Gráinne H. Long

Deformed wing virus is a recent global epidemic in honeybees driven by Varroa mites

Varroa-vectored virus pandemic Bees are facing several threats that are causing population collapses. Wilfert et al. found that European honey bees are the primary source of deformed wing virus (DWV) (see the Perspective by Villalobos). However, paradoxically, transmission between bees is inefficient. It seems that parasitic mites can facilitate virus transmission. European honeybees acquired the rapidly spreading Varroa mite from Asian honey bees, possibly via the commercial exchange of queens. Not only do bees suffer direct damage from the mites, but the bees are also efficiently inoculated with DWV. Science, this issue p. 594; see also p. 554 Pandemic virus infection in honeybees has been facilitated by the recent spread of a parasitic mite and by human trade. [Also see Perspective by Villalobos] Deformed wing virus (DWV) and its vector, the mite Varroa destructor, are a major threat to the world’s honeybees. Although the impact of Varroa on colony-level DWV epidemiology is evident, we have little understanding of wider DWV epidemiology and the role that Varroa has played in its global spread. A phylogeographic analysis shows that DWV is globally distributed in honeybees, having recently spread from a common source, the European honeybee Apis mellifera. DWV exhibits epidemic growth and transmission that is predominantly mediated by European and North American honeybee populations and driven by trade and movement of honeybee colonies. DWV is now an important reemerging pathogen of honeybees, which are undergoing a worldwide manmade epidemic fueled by the direct transmission route that the Varroa mite provides.

Partitioning Regulatory Mechanisms of Within-Host Malaria Dynamics Using the Effective Propagation Number

As malaria progresses, red blood cell availability and immune control change depending on the initial dose of parasites. Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitatively partitioning the relative roles of these effects through time is challenging. Using data from rodent malaria, we estimated the effective propagation number, which reflects the relative importance of contrasting within-host control mechanisms through time and is sensitive to the inoculating parasite dose. Our analysis showed that the capacity of innate responses to restrict initial parasite growth saturates with parasite dose and that experimentally enhanced innate immunity can affect parasite density indirectly via resource depletion. Such a statistical approach offers a tool to improve targeting of drugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatory mechanisms.

Generalism and the evolution of parasite virulence

The evolution of parasite-imposed host harm (virulence) will be affected by numerous factors, not least the range of hosts that parasites can infect. Here, we consider four ways that parasite host range (generalism) might directly affect observed levels of parasite virulence: costs of generalism, multiplicity of infection, maladaptive virulence, and host availability. Integrating parasite infectivity range with life-history evolution will generate novel general hypotheses for the evolutionary ecology of virulence, as well as explicit predictions about the virulence of emerging diseases resulting from host shifts.

Experimental manipulation of immune-mediated disease and its fitness costs for rodent malaria parasites

BackgroundExplaining parasite virulence (harm to the host) represents a major challenge for evolutionary and biomedical scientists alike. Most theoretical models of virulence evolution assume that virulence arises as a direct consequence of host exploitation, the process whereby parasites convert host resources into transmission opportunities. However, infection-induced disease can be immune-mediated (immunopathology). Little is known about how immunopathology affects parasite fitness, or how it will affect the evolution of parasite virulence. Here we studied the effects of immunopathology on infection-induced host mortality rate and lifetime transmission potential – key components of parasite fitness – using the rodent malaria model, Plasmodium chabaudi chabaudi.ResultsNeutralizing interleukin [IL]-10, an important regulator of inflammation, allowed us to experimentally increase the proportion of virulence due to immunopathology for eight parasite clones. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in a shorter time to death that was independent of parasite density and was particularly marked for normally avirulent clones. This suggests that IL-10 induction may provide a pathway to avirulence for P. c. chabaudi. Despite the increased investment in transmission-stage parasites observed for some clones in response to IL-10R blockade, experimental enhancement of immunopathology incurred a uniform fitness cost to all parasite clones by reducing lifetime transmission potential.ConclusionThis is the first experimental study to demonstrate that infection-induced immunopathology and parasite genetic variability may together have the potential to shape virulence evolution. In accord with recent theory, the data show that some forms of immunopathology may select for parasites that make hosts less sick.

Acellular pertussis vaccination facilitates Bordetella parapertussis infection in a rodent model of bordetellosis.

Despite over 50 years of population-wide vaccination, whooping cough incidence is on the rise. Although Bordetella pertussis is considered the main causative agent of whooping cough in humans, Bordetella parapertussis infections are not uncommon. The widely used acellular whooping cough vaccines (aP) are comprised solely of B. pertussis antigens that hold little or no efficacy against B. parapertussis. Here, we ask how aP vaccination affects competitive interactions between Bordetella species within co-infected rodent hosts and thus the aP-driven strength and direction of in-host selection. We show that aP vaccination helped clear B. pertussis but resulted in an approximately 40-fold increase in B. parapertussis lung colony-forming units (CFUs). Such vaccine-mediated facilitation of B. parapertussis did not arise as a result of competitive release; B. parapertussis CFUs were higher in aP-relative to sham-vaccinated hosts regardless of whether infections were single or mixed. Further, we show that aP vaccination impedes host immunity against B. parapertussis—measured as reduced lung inflammatory and neutrophil responses. Thus, we conclude that aP vaccination interferes with the optimal clearance of B. parapertussis and enhances the performance of this pathogen. Our data raise the possibility that widespread aP vaccination can create hosts more susceptible to B. parapertussis infection.

Consequences of immunopathology for pathogen virulence evolution and public health: malaria as a case study

Evolutionary theories explaining virulence—the fitness damage incurred by infected hosts—often focus on parasite strategies for within‐host exploitation. However, much virulence can be caused by the host’s own immune response: for example, pro‐inflammatory cytokines, although essential for killing malaria parasites, also damage host tissue. Here we argue that immune‐mediated virulence, or ‘immunopathology,’ may affect malaria virulence evolution and should be considered in the design of medical interventions. Our argument is based on the ability of immunopathology to disrupt positive virulence‐transmission relationships assumed under the trade‐off theory of virulence evolution. During rodent malaria infections, experimental reduction of inflammation using reagents approved for field use decreases virulence but increases parasite transmission potential. Importantly, rodent malaria parasites exhibit genetic diversity in the propensity to induce inflammation and invest in transmission‐stage parasites in the presence of pro‐inflammatory cytokines. If immunopathology positively correlates with malaria parasite density, theory suggests it could select for relatively low malaria virulence. Medical interventions which decrease immunopathology may therefore inadvertently select for increased malaria virulence. The fitness consequences to parasites of variations in immunopathology must be better understood in order to predict trajectories of parasite virulence evolution in heterogeneous host populations and in response to medical interventions.

Blockade of TNF receptor 1 reduces disease severity but increases parasite transmission during Plasmodium chabaudi chabaudi infection

Reducing host carriage of transmission-stage malaria parasites (gametocytes) is expected to decrease the population-wide burden of malaria. Some malaria disease severity is attributed to the induction of the pro-inflammatory cytokines TNF-alpha and lymphotoxin-alpha (LT-alpha), and we are interested in whether anti-malaria interventions which ameliorate the symptoms induced by those cytokines may have the capacity to alter malaria transmission. As many functions of TNF-alpha and LT-alpha are exerted through TNF receptor 1 (TNFR1), we investigated the effect TNFR1 blockade exerted on parasite transmission using the rodent malaria Plasmodium chabaudi chabaudi. We found that blocking TNFR1 simultaneously increased gametocyte density and infectivity to mosquitoes, whilst reducing disease severity (weight loss). These transmission-enhancing and severity-reducing effects of TNFR1 blockade were independent of asexual parasite load and were observed for several P. c. chabaudi genotypes. These results suggest that the effects of candidate malaria interventions on infectivity should be examined alongside effects on disease severity so that the epidemiological consequences of such interventions can be evaluated.

Parasite genetic diversity does not influence TNF-mediated effects on the virulence of primary rodent malaria infections

The pro-inflammatory cytokine tumour necrosis factor alpha (TNF-alpha) is associated with malaria virulence (disease severity) in both rodents and humans. We are interested in whether parasite genetic diversity influences TNF-mediated effects on malaria virulence. Here, primary infections with genetically distinct Plasmodium chabaudi chabaudi (P.c.c.) clones varied in the virulence and cytokine responses induced in female C57BL/6 mice. Even when parasitaemia was controlled for, a greater day 7 TNF-alpha response was induced by infection with more virulent P.c.c. clones. Since many functions of TNF-alpha are exerted through TNF receptor 1 (TNFR1), a TNFR-1 fusion protein (TNFR-Ig) was used to investigate whether TNFR1 blockade eliminated clone virulence differences. We found that TNFR-1 blockade ameliorated the weight loss but not the anaemia induced by malaria infection, regardless of P.c.c. clone. We show that distinct P.c.c. infections induced significantly different plasma interferon gamma (IFN-gamma), interleukin 6 (IL-6) and interleukin 10 (IL-10) levels. Our results demonstrate that regardless of P.c.c. genotype, blocking TNFR1 signalling protected against weight loss, but had negligible effects on both anaemia and asexual parasite kinetics. Thus, during P.c.c. infection, TNF-alpha is a key mediator of weight loss, independent of parasite load and across parasite genotypes.

Healthy Behavior Change and Cardiovascular Outcomes in Newly Diagnosed Type 2 Diabetic Patients: A Cohort Analysis of the ADDITION-Cambridge Study

OBJECTIVE To examine whether improvements in health behaviors are associated with reduced risk of cardiovascular disease (CVD) in individuals with newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS Population-based prospective cohort study of 867 newly diagnosed diabetic patients aged between 40 and 69 years from the treatment phase of the ADDITION-Cambridge study. Because the results for all analyses were similar by trial arm, data were pooled, and results were presented for the whole cohort. Participants were identified via population-based stepwise screening between 2002 and 2006, and underwent assessment of physical activity (European Prospective Investigation into Cancer-Norfolk Physical Activity Questionnaire), diet (plasma vitamin C and self-report), and alcohol consumption (self-report) at baseline and 1 year. A composite primary CVD outcome was examined, comprised of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and revascularization. RESULTS After a median (interquartile range) follow-up period of 5.0 years (1.3 years), 6% of the cohort experienced a CVD event (12.2 per 1,000 person-years; 95% CI 9.3–15.9). CVD risk was inversely related to the number of positive health behaviors changed in the year after diabetes diagnosis. The relative risk for primary CVD event in individuals who did not change any health behavior compared with those who adopted three/four healthy behaviors was 4.17 (95% CI 1.02–17.09), adjusting for age, sex, study group, social class, occupation, and prescription of cardioprotective medication (P for trend = 0.005). CONCLUSIONS CVD risk was inversely associated with the number of healthy behavior changes adopted in the year after the diagnosis of diabetes. Interventions that promote early achievement of these goals in patients with newly diagnosed diabetes could help reduce the burden of diabetes-related morbidity and mortality.

The implications of immunopathology for parasite evolution

By definition, parasites harm their hosts, but in many infections much of the pathology is driven by the host immune response rather than through direct damage inflicted by parasites. While these immunopathological effects are often well studied and understood mechanistically in individual disease interactions, there remains relatively little understanding of their broader impact on the evolution of parasites and their hosts. Here, we theoretically investigate the implications of immunopathology, broadly defined as additional mortality associated with the hosts immune response, on parasite evolution. In particular, we examine how immunopathology acting on different epidemiological traits (namely transmission, virulence and recovery) affects the evolution of disease severity. When immunopathology is costly to parasites, such that it reduces their fitness, for example by decreasing transmission, there is always selection for increased disease severity. However, we highlight a number of host–parasite interactions where the parasite may benefit from immunopathology, and highlight scenarios that may lead to the evolution of slower growing parasites and potentially reduced disease severity. Importantly, we find that conclusions on disease severity are highly dependent on how severity is measured. Finally, we discuss the effect of treatments used to combat disease symptoms caused by immunopathology.