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1.  Aedesin: Structure and Antimicrobial Activity against Multidrug Resistant Bacterial Strains 
PLoS ONE  2014;9(8):e105441.
Multidrug resistance, which is acquired by both Gram-positive and Gram-negative bacteria, causes infections that are associated with significant morbidity and mortality in many clinical settings around the world. Because of the rapidly increasing incidence of pathogens that have become resistant to all or nearly all available antibiotics, there is a need for a new generation of antimicrobials with a broad therapeutic range for specific applications against infections. Aedesin is a cecropin-like anti-microbial peptide that was recently isolated from dengue virus-infected salivary glands of the Aedes aegypti mosquito. In the present study, we have refined the analysis of its structural characteristics and have determined its antimicrobial effects against a large panel of multidrug resistant bacterial strains, directly isolated from infected patients. Based the results from nuclear magnetic resonance spectroscopy analysis, Aedesin has a helix-bend-helix structure typical for a member of the family of α-helix anti-microbial peptides. Aedesin efficiently killed Gram-negative bacterial strains that display the most worrisome resistance mechanisms encountered in the clinic, including resistance to carbapenems, aminoglycosides, cephalosporins, 4th generation fluoroquinolones, folate inhibitors and monobactams. In contrast, Gram-positive strains were insensitive to the lytic effects of the peptide. The anti-bacterial activity of Aedesin was found to be salt-resistant, indicating that it is active under physiological conditions encountered in body fluids characterized by ionic salt concentrations. In conclusion, because of its strong lytic activity against multidrug resistant Gram-negative bacterial strains displaying all types of clinically relevant resistance mechanisms known today, Aedesin might be an interesting candidate for the development of alternative treatment for infections caused by these types of bacteria.
PMCID: PMC4146511  PMID: 25162372
3.  Incidence of adult brain cancers is higher in countries where the protozoan parasite Toxoplasma gondii is common 
Biology Letters  2011;8(1):101-103.
We explored associations between the common protozoan parasite Toxoplasma gondii and brain cancers in human populations. We predicted that T. gondii could increase the risk of brain cancer because it is a long-lived parasite that encysts in the brain, where it provokes inflammation and inhibits apoptosis. We used a medical geography approach based on the national incidence of brain cancers and seroprevalence of T. gondii. We corrected reports of incidence for national gross domestic product because wealth probably increases the ability to detect cancer. We also included gender, cell phone use and latitude as variables in our initial models. Prevalence of T. gondii explained 19 per cent of the residual variance in brain cancer incidence after controlling for the positive effects of gross domestic product and latitude among nations. Infection with T. gondii was associated with a 1.8-fold increase in the risk of brain cancers across the range of T. gondii prevalence in our dataset (4–67%). These results, though correlational, suggest that T. gondii should be investigated further as a possible oncogenic pathogen of humans.
PMCID: PMC3259962  PMID: 21795265
Toxoplasma gondii; brain cancer; medical geography
4.  Applying ecological and evolutionary theory to cancer: a long and winding road 
Evolutionary Applications  2012;6(1):1-10.
Since the mid 1970s, cancer has been described as a process of Darwinian evolution, with somatic cellular selection and evolution being the fundamental processes leading to malignancy and its many manifestations (neoangiogenesis, evasion of the immune system, metastasis, and resistance to therapies). Historically, little attention has been placed on applications of evolutionary biology to understanding and controlling neoplastic progression and to prevent therapeutic failures. This is now beginning to change, and there is a growing international interest in the interface between cancer and evolutionary biology. The objective of this introduction is first to describe the basic ideas and concepts linking evolutionary biology to cancer. We then present four major fronts where the evolutionary perspective is most developed, namely laboratory and clinical models, mathematical models, databases, and techniques and assays. Finally, we discuss several of the most promising challenges and future prospects in this interdisciplinary research direction in the war against cancer.
PMCID: PMC3567465  PMID: 23397042
cancer, disease biology; evolutionary medicine; evolutionary theory
5.  From forest and agro-ecosystems to the microecosystems of the human body: what can landscape ecology tell us about tumor growth, metastasis, and treatment options? 
Evolutionary Applications  2012;6(1):82-91.
Cancer is now understood to be a process that follows Darwinian evolution. Heterogeneous populations of cancerous cells that make up the tumor inhabit the tissue ‘microenvironment’, where ecological interactions analogous to predation and competition for resources drive the somatic evolution of cancer. The tumor microenvironment plays a crucial role in the tumor genesis, development, and metastasis processes, as it creates the microenvironmental selection forces that ultimately determine the cellular characteristics that result in the greatest fitness. Here, we explore and offer new insights into the spatial aspects of tumor–microenvironment interactions through the application of landscape ecology theory to tumor growth and metastasis within the tissue microhabitat. We argue that small tissue microhabitats in combination with the spatial distribution of resources within these habitats could be important selective forces driving tumor invasiveness. We also contend that the compositional and configurational heterogeneity of components in the tissue microhabitat do not only influence resource availability and functional connectivity but also play a crucial role in facilitating metastasis and may serve to explain, at least in part, tissue tropism in certain cancers. This novel work provides a compelling argument for the necessity of taking into account the structure of the tissue microhabitat when investigating tumor progression.
PMCID: PMC3567473  PMID: 23396712
cancer ecology; evolutionary medicine; landscape ecology; tissue microhabitat landscape
6.  Peto's paradox revisited: theoretical evolutionary dynamics of cancer in wild populations 
Evolutionary Applications  2012;6(1):109-116.
If the occurrence of cancer is the result of a random lottery among cells, then body mass, a surrogate for cells number, should predict cancer incidence. Despite some support in humans, this assertion does not hold over the range of different natural animal species where cancer incidence is known. Explaining the so-called ‘Peto's paradox' is likely to increase our understanding of how cancer defense mechanisms are shaped by natural selection. Here, we study how body mass may affect the evolutionary dynamics of tumor suppressor gene (TSG) inactivation and oncogene activation in natural animal species. We show that the rate of TSG inactivation should evolve to lower values along a gradient of body mass in a nonlinear manner, having a threshold beyond which benefits to adaptive traits cannot overcome their costs. We also show that oncogenes may be frequently activated within populations of large organisms. We then propose experimental settings that can be employed to identify protection mechanisms against cancer. We finally highlight fundamental species traits that natural selection should favor against carcinogenesis. We conclude on the necessity of comparing genomes between populations of a single species or genomes between species to better understand how evolution has molded protective mechanisms against cancer development and associated mortality.
PMCID: PMC3567476  PMID: 23396800
biomedicine; disease biology; evolutionary medicine; evolutionary theory
7.  Preventive Evolutionary Medicine of Cancers 
Evolutionary Applications  2012;6(1):134-143.
Evolutionary theory predicts that once an individual reaches an age of sufficiently low Darwinian fitness, (s)he will have reduced chances of keeping cancerous lesions in check. While we clearly need to better understand the emergence of precursor states and early malignancies as well as their mitigation by the microenvironment and tissue architecture, we argue that lifestyle changes and preventive therapies based in an evolutionary framework, applied to identified high-risk populations before incipient neoplasms become clinically detectable and chemoresistant lineages emerge, are currently the most reliable way to control or eliminate early tumours. Specifically, the relatively low levels of (epi)genetic heterogeneity characteristic of many if not most incipient lesions will mean a relatively limited set of possible adaptive traits and associated costs compared to more advanced cancers, and thus a more complete and predictable understanding of treatment options and outcomes. We propose a conceptual model for preventive treatments and discuss the many associated challenges.
PMCID: PMC3567478  PMID: 23396860
cancer; chemotherapy; evolution; evolutionary cell biology; lifestyle; microenvironment; preventative evolutionary medicine; prevention
8.  The cost of a bodyguard 
Biology Letters  2011;7(6):843-846.
Host manipulation by parasites not only captures the imagination but has important epidemiological implications. The conventional view is that parasites face a trade-off between the benefits of host manipulation and their costs to fitness-related traits, such as longevity and fecundity. However, this trade-off hypothesis remains to be tested. Dinocampus coccinellae is a common parasitic wasp of the spotted lady beetle Coleomegilla maculata. Females deposit a single egg in the haemocoel of the host, and during larval development the parasitoid feeds on host tissues. At the prepupal stage, the parasitoid egresses from its host by forcing its way through the coccinellid's abdominal segments and begins spinning a cocoon between the ladybird's legs. Remarkably, D. coccinellae does not kill its host during its development, an atypical feature for parasitoids. We first showed under laboratory conditions that parasitoid cocoons that were attended by a living and manipulated ladybird suffered less predation than did cocoons alone or cocoons under dead ladybirds. We then demonstrated that the length of the manipulation period is negatively correlated with parasitoid fecundity but not with longevity. In addition to documenting an original case of bodyguard manipulation, our study provides the first evidence of a cost required for manipulating host behaviour.
PMCID: PMC3210670  PMID: 21697162
host–parasitoid interactions; bodyguard manipulation; manipulative costs; trade-off
9.  Natural resistance to cancers: a Darwinian hypothesis to explain Peto’s paradox 
BMC Cancer  2012;12:387.
Peto's paradox stipulates that there is no association between body mass (a surrogate of number of cells and longevity) and cancer prevalence in wildlife species. Resolving this paradox is a very promising research direction to understand mechanisms of cancer resistance. As of present, research has been focused on the consequences of these evolutionary pressures rather than of their causes.
Here, we argue that evolution through natural selection may have shaped mechanisms of cancer resistance in wildlife species and that this can result in a threshold in body mass above which oncogenic and tumor suppressive mechanisms should be increasingly purified and positively selected, respectively.
We conclude that assessing wildlife species in their natural ecosystems, especially through theoretical modeling, is the most promising way to understand how evolutionary processes can favor one or the other pathway. This will provide important insights into mechanisms of cancer resistance.
PMCID: PMC3488527  PMID: 22943484
10.  High Influenza A Virus Infection Rates in Mallards Bred for Hunting in the Camargue, South of France 
PLoS ONE  2012;7(8):e43974.
During the last decade, the role of wildlife in emerging pathogen transmission to domestic animals has often been pointed out. Conversely, far less attention has been paid to pathogen transmission from domestic animals to wildlife. Here, we focus on the case of game restocking, which implies the release of millions of animals worldwide each year. We conducted a 2-year study in the Camargue (Southern France) to investigate the influence of hand-reared Mallard releases on avian influenza virus dynamics in surrounding wildlife. We sampled Mallards (cloacal swabs) from several game duck facilities in 2009 and 2010 before their release. A very high (99%) infection rate caused by an H10N7 strain was detected in the game bird facility we sampled in 2009. We did not detect this strain in shot ducks we sampled, neither during the 2008/2009 nor the 2009/2010 hunting seasons. In 2010 infection rates ranged from 0 to 24% in hand-reared ducks. The 2009 H10N7 strain was fully sequenced. It results from multiple reassortment events between Eurasian low pathogenic strains. Interestingly, H10N7 strains had previously caused human infections in Egypt and Australia. The H10 and N7 segments we sequenced were clearly distinct from the Australian ones but they belonged to the same large cluster as the Egyptian ones. We did not observe any mutation linked to increased virulence, transmission to mammals, or antiviral resistance in the H10N7 strain we identified. Our results indicate that the potential role of hand-reared Mallards in influenza virus epizootics must be taken into account given the likely risk of viral exchange between game bird facilities and wild habitats, owing to duck rearing conditions. Measures implemented to limit transmission from wildlife to domestic animals as well as measures to control transmission from domestic animals to wild ones need to be equally reinforced.
PMCID: PMC3428329  PMID: 22952832
11.  Can we understand modern humans without considering pathogens? 
Evolutionary Applications  2012;5(4):368-379.
Throughout our evolutionary history, humankind has always lived in contact with large numbers of pathogens. Some cultural traits, such as sedentarization and animal domestication, have considerably increased new parasitic contacts and epidemic transitions. Here, we review the various phenotypic traits that have been proposed to be affected by the highly parasitic human environment, including fertility, birth weight, fluctuating asymmetry, body odours, food recipes, sexual behaviour, pregnancy sickness, language, religion and intellectual quotient. We also discuss how such knowledge is important to understanding several aspects of the current problems faced by humanity in our changing world and to predicting the long-term consequences of parasite eradication policies on our health and well-being. The study of the evolutionary interactions between humans and parasites is a burgeoning and most promising field, as demonstrated by the recent increasing popularity of Darwinian medicine.
PMCID: PMC3353360
behavior/social evolution; evolutionary medicine; host parasite interactions; life history evolution; natural selection and contemporary evolution; parasitology
12.  Proteomic analysis of an Aedes albopictus cell line infected with Dengue serotypes 1 and 3 viruses 
Parasites & Vectors  2011;4:138.
Proteomic analysis was performed to identify proteins regulated during infection by Dengue serotypes 1 and 3 in an Aedes albopictus cell line. The potential of these viruses to cause severe disease at primary infection is of interest although few studies have been performed with these two Dengue serotypes.
The most relevant observation of our study is the significant overexpression of proteins involved in the cellular stress response and the glycolysis pathway after 48 hours of infection. Viral infection activates the translation of some host genes, which may result in stress due to responses involving unfolded proteins.
Therefore, the oxidation reduction and glycolytic mechanisms could participate in the antiviral response against Dengue virus. The results of our study should help to improve our knowledge of the virus-mosquito interaction at a cellular level with the aim of designing efficient strategies for the control of Dengue virus.
PMCID: PMC3151224  PMID: 21767351
13.  Water-seeking behavior in worm-infected crickets and reversibility of parasitic manipulation 
Behavioral Ecology  2011;22(2):392-400.
One of the most fascinating examples of parasite-induced host manipulation is that of hairworms, first, because they induce a spectacular “suicide” water-seeking behavior in their terrestrial insect hosts and, second, because the emergence of the parasite is not lethal per se for the host that can live several months following parasite release. The mechanisms hairworms use to increase the encounter rate between their host and water remain, however, poorly understood. Considering the selective landscape in which nematomorph manipulation has evolved as well as previously obtained proteomics data, we predicted that crickets harboring mature hairworms would display a modified behavioral response to light. Since following parasite emergence in water, the cricket host and parasitic worm do not interact physiologically anymore, we also predicted that the host would recover from the modified behaviors. We examined the effect of hairworm infection on different behavioral responses of the host when stimulated by light to record responses from uninfected, infected, and ex-infected crickets. We showed that hairworm infection fundamentally modifies cricket behavior by inducing directed responses to light, a condition from which they mostly recover once the parasite is released. This study supports the idea that host manipulation by parasites is subtle, complex, and multidimensional.
PMCID: PMC3071748  PMID: 22476265
behavior; insects; nematomorph; parasite manipulation; parasitism; phototaxis
14.  Induction of a Peptide with Activity against a Broad Spectrum of Pathogens in the Aedes aegypti Salivary Gland, following Infection with Dengue Virus 
PLoS Pathogens  2011;7(1):e1001252.
The ultimate stage of the transmission of Dengue Virus (DENV) to man is strongly dependent on crosstalk between the virus and the immune system of its vector Aedes aegypti (Ae. aegypti). Infection of the mosquito's salivary glands by DENV is the final step prior to viral transmission. Therefore, in the present study, we have determined the modulatory effects of DENV infection on the immune response in this organ by carrying out a functional genomic analysis of uninfected salivary glands and salivary glands of female Ae. aegypti mosquitoes infected with DENV. We have shown that DENV infection of salivary glands strongly up-regulates the expression of genes that encode proteins involved in the vector's innate immune response, including the immune deficiency (IMD) and Toll signalling pathways, and that it induces the expression of the gene encoding a putative anti-bacterial, cecropin-like, peptide (AAEL000598). Both the chemically synthesized non-cleaved, signal peptide-containing gene product of AAEL000598, and the cleaved, mature form, were found to exert, in addition to antibacterial activity, anti-DENV and anti-Chikungunya viral activity. However, in contrast to the mature form, the immature cecropin peptide was far more effective against Chikungunya virus (CHIKV) and, furthermore, had strong anti-parasite activity as shown by its ability to kill Leishmania spp. Results from circular dichroism analysis showed that the immature form more readily adopts a helical conformation which would help it to cause membrane permeabilization, thus permitting its transfer across hydrophobic cell surfaces, which may explain the difference in the anti-pathogenic activity between the two forms. The present study underscores not only the importance of DENV-induced cecropin in the innate immune response of Ae. aegypti, but also emphasizes the broad-spectrum anti-pathogenic activity of the immature, signal peptide-containing form of this peptide.
Author Summary
Dengue viruses (DENV) are generally maintained in a cycle which requires horizontal transmission via their arthropod vector, Ae. aegypti, to the vertebrate host. One important consequence of this process is the interference of the virus with the immune systems of both the mosquito and its host. While infection of humans causes disease, the presence of DENV in mosquitoes gives rise to life-long and persistent infection with active viral replication in the salivary glands. In the present study, we have evaluated the mosquito's immune response following DENV infection by analyzing the gene expression profile of infected and uninfected salivary glands. The results show that DENV infection activates signaling pathways and induces the expression of gene products that are involved in the innate immune response to DENV infection, and in particular a putative antibacterial cecropin-like peptide. The immature and mature forms of this peptide were found to be active against a variety of pathogens including DENV and Chikungunya viruses, as well as the Leishmania parasite. This study is the first to establish a comparative analysis of uninfected salivary glands and salivary glands of female Ae. aegypti mosquitoes infected with DENV. We demonstrate that certain DENV-induced peptides possess broad-spectrum anti-pathogenic activity and may have therapeutic potential in the treatment of human infectious disease.
PMCID: PMC3020927  PMID: 21249175
15.  The Alarming Proximity of Parasites 
PLoS Biology  2010;8(11):e1000526.
PMCID: PMC2970555
16.  Persistence of Highly Pathogenic Avian Influenza Viruses in Natural Ecosystems 
Emerging Infectious Diseases  2010;16(7):1057-1062.
Differences in virus evolution may explain virulence heterogeneity.
Understanding of ecologic factors favoring emergence and maintenance of highly pathogenic avian influenza (HPAI) viruses is limited. Although low pathogenic avian influenza viruses persist and evolve in wild populations, HPAI viruses evolve in domestic birds and cause economically serious epizootics that only occasionally infect wild populations. We propose that evolutionary ecology considerations can explain this apparent paradox. Host structure and transmission possibilities differ considerably between wild and domestic birds and are likely to be major determinants of virulence. Because viral fitness is highly dependent on host survival and dispersal in nature, virulent forms are unlikely to persist in wild populations if they kill hosts quickly or affect predation risk or migratory performance. Interhost transmission in water has evolved in low pathogenic influenza viruses in wild waterfowl populations. However, oropharyngeal shedding and transmission by aerosols appear more efficient for HPAI viruses among domestic birds.
PMCID: PMC3321889  PMID: 20587174
Influenza A (H5N1); wild birds; highly pathogenic avian influenza viruses; viruses; influenza; poultry; free-grazing ducks; live bird markets; environment; perspective
17.  Beer Consumption Increases Human Attractiveness to Malaria Mosquitoes 
PLoS ONE  2010;5(3):e9546.
Malaria and alcohol consumption both represent major public health problems. Alcohol consumption is rising in developing countries and, as efforts to manage malaria are expanded, understanding the links between malaria and alcohol consumption becomes crucial. Our aim was to ascertain the effect of beer consumption on human attractiveness to malaria mosquitoes in semi field conditions in Burkina Faso.
Methodology/Principal Findings
We used a Y tube-olfactometer designed to take advantage of the whole body odour (breath and skin emanations) as a stimulus to gauge human attractiveness to Anopheles gambiae (the primary African malaria vector) before and after volunteers consumed either beer (n = 25 volunteers and a total of 2500 mosquitoes tested) or water (n = 18 volunteers and a total of 1800 mosquitoes). Water consumption had no effect on human attractiveness to An. gambiae mosquitoes, but beer consumption increased volunteer attractiveness. Body odours of volunteers who consumed beer increased mosquito activation (proportion of mosquitoes engaging in take-off and up-wind flight) and orientation (proportion of mosquitoes flying towards volunteers' odours). The level of exhaled carbon dioxide and body temperature had no effect on human attractiveness to mosquitoes. Despite individual volunteer variation, beer consumption consistently increased attractiveness to mosquitoes.
These results suggest that beer consumption is a risk factor for malaria and needs to be integrated into public health policies for the design of control measures.
PMCID: PMC2832015  PMID: 20209056
18.  Spread of Avian Influenza Viruses by Common Teal (Anas crecca) in Europe 
PLoS ONE  2009;4(10):e7289.
Since the recent spread of highly pathogenic (HP) H5N1 subtypes, avian influenza virus (AIV) dispersal has become an increasing focus of research. As for any other bird-borne pathogen, dispersal of these viruses is related to local and migratory movements of their hosts. In this study, we investigated potential AIV spread by Common Teal (Anas crecca) from the Camargue area, in the South of France, across Europe. Based on bird-ring recoveries, local duck population sizes and prevalence of infection with these viruses, we built an individual-based spatially explicit model describing bird movements, both locally (between wintering areas) and at the flyway scale. We investigated the effects of viral excretion duration and inactivation rate in water by simulating AIV spread with varying values for these two parameters. The results indicate that an efficient AIV dispersal in space is possible only for excretion durations longer than 7 days. Virus inactivation rate in the environment appears as a key parameter in the model because it allows local persistence of AIV over several months, the interval between two migratory periods. Virus persistence in water thus represents an important component of contamination risk as ducks migrate along their flyway. Based on the present modelling exercise, we also argue that HP H5N1 AIV is unlikely to be efficiently spread by Common Teal dispersal only.
PMCID: PMC2750755  PMID: 19802387

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