Exploring the lower thermal limits for development of the human malaria parasite, Plasmodium falciparum.

The rate of malaria transmission is strongly determined by parasite development time in the mosquito, known as the extrinsic incubation period (EIP), since the quicker parasites develop, the greater the chance that the vector will survive long enough for the parasite to complete development and be transmitted. EIP is known to be temperature-dependent but this relationship is surprisingly poorly characterized. There is a single degree-day model for EIP of Plasmodium falciparum that derives from a limited number of poorly controlled studies conducted almost a century ago. Here, we show that the established degree-day model greatly underestimates the rate of development of P. falciparum in both Anopheles stephensi and An. gambiae mosquitoes at temperatures in the range of 17-20°C. We also show that realistic daily temperature fluctuation further speeds parasite development. These novel results challenge one of the longest standing models in malaria biology and have potentially important implications for understanding the impacts of future climate change.

Empirical and theoretical investigation into the potential impacts of insecticide resistance on the effectiveness of insecticide-treated bed nets.

In spite of widespread insecticide resistance in vector mosquitoes throughout Africa, there is limited evidence that long-lasting insecticidal bed nets (LLINs) are failing to protect against malaria. Here, we showed that LLIN contact in the course of host-seeking resulted in higher mortality of resistant Anopheles spp. mosquitoes than predicted from standard laboratory exposures with the same net. We also found that sublethal contact with an LLIN caused a reduction in blood feeding and subsequent host-seeking success in multiple lines of resistant mosquitoes from the laboratory and the field. Using a transmission model, we showed that when these LLIN-related lethal and sublethal effects were accrued over mosquito lifetimes, they greatly reduced the impact of resistance on malaria transmission potential under conditions of high net coverage. If coverage falls, the epidemiological impact is far more pronounced. Similarly, if the intensity of resistance intensifies, the loss of malaria control increases nonlinearly. Our findings help explain why insecticide resistance has not yet led to wide-scale failure of LLINs, but reinforce the call for alternative control tools and informed resistance management strategies.

Rethinking the extrinsic incubation period of malaria parasites.

The time it takes for malaria parasites to develop within a mosquito, and become transmissible, is known as the extrinsic incubation period, or EIP. EIP is a key parameter influencing transmission intensity as it combines with mosquito mortality rate and competence to determine the number of mosquitoes that ultimately become infectious. In spite of its epidemiological significance, data on EIP are scant. Current approaches to estimate EIP are largely based on temperature-dependent models developed from data collected on parasite development within a single mosquito species in the 1930s. These models assume that the only factor affecting EIP is mean environmental temperature. Here, we review evidence to suggest that in addition to mean temperature, EIP is likely influenced by genetic diversity of the vector, diversity of the parasite, and variation in a range of biotic and abiotic factors that affect mosquito condition. We further demonstrate that the classic approach of measuring EIP as the time at which mosquitoes first become infectious likely misrepresents EIP for a mosquito population. We argue for a better understanding of EIP to improve models of transmission, refine predictions of the possible impacts of climate change, and determine the potential evolutionary responses of malaria parasites to current and future mosquito control tools.

Increasing the potential for malaria elimination by targeting zoophilic vectors.

Countries in the Asia Pacific region aim to eliminate malaria by 2030. A cornerstone of malaria elimination is the effective management of Anopheles mosquito vectors. Current control tools such as insecticide treated nets or indoor residual sprays target mosquitoes in human dwellings. We find in a high transmission region in India, malaria vector populations show a high propensity to feed on livestock (cattle) and rest in outdoor structures such as cattle shelters. We also find evidence for a shift in vector species complex towards increased zoophilic behavior in recent years. Using a malaria transmission model we demonstrate that in such regions dominated by zoophilic vectors, existing vector control tactics will be insufficient to achieve elimination, even if maximized. However, by increasing mortality in the zoophilic cycle, the elimination threshold can be reached. Current national vector control policy in India restricts use of residual insecticide sprays to domestic dwellings. Our study suggests substantial benefits of extending the approach to treatment of cattle sheds, or deploying other tactics that target zoophilic behavior. Optimizing use of existing tools will be essential to achieving the ambitious 2030 elimination target.

Eave tubes for malaria control in Africa: a modelling assessment of potential impact on transmission.

BACKGROUND: Novel interventions for malaria control are necessary in the face of problems such as increasing insecticide resistance and residual malaria transmission. One way to assess performance prior to deployment in the field is through mathematical modelling. Modelled here are a range of potential outcomes for eave tubes, a novel mosquito control tool combining house screening and targeted use of insecticides to provide both physical protection and turn the house into a lethal mosquito killing device. METHODS: The effect of eave tubes was modelled by estimating the reduction of infectious mosquito bites relative to no intervention (a transmission metric defined as relative transmission potential, RTP). The model was used to assess how RTP varied with coverage when eave tubes were used as a stand-alone intervention, or in combination with either bed nets (LLINs) or indoor residual spraying (IRS). RESULTS: The model indicated the impact of eave tubes on transmission increases non-linearly as coverage increases, suggesting a community level benefit. For example, based on realistic assumptions, just 30 % coverage resulted in around 70 % reduction in overall RTP (i.e. there was a benefit for those houses without eave tubes). Increasing coverage to around 70 % reduced overall RTP by >90 %. Eave tubes exhibited some redundancy with existing interventions, such that combining interventions within properties did not give reductions in RTP equal to the sum of those provided by deploying each intervention singly. However, combining eave tubes and either LLINs or IRS could be extremely effective if the technologies were deployed in a non-overlapping way. CONCLUSION: Using predictive models to assess the benefit of new technologies has great value, and is especially pertinent prior to conducting expensive, large scale, randomized controlled trials. The current modelling study indicates eave tubes have considerable potential to impact malaria transmission if deployed at scale and can be used effectively with existing tools, especially if they are combined strategically with, for example, IRS and eave tubes targeting different houses.

Alterations in mosquito behaviour by malaria parasites: potential impact on force of infection.

BACKGROUND: A variety of studies have reported that malaria parasites alter the behaviour of mosquitoes. These behavioural alterations likely increase transmission because they reduce the risk of vector death during parasite development and increase biting after parasites become infectious. METHODS: A mathematical model is used to investigate the potential impact of these behavioural alterations on the lifetime number of infectious bites delivered. The model is used to explore the importance of assumptions about the magnitude and distribution of mortality as well as the importance of extrinsic incubation period and gonotrophic cycle length. Additionally, the model is applied to four datasets taken from actual transmission settings. RESULTS: The impact of behavioural changes on the relative number of lifetime bites is highly dependent on assumptions about the distribution of mortality over the mosquito-feeding cycle. Even using fairly conservative estimates of these parameters and field collected data, the model outputs suggest that altered feeding could easily cause a doubling in the force of infection. CONCLUSIONS: Infection-induced behavioural alterations have their greatest impact on the lifetime number of infectious bites in environments with high feeding-related adult mortality and many pre-infectious feeding cycles. Interventions that increase feeding-associated mortality are predicted to amplify the relative fitness benefits and hence enhance the strength of selection for behavioural alteration.

Prospective malaria control using entomopathogenic fungi: comparative evaluation of impact on transmission and selection for resistance.

BACKGROUND: Chemical insecticides against adult mosquitoes are a key element in most malaria management programmes, but their efficacy is threatened by the evolution of insecticide-resistant mosquitoes. By killing only older mosquitoes, entomopathogenic fungi can in principle significantly impact parasite transmission while imposing much less selection for resistance. Here an assessment is made as to which of the wide range of possible virulence characteristics for fungal biopesticides best realise this potential. METHODS: With mathematical models that capture relevant timings and survival probabilities within successive feeding cycles, transmission and resistance-management metrics are used to compare susceptible and resistant mosquitoes exposed to no intervention, to conventional instant-kill interventions, and to delayed-action biopesticides with a wide range of virulence characteristics. RESULTS: Fungal biopesticides that generate high rates of mortality at around the time mosquitoes first become able to transmit the malaria parasite offer potential for large reductions in transmission while imposing low fitness costs. The best combinations of control and resistance management are generally accessed at high levels of coverage. Strains which have high virulence in malaria-infected mosquitoes but lower virulence in malaria-free mosquitoes offer the ultimate benefit in terms of minimizing selection pressure whilst maximizing impact on transmission. Exploiting this phenotype should be a target for product development. For indoor residual spray programmes, biopesticides may offer substantial advantages over the widely used pyrethroid-based insecticides. Not only do fungal biopesticides provide substantial resistance management gains in the long term, they may also provide greater reductions in transmission before resistance has evolved. This is because fungal spores do not have contact irritancy, reducing the chances that a blood-fed mosquito can survive an encounter and thus live long enough to transmit malaria. CONCLUSIONS: Delayed-action products, such as fungal biopesticides, have the potential to achieve reductions in transmission comparable with those achieved with existing instant-kill insecticides, and to sustain this control for substantially longer once resistant alleles arise. Given the current insecticide resistance crisis, efforts should continue to fully explore the operational feasibility of this alternative approach.

Do malaria parasites manipulate mosquitoes?

Malaria parasites have been suggested to alter the behavior of mosquito vectors to increase the likelihood of transmission. Some empirical evidence supports this hypothesis, yet the role of manipulation is ignored in most epidemiological models, and behavioral differences between infected and uninfected females are not considered in the development or implementation of control measures. We suggest that this disconnect exists because the link between behavioral alteration and actual transmission in the field has yet to be demonstrated or quantified fully. We review and discuss the current evidence for manipulation, explore its potential significance for malaria transmission, and suggest ways to move this hypothesis forward from theory to potential application in malaria control.

How to make evolution-proof insecticides for malaria control.

Insecticides are one of the cheapest, most effective, and best proven methods of controlling malaria, but mosquitoes can rapidly evolve resistance. Such evolution, first seen in the 1950s in areas of widespread DDT use, is a major challenge because attempts to comprehensively control and even eliminate malaria rely heavily on indoor house spraying and insecticide-treated bed nets. Current strategies for dealing with resistance evolution are expensive and open ended, and their sustainability has yet to be demonstrated. Here we show that if insecticides targeted old mosquitoes, and ideally old malaria-infected mosquitoes, they could provide effective malaria control while only weakly selecting for resistance. This alone would greatly enhance the useful life span of an insecticide. However,such weak selection for resistance can easily be overwhelmed if resistance is associated with fitness costs. In that case, late-life-acting insecticides would never be undermined by mosquito evolution.We discuss a number of practical ways to achieve this, including different use of existing chemical insecticides,biopesticides, and novel chemistry. Done right, a one-off investment in a single insecticide would solve the problem of mosquito resistance forever.

Towards evolution-proof malaria control with insecticides.

As many strategies to control malaria use insecticides against adult mosquitoes, control is undermined by the continual evolution of resistant mosquitoes. Here we suggest that using alternative insecticides, or conventional insecticides in alternative ways might enable effective control, but delay considerably or prevent the evolution of resistance. Our reasoning relies on an epidemiological and an evolutionary principle: (i) the epidemiology of malaria is strongly influenced by the life-span of mosquitoes, as most infected mosquitoes die before the malaria parasite has completed its development; and (ii) evolutionary pressure is strongest in young individuals, for selection on individuals that have completed most of their reproduction has little evolutionary effect. It follows from these principles, first, that insecticides that kill mosquitoes several days after exposure can delay considerably the evolution of resistance and, second, that the evolution of resistance against larvicides can actually benefit control, if it is associated with shorter life-span or reduced biting in adults. If a late-acting insecticide and a larvicide are combined, the evolution of resistance against larvicides can in some circumstances prevent the evolution of resistance against the more effective, late-acting insecticide, leading to sustainable, effective control. We discuss several potential options to create such insecticides, focussing on biopesticides.

How will public and animal health interventions drive life-history evolution in parasitic nematodes?

Infection caused by parasitic nematodes of humans and livestock can have significant health and economic costs. Treatments aimed at alleviating these costs, such as chemotherapy and vaccination, alter parasite survival and reproduction, the main selective pressures shaping life-history traits such as age to maturity, size and fecundity. Most authors have argued that the life-history evolution prompted by animal and public health programmes would be clinically beneficial, generating smaller, less fecund worms, and several mathematical models support this view. However, using mathematical models of long-lasting interventions, such as vaccination, and regularly repeated short interventions, such as drenching, we show here that the expected outcome actually depends on how mortality rates vary as a function of worm size and developmental status. Interventions which change mortality functions can exert selection pressure to either shorten or extend the time to maturity, and thus increase or decrease worm fecundity and size. The evolutionary trajectory depends critically on the details of the mortality functions with and without the intervention. Earlier optimism that health interventions would always prompt the evolution of smaller, less fecund and hence clinically less damaging worms is premature.