In the years during and after World War II, the Microbiological Research Establishment (MRE) at Porton Down was the UK Government’s centre for germ warfare research (or defence, depending on who you believe). There were two parts to the MRE, the part “outside the wire”, which contained among other things, the Common Cold Unit, and the section “inside the wire”, which was top secret and has been the subject of much rumour and speculation.
To control influenza outbreaks or a pandemic, it is important to identify and characterize the different vectors that could promote influenza virus transmission between people. The respiratory tract of influenza virus-infected individuals is the main reservoir for the chain of transmission in a community. Based on experiments with animal models and observational field studies, large respiratory droplets are considered to be the most frequent vectors sustaining influenza transmission. However, experimental studies with animals with no direct contact have demonstrated that aerosols also play a significant role. In humans, the hypothesis that there is an aerosol route of transmission is supported by indirect evidence in special circumstances, such as confinement for a prolonged period of time in an airplane in the presence of a patient infected with influenza virus. In addition, it has been documented that human influenza A viruses can survive for a prolonged period on different types of surfaces once they are present in the environment. Although controversial, the possibility that contaminated surfaces and fomites could act as vectors of transmission needs to be considered in the context of overall influenza pandemic preparedness.
For any environmental contamination to be relevant, the virus should not only remain infectious but also persist at a sufficient concentration to enable it to reach the respiratory tract via finger contamination. Rhinovirus is the most common respiratory virus known to be easily transmitted by this route. Whether influenza virus is also commonly transmitted by this route remains a subject of debate. However, given that the biological properties of a potential influenza virus pandemic strain have not been established, this route of transmission has to be considered. The severe acute respiratory syndrome coronavirus SARS highlighted the ability of respiratory viruses to act in unconventional ways since environmental contamination by stools played a significant role in some population clusters. All these questions should be considered not only from a scientific standpoint. We must also take into account and provide answers to the many possible questions raised by various communities and public health authorities.
The authors of a recent paper hypothesized that banknotes may be one of various possible influenza vectors and may offer opportunities for infection. In Switzerland, a small country with a population of approximately 7 million, it is estimated that 20 to 100 million banknotes are exchanged each day, and billions of individual notes are exchanged daily worldwide. So could influenza be transmitted by money?
Survival of influenza virus on banknotes. Appl Environ Microbiol 2008 74: 3002-7
Successful control of a viral disease requires knowledge of the different vectors that could promote its transmission among hosts. We assessed the survival of human influenza viruses on banknotes given that billions of these notes are exchanged daily worldwide. Banknotes were experimentally contaminated with representative influenza virus subtypes at various concentrations, and survival was tested after different time periods. Influenza A viruses tested by cell culture survived up to 3 days when they were inoculated at high concentrations. The same inoculum in the presence of respiratory mucus showed a striking increase in survival time (up to 17 days). Similarly, B/Hong Kong/335/2001 virus was still infectious after 1 day when it was mixed with respiratory mucus. When nasopharyngeal secretions of naturally infected children were used, influenza virus survived for at least 48 h in one-third of the cases. The unexpected stability of influenza virus in this nonbiological environment suggests that unusual environmental contamination should be considered in the setting of pandemic preparedness.
Leishmaniasis is an antropozoonotic disease with a wide range of clinical manifestations. In humans, signs of disease vary from skin and mucosal ulcers to enlargement of internal organs such as the liver and spleen. The unicellular parasite Leishmania amazonensis is able to infect humans and cause localized or diffuse skin lesions. The treatment for this disease is difficult, as it requires prolonged and painful applications of toxic drugs that are poorly tolerated. Therefore, a key area in leishmaniasis research is the study of new therapeutic schemes and less toxic drugs.
Researchers from the University of Sao Paulo, Brazil, have shown the efficacy of tamoxifen against L. amazonensis, one of the species that causes cutaneous leishmaniasis in South America. The paper explains how tamoxifen, a medication widely used in the treatment and prevention of breast cancer, fights the parasitic disease in experimentally infected mice. Unicellular parasites of Leishmania genus are the causative agents of leishmaniasis. Treatment of leishmaniasis requires the administration of toxic and poorly tolerated drugs. Having previously demonstrated that tamoxifen was active against parasites in vitro, the authors now show its efficacy in a rodent model of infection with L. amazonensis. The Brazilian group observed that infected mice treated with tamoxifen for two weeks showed a significant reduction in parasite burden. Researchers also detected a notable delay in the development of skin ulcers, a typical symptom of the disease caused by L. amazonensis. The promising results presented in this study, coupled with the fact that tamoxifen’s safety and pharmacological profiles in humans are well established (the compound that has been in clinical use since the 1970s for the treatment of breast cancer), point to a new alternative in the treatment of leishmaniasis. Further trials will be necessary in other experimental models of infection before the drug is tested in humans.
Tamoxifen Is Effective in the Treatment of Leishmania amazonensis Infections in Mice. PLoS Negl Trop Dis 2008 2(6): e249
Chemotherapy is still a critical issue in the management of leishmaniasis. Until recently, pentavalent antimonials, amphotericin B or pentamidine compounded the classical arsenal of treatment. All these drugs are toxic and have to be administered by the parenteral route. Tamoxifen has been used as an antiestrogen in the treatment and prevention of breast cancer for many years. Its safety and pharmacological profiles are well established in humans. We have shown that tamoxifen is active as an antileishmanial compound in vitro, and in this paper we analyzed the efficacy of tamoxifen for the treatment of mice infected with Leishmania amazonensis, an etiological agent of localized cutaneous leishmaniasis and the main cause of diffuse cutaneous leishmaniasis in South America. Treatment of BALB/c mice infected with L. amazonensis for 15 days with tamoxifen resulted in significant decrease in lesion size and parasite burden. BALB/c mice infected with L. amazonensis represents a model of extreme susceptibility, and the striking and sustained reduction in the number of parasites in treated animals supports the proposal of further testing of this drug in other models of leishmaniasis.
Dengue is a mosquito-borne disease caused by four serotypes of dengue virus (DENV1–DENV4) and is currently the most common arbovirus (arthropod-transmitted) disease worldwide. Primary infection with any of the four DV serotypes typically results in dengue fever (DF), a relatively mild influenza-like illness which subsequently provides lifelong immunity to the infecting strain. However, the bad news is that secondary infection with different DV serotype is associated with an increased risk of developing more serious conditions such as dengue haemorrhagic fever (DHF) and the life-threatening dengue shock syndrome (DSS).
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The first well documented outbreaks of dengue occurred in the eighteenth century, although the disease may have been around in China eight hundred years earlier. Dengue virus was first isolated by Japanese and American scientists during World War II. Dengue is now a major public health problem, with approximately 50 million people infected each year (of whom around 20,000 die) and nearly half the world’s population, about 3.5 billion people, at risk of infection. Unfortunately, no dengue virus-specific therapies or vaccines are currently available. The incidence of dengue infection has increased dramatically in the past 50 years. This is due in part to population growth and urbanization in tropical and subtropical countries. Originally found in the jungles and rural areas of Southeast Asia, dengue virus is now maintained primarily in an urban cycle involving human hosts and Aedes aegypti and A. albopictus mosquitoes. Urban areas frequently contain many breeding sites for the mosquitoes that transmit the virus, such as rain-filled old tyres. Successful mosquito control has also been problematic. Dengue viruses have evolved rapidly as they have spread worldwide, and genotypes associated with increased virulence have expanded from South and Southeast Asia into the Pacific and the Americas.
The pathogenesis of dengue haemorrhagic fever and dengue shock syndrome remain unclear. The requirement for a second infection with a different serotype of the virus suggested that antibody-dependent enhancement is involved in these more serious conditions. After an initial period of protection, antibodies from the primary infection can cross-react with other dengue virus serotypes but have waned to non-neutralizing levels. These non-neutralizing antibodies could then mediate an increased uptake of virus into monocyte/macrophage cells via Fc receptors, leading to increased virus replication and immune activation including massive cytokine release (known as a “cytokine storm”). An alternative theory involves reactivation of cross-reactive memory T cells specific for the previous rather than the current virus strain, resulting in delayed virus clearance and/or increased cytokine secretion along with increased apoptosis of both infected and uninfected bystander cells (known as “original antigenic sin”).
With only around 65% homology based on amino acid sequence, the four dengue viruses could have been classified as separate virus groups but instead are treated as four serotypes belonging to a single group. It appears that there may be differences between the viruses, with DENV2 most commonly been associated with DHF/DSS and DENV4 the least likely to cause the more serious infections, but all serotypes can cause all of the conditions.
Because of the nature of dengue virus pathogenesis, a tetravalent vaccine effective against all four dengue virus serotypes is urgently needed. Vaccines which induce weak immune responses below protective levels over time are not acceptable because of the severe consequences of secondary DENV infections. Efforts to develop a dengue vaccine have encompassed live attenuated virus vaccines, inactivated virus vaccines, subunit vaccines and DNA vaccines. Vaccines of each type are currently or have been subjected to clinical trials, but none has yet been approved for use. Travelers to affected regions should take precautions against being bitten by mosquitos, use insect repellent day and night and check that hotels provide mosquito nets. Just another joy of those long-haul holidays.
Polyparasitic infections have been recognized as the norm in many tropical developing countries, but the significance of this phenomenon for helminth-associated morbidities is largely unexplored. Earlier studies have suggested that multi-species, low-intensity parasitic infections were associated with higher odds of anemia among school-age children relative to their uninfected counterparts or those with one low-intensity infection. However, specific studies of the nature of interactions between helminth species in the mediation of helminth-associated morbidities are lacking. A new study quantifies the extent to which polyparasitic infections have more than the sum of adverse effects associated with individual infections in the context of childhood anemia. The study finds that the risk of anemia is amplified beyond the sum of risks for individual infections in children simultaneously exposed to 1) hookworm and schistosomiasis, and 2) hookworm and Trichuris, and suggests that combined treatment for some geohelminth species and schistosomiasis could yield greater than additive benefits for the reduction of childhood anemia in helminth-endemic areas. However, more studies to understand the full range of interactions between parasitic species in their joint effects on helminth associated morbidities will be necessary to better predict the impact of any future public health intervention.
The study suggests that for children in helminth endemic regions, contemporaneous infections with hookworm and either Schistosoma japonicum or Trichuris may result in higher levels of anemia than would be expected if the effects of these species on anemia were simply additive. The results provide support for the hypothesis that co-infecting parasites, even living in separate anatomic locations, can interact synergistically to modify anemia, likely via the hosts’ immune response to concomitant infections. The presence of synergistic interactions between some helminth species as demonstrated here has implications for treatment given the high burden of anemia associated with concomitant infections of hookworm and S. japonicum or Trichuris. Specifically, the results support the notion that concomitant treatment for S. japonicum and some geohelminths may provide an even greater public health benefit than that based on the assumption of additive morbidity. This is a particularly appealing option given joint treatment with albendazole and praziquantel has been shown to significantly improve hemoglobin levels, without greater side-effects than treatment with praziquantel alone. The authors note however, that in light of the limited number of studies on the morbidity consequence of polyparasitic helminth infections in general, and of the biologic interactions between concurrent infections in the mediation of helminth-associated morbidities in particular, more epidemiologic studies of this phenomenon are necessary to better predict the impact of any public health intervention. Specifically, epidemiologic studies that explore the full range of biologic interactions between co-infecting species - including the possibility of antagonism, in their joint effects on anemia and other helminthassociated morbidities are necessary to fully evaluate the possible risks and benefits of combined mass therapy in helminth endemic regions.
Of the four species of Plasmodium (protozoan parasites) that can cause malaria in humans, Plasmodium falciparum is the most dangerous, being responsible for over 1 million deaths each year. It is transmitted when an infected human is bitten by an Anopheles mosquito that goes on to bite another person. The Plasmodium life cycle is complex; the asexually replicating forms which cause disease symptoms are quite distinct from the sexual forms, which mediate transmission between individuals via the bite of a mosquito. In the human, the parasite invades red blood cells, divides clonally, and causes the symptoms of disease. Sexual forms of the parasite also develop in the bloodstream, but only when they are taken up by the mosquito can the second phase of the life cycle proceed. Within the mosquito stomach a conversion occurs: the sexual forms change from crescent-shaped to round before fertilization can occur. This transition is referred to as “rounding up” and the signalling system underlying it, which reacts to the change in host (human to mosquito), has previously been poorly characterized.
After a period of growth in the human host, these sexual forms (gametocytes) lie dormant until taken up by a mosquito. The change in environment from human to mosquito triggers differentiation into mature gametes. In a newly published study, scientists have identified a protein kinase from the parasite that is instrumental in mediating this essential differentiation step. They also gained insight into how this protein kinase might interact with calcium to coordinate these events. By using genetically modified malaria parasites in combination with specific inhibitors of the protein kinase, they showed the feasibility of blocking development of the sexual stage of the parasite’s life cycle. Development of a drug that targets this parasite stage, for use in combination with a curative drug, would be an important tool for controlling the spread of drug resistance.
New work has identified one of the molecules required for the activation of the sexual cycle within the mosquito: PKG. The new paper identifies a protein crucial for the reproductive stages of the pathogen’s lifecycle, called cGMP-dependent protein kinase, or PKG. PKG is an enzyme produced by the malaria parasite. The authors have shown that it is essential for induction of “rounding up”. Normal pathogens are unable to respond to the change in host if PKG is experimentally blocked with an inhibitor; thus, PKG is necessary for the pathogen to become sexually mature. Further, the authors genetically modified the parasite so that PKG was insensitive to the inhibitor, and in these mutants, “rounding up” could proceed normally in the presence of the inhibitor. It is, therefore, PKG specifically (rather than another enzyme) that is the target of the inhibitor. This work suggests a new potential target for anti-malarial drugs. The findings may have important implications for fighting the spread of drug resistance and malaria control, for if you could block PKG activity in the pathogen, which the authors have done using a specific inhibitor, then you have a means of controlling transmission of malaria between individuals.
According to the hygiene hypothesis, reduced exposure to infections in early childhood - owing to diminishing family size and improvements in living standards and personal hygiene, for example - may increase the risk of allergic and autoimmune disease. This concept is supported by epidemiological and clinical reports documenting increased incidences of inflammatory bowel diseases, colon cancer, asthma, type 1 diabetes and multiple sclerosis over the past 50 years in societies with improved medical care and hygiene (for example, Europe, the United States and Japan) but not in undeveloped countries. However, the application of major interventions, including vaccination, sanitation, and antibacterial and antiviral therapies, often does not permit discrimination between infectious and non-infectious microorganisms and has undoubtedly led to changes in human association with the microbial world as a whole. The hygiene hypothesis does not address humanity’s primary relationship with bacteria: the harbouring of multitudes of microbial species during commensalism. A new study just published shows that symbiotic bacteria residing in the mammalian gastrointestinal tract produce molecules that mediate healthy immune responses and protect the host from inflammatory disease. The authors propose that the mammalian genome does not encode for all functions required for immunological development but rather that mammals depend on critical interactions with their microbiome (the collective genomes of the microbiota) for health.
A microbial symbiosis factor prevents intestinal inflammatory disease
Nature 453: 620-625, 29 May 2008
Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.
Reduction of food intake, commonly referred to as dietary restriction, has been shown to slow ageing and extend lifespan in virtually every biological system examined. However, the underlying mechanisms that couple dietary restriction to lifespan extension remain poorly defined. Recently, the relatively simple eukaryote Saccharomyces cerevisiae (bakers’ yeast) has emerged as a powerful model system to study the genetic and physiological factors that alter lifespan. A recent paper shows that caffeine extends the lifespan of yeast.
This begs the question: can caffeine extend lifespan in humans? Caffeine is the most widely used psychoactive drug worldwide with coffee being the main source of caffeine in the Western diet. Tantalizingly, epidemiological studies have correlated habitual coffee consumption with a decreased relative risk of mortality. Drinking one cup of coffee results in an approximate peak plasma concentration of 1–10 μM caffeine in humans (with an estimated half-life of 2.5–4.5 h). Assuming that caffeine acts in a similar way in humans as in yeast, moderate coffee consumption compares well with the with the levels calculated to be necessary for lifespan extension in yeast, and thus provides mechanistic support for the correlative links between coffee consumption and longevity described above. At this concentration, caffeine does not appear to have deleterious consequences. Finally, caffeine has recently been shown to suppress cell transformation, suggesting that caffeine may also be a (well-tolerated) and effective anti-cancer agent.
Caffeine extends yeast lifespan by targeting TORC1. Molecular Microbiology 27 May 2008
Dietary nutrient limitation (dietary restriction) is known to increase lifespan in a variety of organisms. Although the molecular events that couple dietary restriction to increased lifespan are not clear, studies of the model eukaryote Saccharomyces cerevisiae have implicated several nutrient-sensitive kinases, including the target of rapamycin complex 1 (TORC1), Sch9, protein kinase A (PKA) and Rim15. We have recently demonstrated that TORC1 activates Sch9 by direct phosphorylation. We now show that Sch9 inhibits Rim15 also by direct phosphorylation. Treatment of yeast cells with the specific TORC1 inhibitor rapamycin or caffeine releases Rim15 from TORC1-Sch9-mediated inhibition and consequently increases lifespan. This kinase cascade appears to have been evolutionarily conserved, suggesting that caffeine may extend lifespan in other eukaryotes, including man.
Haemorrhagic disease, encephalitis, biphasic fever, flaccid paralysis, and jaundice are typical manifestations of diseases in human beings after infections by mosquito-borne or tick-borne flaviviruses such as yellow fever, dengue, West Nile, St Louis encephalitis, Japanese encephalitis, tick-borne encephalitis, Kyasanur Forest disease, and Omsk haemorrhagic fever. Although the characteristics of these viruses are well defined, they are still unpredictable with increases in disease severity, unusual clinical manifestations, unexpected methods of transmission, long-term persistence, and the discovery of new species. This paper compares the epidemiological and clinical features of the medically important flaviviruses, consider the effect of human activity on their evolution and dispersal, and draw attention to new findings and some of the unanswered questions, unresolved issues, and controversies that remain.
In the years during and after World War II, the Microbiological Research Establishment (MRE) at Porton Down was the UK Government’s centre for germ warfare research (or defence, depending on who you believe). There were two parts to the MRE, the part “outside the wire”, which contained among other things, the Common Cold Unit, and the section “inside the wire”, which was top secret and has been the subject of much rumour and speculation.
