulcerans (ulcère de Buruli). Quatre observations en Guyane française.

BACKGROUND: In recent years, first-line therapy for Mycobacterium ulcerans infection in French Guiana has consisted of antibiotics active against this organism. Two regimens are used comprising rifampicin associated with clarithromycin or amikacin. PATIENTS AND METHODS: We describe four patients presenting apparent worsening of their lesions during treatment: ulceration of a nodular lesion in a 32-year-old woman and worsening of an ulcerated lesion in three patients aged 16, 27 and 79 years. DISCUSSION: In these 4 patients, we concluded that the symptoms were caused by a paradoxical response or a reaction, a phenomenon already described in tuberculosis and leprosy. Such worsening is transient and must not be misinterpreted as failure to respond to treatment. The most plausible pathophysiological hypothesis involves the re-emergence of potentially necrotizing cellular immunity secondary to the loss of mycolactone, a necrotizing and immunosuppressive toxin produced by M. ulcerans, resulting from the action of the antibiotics.

Tracking a heterosis effect in the field: tadpole resistance to parasites in the water frog hybridogenetic complex.

Depending on the extent of evolutionary divergence among parent taxa, hybrids may suffer from a breakdown of co-adapted genes or may conversely exhibit vigour due to the heterosis effect, which confers advantages to increased genetic diversity. That last mechanism could explain the success of hybrids when hybridization zones are large and long lasting, such as in the water frog hybridization complex. In this hybridogenetic system, hybrid individuals exhibit full heterozygosity that makes it possible to investigate in situ the impact of hybridization. We have compared parasite intensity between hybrid Rana esculenta and parental R. lessonae individuals at the tadpole stage in two populations inhabiting contrasted habitats. We estimated intensity of Gyrinicola sp. (Nematoda) in the gut, Echinostome metacercariae in the kidneys and Haplometra cylindracea in the body cavity (both species belong to Trematoda). Despite high sampling effort, no variation in parasite intensity was detected between taxa, except a possible higher tolerance to H. cylindracea in hybrid tadpoles. The low effect of hybridization suggests efficient gene co-adaptation between the two genomes that could result from hemiclonal selection. Variation in infection intensity among ponds could support the Red Queen hypothesis.

How the biodiversity sciences may aid biological tools and ecological engineering to assess the impact of climatic changes.

This paper addresses how climate changes interact with other global changes caused by humans (habitat fragmentation, changes in land use, bioinvasions) to affect biodiversity. Changes in biodiversity at all levels (genetic, population and community) affect the functioning of ecosystems, in particular host-pathogen interactions, with major consequences in health ecology (emergence and re-emergence; the evolution of virulence and resistance). In this paper, the authors demonstrate that the biodiversity sciences, epidemiological theory and evolutionary ecology are indispensable in assessing the impact of climate changes, and also for modelling the evolution of host-pathogen interactions in a changing environment. The next step is to apply health ecology to the science of ecological engineering.

Heterozygosity and parasite intensity: lung parasites in the water frog hybridization complex.

In hybridogenetic systems, hybrid individuals are fully heterozygous because one of the parental genomes is discarded from the germinal line before meiosis. Such systems offer the opportunity to investigate the influence of heterozygosity on susceptibility to parasites. We studied the intensity of lung parasites (the roundworm Rhabdias bufomis and the fluke Haplometra cylindracea) in 3 populations of water frogs of the Rana lessonae-esculenta complex in eastern France. In these mixed populations, hybrid frogs (R. esculenta) outnumbered parental ones (R. lessonae). Despite variation in parasite intensity and demographic variability among populations, the relationship between host age and intensity of parasitism suggests a higher susceptibility in parentals than in hybrids. Mortality is probably enhanced by lung parasites in parental frogs. On the other hand, while parental frogs harboured higher numbers of H. cylindracea than hybrid frogs, the latter had higher numbers of R. bufonis. Despite such discrepancies, these results support the hybrid resistance hypothesis, although other factors, such as differences in body size, age-related immunity, differential exposure risks and hemiclonal selection, could also contribute to the observed patterns of infection.

On the power of some binomial modifications of the Bonferroni multiple test.

Widely used in testing statistical hypotheses, the Bonferroni multiple test has a rather low power that entails a high risk to accept falsely the overall null hypothesis and therefore to not detect really existing effects. We suggest that when the partial test statistics are statistically independent, it is possible to reduce this risk by using binomial modifications of the Bonferroni test. Instead of rejecting the null hypothesis when at least one of n partial null hypotheses is rejected at a very high level of significance (say, 0.005 in the case of n = 10), as it is prescribed by the Bonferroni test, the binomial tests recommend to reject the null hypothesis when at least k partial null hypotheses (say, k = [n/2]) are rejected at much lower level (up to 30-50%). We show that the power of such binomial tests is essentially higher as compared with the power of the original Bonferroni and some modified Bonferroni tests. In addition, such an approach allows us to combine tests for which the results are known only for a fixed significance level. The paper contains tables and a computer program which allow to determine (retrieve from a table or to compute) the necessary binomial test parameters, i.e. either the partial significance level (when k is fixed) or the value of k (when the partial significance level is fixed).

Human birthweight evolution across contrasting environments.

We explore from both theoretical and empirical perspectives the hypothesis that a significant part of the worldwide variability in human birthweight results from adaptive responses to local selective pressures. We first developed an agent-based model to simulate the process of evolutionary selection on life history strategy, and then we performed a comparative analysis across 89 countries worldwide. The model illustrates that optimal birthweight depends on which fitness-reducing risk locally predominates (somatic diseases, parasitic diseases or adverse environmental conditions). When fitness variations between individuals mainly result from somatic diseases (e.g. industrialized countries), or conversely from infectious and parasitic diseases (e.g. developing countries), selection is expected to favour individuals producing larger children. Conversely, when environmental risks increase in relative importance, selective pressures for producing children with high birthweight are reduced. The comparative analysis supports these theoretical expectations, in particular the finding that birthweight is higher than predicted in highly parasitized countries.

Evidence for phylogenetic inheritance in pathogenicity of Mycobacterium.

In this study, we attempt to highlight part of the adaptive and phylogenetic constraints in mycobacterial pathogenicity. For this purpose, we first provide a phylogeny of Mycobacteria based on cladistic analyses of 64 different taxa. We then performed a comparative analysis, taking into account both ecological factors and phylogenetic relationships. The GLIM modelling analysis showed that different ecological and phylogenetic factors might be invoked to explain the variation in pathogenicity levels. Interestingly, the most harmful species were shown to be connected with the most diversified habitats. However, the independent contrast analysis revealed that once phylogeny was taken into account, none of the relationships between ecological factors and pathogenicity remained significant, and the pathogenicity appeared to be phylogenetically inherited among mycobacteria. The most pathogen were found in the slow-growing/long helix 18 group, and within this group in the most derived taxa.

High prevalence anti-Trypanosoma cruzi antibodies, among blood donors in the State of Puebla, a non-endemic area of Mexico.

Blood transfusion is the second most common transmission route of Chagas disease in many Latin American countries. In Mexico, the prevalence of Chagas disease and impact of transfusion of Trypanosoma cruzi-contaminated blood is not clear. We determined the seropositivity to T. cruzi in a representative random sample, of 2,140 blood donors (1,423 men and 647 women, aged 19-65 years), from a non-endemic state of almost 5 millions of inhabitants by the indirect hemagglutination (IHA) and enzyme linked immunosorbent assay (ELISA) tests using one autochthonous antigen from T. cruzi parasites, which were genetically characterized like TBAR/ME/1997/RyC-V1 (T. cruzi I) isolated from a Triatoma barberi specimen collected in the same locality. The seropositivity was up to 8.5% and 9% with IHA and ELISA tests, respectively, and up to 7.7% using both tests in common. We found high seroprevalence in a non-endemic area of Mexico, comparable to endemic countries where the disease occurs, e.g. Brazil (0.7%), Bolivia (13.7%) and Argentina (3.5%). The highest values observed in samples from urban areas, associated to continuous rural emigration and the absence of control in blood donors, suggest unsuspected high risk of transmission of T. cruzi, higher than those reported for infections by blood e.g. hepatitis (0.1%) and AIDS (0.1%) in the same region.

High prevalence anti-Trypanosoma cruzi antibodies, among blood donors in the State of Puebla, a non-endemic area of Mexico

Blood transfusion is the second most common transmission route of Chagas disease in many Latin American countries. In Mexico, the prevalence of Chagas disease and impact of transfusion of Trypanosoma cruzi-contaminated blood is not clear. We determined the seropositivity to T. cruzi in a representative random sample, of 2,140 blood donors (1,423 men and 647 women, aged 19-65 years), from a non-endemic state of almost 5 millions of inhabitants by the indirect hemagglutination (IHA) and enzyme linked immunosorbent assay (ELISA) tests using one autochthonous antigen from T. cruzi parasites, which were genetically characterized like TBAR/ME/1997/RyC-V1 (T. cruzi I) isolated from a Triatoma barberi specimen collected in the same locality. The seropositivity was up to 8.5 percent and 9 percent with IHA and ELISA tests, respectively, and up to 7.7 percent using both tests in common. We found high seroprevalence in a non-endemic area of Mexico, comparable to endemic countries where the disease occurs, e.g. Brazil (0.7 percent), Bolivia (13.7 percent) and Argentina (3.5 percent). The highest values observed in samples from urban areas, associated to continuous rural emigration and the absence of control in blood donors, suggest unsuspected high risk of transmission of T. cruzi, higher than those reported for infections by blood e.g. hepatitis (0.1 percent) and AIDS (0.1 percent) in the same region

Host manipulation by Ligula intestinalis: a cause or consequence of parasite aggregation?

Previous investigations suggest that the infection of the cyprinid roach, Rutilus rutilus, with the larval plerocercoid forms of the cestode, Ligula intestinalis, creates behavioural and morphological changes in the fish host, potentially of adaptive significance to the parasite in promoting transmission to definitive avian hosts. Here we consider whether these behavioural changes are important in shaping the distribution of parasite individuals across the fish population. An examination of field data illustrates that fish infected with a single parasite were more scarce than expected under the negative binomial distribution, and in many months were more scarce than burdens of two, three or more, leading to a bimodal distribution of worm counts (peaks at 0 and >1). This scarcity of single-larval worm infections could be accounted for a priori by a predominance of multiple infection. However, experimental infections of roach gave no evidence for the establishment of multiple worms, even when the host was challenged with multiple intermediate crustacean hosts, each multiply infected. A second hypothesis assumes that host manipulation following an initial single infection leads to an increased probability of subsequent infection (thus creating a contagious distribution). If manipulated fish are more likely to encounter infected first-intermediate hosts (through microhabitat change, increased ingestion, or both), then host manipulation could act as a powerful cause of aggregation. A number of scenarios based on contagious distribution models of aggregation are explored, contrasted with alternative compound Poisson models, and compared with the empirical data on L. intestinalis aggregation in their roach intermediate hosts. Our results indicate that parasite-induced host manipulation in this system can function simultaneously as both a consequence and a cause of parasite aggregation. This mutual interaction between host manipulation and parasite aggregation points to a set of ecological interactions that are easily missed in most experimental studies of either phenomenon.

Phenotypic modification of roach (Rutilus rutilus L.) infected with Ligula intestinalis L. (Cestoda: Pseudophyllidea).

In European freshwater, cyprinid fish may be heavily infected by plerocercoids of the pseudophyllidea cestode Ligula intestinalis (L.). During their development, these parasites grow rapidly to a large size in the fish's body cavity, characteristically distending the abdomen. In this study, the influence of this tapeworm on roach (Rutilus rutilus L.) morphology was analyzed. Forty-five infected and 45 uninfected roach were collected from the Lavernose-Lacasse gravel pit in Toulouse, south western France and examined for 40 morphological measurements to study phenotypic modification of the body and 14 bilateral characters for an analysis of asymmetry. Results indicate that the degree of bilateral asymmetry does not change between infected and uninfected roach, despite the strong host-morphological modifications such as deformation of the abdomen, fin displacements at the level of the tail, and sagging of the vertebral column. The intensity of abdominal distension and fish morphology changes depends on the total parasite biomass present. Differences were observed in morphology at different levels of infection, which relate to established effects of L. intestinalis on the physiology and behavior of intermediate hosts. These morphological changes induced by the parasite could increase trophic transmission to the definitive avian hosts.

Trying to predict and explain the presence of African trypanosomes in tsetse flies.

Trypanosome infections identified by polymerase chain reaction on field-caught tsetse flies from various locations were analyzed with respect to factors intrinsic and extrinsic to the trypanosome-tsetse association. These factors were then simultaneously analyzed using artificial neural networks (ANNs) and the important factors were identified to predict and explain the presence of trypanosomes in tsetse. Among 4 trypanosome subgroups (Trypanosoma brucei s.l., T. congolense of the 'savannah' and of the 'riverine-forest' types, and T. simiae), the presence of the 2 types of T. congolense was predictable in more than 80% of cases, suggesting that the model incorporated some of the key variables. These 2 types of T. congolense were significantly associated in tsetse. Among all the examined factors, it was the presence of T. congolense savannah type that best explained the presence of T. congolense riverine forest type. One possible biological mechanism would be 'hitchhiking,' as previously suspected for other parasites. The model could be improved by adding other important variables to the trypanosome tsetse associations.

Host manipulation by Ligula intestinalis: accident or adaptation?

Numerous studies have demonstrated that parasites with complex life-cycles can cause phenotypic modifications in their hosts that lead to an increased rate of transmission, and suggest that these modifications are the result of parasitic adaptations to manipulate the host. Little attention is paid, however, to separating the possibility of adaptive host manipulation from incidental (if fortuitous) side-effects of infection. In this study we combine statistical and analytical tools to interpret the impact of the macroparasite Ligula intestinalis L. (Cestoda, Pseudophyllidea) on the behaviour of its intermediate fish host (the roach, Rutilus rutilus L.), using field data on a natural system. Two distinct sets of generalized linear models agree that both the presence and the intensity of infection contribute to a modified behavioural response in the host. This was illustrated by a preference for the lake-edge in infected fish during autumn. Furthermore, the effect of parasites upon their host is heterogeneous with respect to parasite size, with larger parasite individuals having a disproportionate impact. A series of game-theoretic models of adaptive host manipulation illustrate a potential rationale for a size-dependent manipulation strategy in parasites. These findings illustrate the potential complexity and functionality of the impact of L. intestinalis upon its fish host, which together reduce the parsimony of the alternative 'incidental effect' hypothesis.

Disease diversity and human fertility.

The existence of parasitic constraints on the evolution of life-history traits in free-living organisms has been demonstrated in several plant and animal species. However, the association between different diseases and human traits is virtually unknown. We conducted a comparative analysis on a global scale to test whether the diversity of human diseases, some of them responsible for high incidences of morbidity and mortality, were associated with host life-history characteristics. After controlling for direct confounding effects exerted by historical, spatial, economic, and population patterns and their interactions, our findings show that human fertility increases with the diversity and structure of disease types. Thus, disease control may not only lower the costs associated with morbidity, but could also contribute directly or indirectly to reductions in human population growth.