NEWS & VIEWS
For News & Views online, go to nature.com/newsandviews
MAL ARIA
Fifteen years of interventions A comprehensive modelling effort has revealed the relative contributions of different malaria-control measures to the massive reductions in disease prevalence that have occurred in Africa between 2000 and 2015. See Article p.207 LOUISE GUBB/CORBIS
J A N E T H E M I N G W AY
I
n 1978, when I began working on insectborne diseases, a child died of malaria every six seconds. Today, although we have made great progress, it is unacceptable that a child still dies every minute from this disease. There are an estimated 600,000 deaths annually, the vast majority of which are in subSaharan Africa. To drive down the malaria burden further, and ultimately to try to eradicate the disease, we need to be able to attribute the contributions of different interventions and use this information to optimize our efforts. In this issue, Bhatt et al.1 (page 207) provide the first authoritative, data-driven models to estimate the relative impact that combination drug therapies and mosquitocontrol strategies have had on clinical cases of malaria in Africa since 2000. Expert opinion on the relative merits of different malaria interventions varies greatly, and over the past half-century there have been major shifts in emphasis and operational implementation of drug- and insecticide-based approaches. The malaria-eradication efforts led by the World Health Organization in the 1960s used both chloroquine drug treatment and indoor residual spraying with DDT (this involves spraying the inside walls of dwellings with the insecticide). The failure of these efforts, which has been variously attributed to drug and insecticide resistance, under-resourcing and lack of political will to support effective implementation, caused a dramatic shift in approach in Africa. Mosquito control was largely abandoned in favour of improving access to prompt treatment with effective drugs, coupled with intermittent preventive drug treatment of particularly vulnerable populations. In 2000, the scale of activity and the emphasis on different malaria interventions shifted again in Africa. Initially, there was the uptake of bednets impregnated with long-lasting pyrethroid insecticides, with widespread free or subsidized distribution of these nets to ‘at risk’ populations. Mosquito control was further supplemented in 2005, supported by the US President’s Malaria Initiative, which reintroduced indoor residual spraying in 15 high-burden countries across the continent. Failing first-line drug treatments
Figure 1 | Net effect. Bhatt et al.1 estimate that 68% of the large reduction in clinical cases of malaria in Africa between 2000 and 2015 is attributable to the use of insecticide-impregnated bednets.
were also replaced with artemisinin-based combination therapies (ACTs) in 79 countries by the end of 2013. Bhatt et al. set out to model the impact of these interventions since 2000, collating the largest global published and unpublished data set ever analysed. They were not able to use the number of deaths from malaria for this modelling, because the quantity and quality of these data in different African settings were inadequate. A more accessible measure was the prevalence rate of malaria parasites in children between the ages of 2 and 10, and so the authors used the number of clinical cases of malaria averted, rather than deaths averted, as the output indicator. The collaborating researchers, who include members of some of the world’s best disease-modelling groups, used three independent malaria-transmission models to generate counterfactual geospatial maps — that is, they estimated what the malaria parasite prevalence rates would have been without each intervention. The authors estimate that 663 million
1 9 8 | NAT U R E | VO L 5 2 6 | 8 O C T O B E R 2 0 1 5
© 2015 Macmillan Publishers Limited. All rights reserved
clinical cases of malaria were averted between 2000 and 2015 (Fig. 1). Most of this improvement (68%) was due to bednets, with 22% resulting from ACTs and 10% from indoor residual spraying. Although these numbers are influenced by the timing, speed and scale on which each intervention was introduced, the massive impact of the mosquito-control interventions will come as a surprise to many who believe that improvements have primarily been driven by the introduction of ACTs2. Over the same 15-year period, malaria infection rates have halved, with threequarters of this improvement occurring in the past decade. Although this massive improvement in malaria control should be applauded, the study provides a timely warning against complacency. The rate of improvement slowed to 5% per year in 2013, and malaria is an infectious disease that could easily resurge. As we move from the era of the United Nations’ Millennium Development Goals, which set the targets for malaria and child-mortality reduction that instigated much of this activity, to the
NEWS & VIEWS RESEARCH Sustainable Development Goals, which are more oriented towards improving health systems and health services, we need to maintain and enhance malaria-control activities. The target of universal bednet coverage for at-risk populations is still a distant dream, nets distributed before 2012 now need replacing, and all three interventions are increasingly threatened by the development of mosquito resistance to the insecticides or parasite resistance to the drugs. ACT drug resistance is already well documented in southeast Asia, and would be catastrophic if it spread widely in Africa3. However, the greatest threat may come from the rapid increases in pyrethroid resistance that have occurred in the two main African malaria-vector mosquito species4. Drug resistance is detected rapidly, because health workers and patients can immediately recognize a failing treatment. But it is less
obvious when mosquitoes fail to respond to insecticides, and resistance will already be widespread in a mosquito population before there is an associated increase in the numbers of malaria cases and deaths. An international effort is already in place to try to stem the movement of ACT-resistant malaria parasites from Asia to Africa, and a more proactive approach is now needed for insecticide resistance. The urgency of this is underscored by the improved understanding that Bhatt and colleagues have provided of the crucial role that vector control has had in reducing malaria over the past decade, and, by extrapolation, of the role it will need to have if we are to eliminate the disease. A healthy portfolio of new antimalarial drugs and insecticides is under development, driven in particular by product-development partnerships coordinated by two non-profit
MOLECUL AR B IO LO GY
Mediating transcription and RNA export The finding that the Mediator protein complex contributes to messenger RNA export from the nucleus in yeast adds to a growing list of roles for the complex in regulating transcriptional processes. J O N AT H A N D . R U B I N & D Y L A N J . TA ATJ E S
G
ene transcription is fundamental to all major physiological processes, and defects in its regulation underlie myriad human diseases. Transcription culminates in the export of messenger RNA transcripts from the nucleus to the cytoplasm, where they are translated into proteins. In a paper in Cell, Schneider et al.1 use a combination of structural and cell biology, biochemistry, yeast genetics and transcript analyses to describe how this process is regulated by cooperation between the mRNA export machinery and Mediator — a large, multi-subunit protein complex best known for regulating the activity of the enzyme RNA polymerase II (pol II) during the early stages of transcription2. Many factors converge on nascent mRNA transcripts to facilitate their export from the nucleus. One such factor, the TREX-2 protein complex, regulates export through interactions with other complexes, including pol II and the nuclear pore complex (NPC)3, which acts as a gateway for cellular components to exit the nucleus and enter the cytoplasm. However, the mechanisms by which TREX-2 acts are uncertain. Schneider et al. investigated TREX-2 in the brewer’s yeast Saccharomyces cerevisiae. In yeast
cells lacking the TREX-2 subunit Sac3, the composition of the Mediator complex changed. Specifically, components of the Mediator ‘Cdk8
organizations, the Medicines for Malaria Venture and the Innovative Vector Control Consortium. But substantial development, financial, regulatory and policy hurdles are impeding the roll-out of these agents. If we can overcome these, stay ahead of the ‘arms race’ of parasite and mosquito resistance, develop an effective vaccine to reduce transmission and optimally deploy these interventions, then no child need die from malaria. ■ Janet Hemingway is at the Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK. e-mail: [email protected] 1. Bhatt, S. et al. Nature 526, 207–211 (2015). 2. Taylor Bright, A. & Winzeler, E. A. Nature 498, 446–447 (2013). 3. White, N. J. et al. Lancet 353, 1965–1967 (1999). 4. Hemingway, J. et al. Lancet http://dx.doi.org/ 10.1016/S0140-6736(15)00417-1 (2015).
kinase’ module failed to associate with the rest of the complex. The authors demonstrated that TREX-2 physically associates with Mediator, and that this association depends on Sac3 and a Mediator subunit implicated in the activation of transcription, Med31. A series of experiments then showed a functional interdependence between Mediator and TREX-2. In yeast, genes that are in the process of being transcribed associate with the NPC, presumably to facilitate mRNA export to the cytoplasm4. Schneider and colleagues demonstrated that, like Sac3, Med31 is required for gene targeting to the NPC, implying that Mediator is involved in mRNA export (Fig. 1). However, in contrast to cells lacking Sac3, mRNA export seemed normal in cells lacking
5′ DNA
Transcription initiation factor Med31
AAAA NPC
TREX-2 Mediator
mRNA Cytoplasm
Cdk8 module
Nucleus
3′ DNA
Figure 1 | Complex interactions in messenger RNA export. Following gene transcription, mRNAs are polyadenylated (adenine (A) bases are added to the 3ʹ end of the transcript). Factors involved in the export of mRNA from the nucleus, such as the TREX-2 protein complex, can associate with the mRNA. Schneider et al.1 report that mRNA export is regulated by interactions between TREX-2 and another protein complex, Mediator. In yeast, the Mediator–TREX-2 interaction seems to stabilize Mediator’s association with its Cdk8 kinase module — possibly through the TREX-2 subunit Sac3 (not shown) and a subunit of Mediator called Med31. Mediator–TREX-2 interactions help to ensure that genes undergoing transcription are close to the nuclear pore complex (NPC), thereby facilitating mRNA export to the cytoplasm. Gene–NPC interactions are also needed to maintain a function called transcriptional memory, which depends on the formation of a looped gene architecture (only the 5ʹ and 3ʹ ends of a DNA loop are shown) that also seems to be facilitated by Mediator7,13. 8 O C T O B E R 2 0 1 5 | VO L 5 2 6 | NAT U R E | 1 9 9
© 2015 Macmillan Publishers Limited. All rights reserved
For News & Views online, go to nature.com/newsandviews
MAL ARIA
Fifteen years of interventions A comprehensive modelling effort has revealed the relative contributions of different malaria-control measures to the massive reductions in disease prevalence that have occurred in Africa between 2000 and 2015. See Article p.207 LOUISE GUBB/CORBIS
J A N E T H E M I N G W AY
I
n 1978, when I began working on insectborne diseases, a child died of malaria every six seconds. Today, although we have made great progress, it is unacceptable that a child still dies every minute from this disease. There are an estimated 600,000 deaths annually, the vast majority of which are in subSaharan Africa. To drive down the malaria burden further, and ultimately to try to eradicate the disease, we need to be able to attribute the contributions of different interventions and use this information to optimize our efforts. In this issue, Bhatt et al.1 (page 207) provide the first authoritative, data-driven models to estimate the relative impact that combination drug therapies and mosquitocontrol strategies have had on clinical cases of malaria in Africa since 2000. Expert opinion on the relative merits of different malaria interventions varies greatly, and over the past half-century there have been major shifts in emphasis and operational implementation of drug- and insecticide-based approaches. The malaria-eradication efforts led by the World Health Organization in the 1960s used both chloroquine drug treatment and indoor residual spraying with DDT (this involves spraying the inside walls of dwellings with the insecticide). The failure of these efforts, which has been variously attributed to drug and insecticide resistance, under-resourcing and lack of political will to support effective implementation, caused a dramatic shift in approach in Africa. Mosquito control was largely abandoned in favour of improving access to prompt treatment with effective drugs, coupled with intermittent preventive drug treatment of particularly vulnerable populations. In 2000, the scale of activity and the emphasis on different malaria interventions shifted again in Africa. Initially, there was the uptake of bednets impregnated with long-lasting pyrethroid insecticides, with widespread free or subsidized distribution of these nets to ‘at risk’ populations. Mosquito control was further supplemented in 2005, supported by the US President’s Malaria Initiative, which reintroduced indoor residual spraying in 15 high-burden countries across the continent. Failing first-line drug treatments
Figure 1 | Net effect. Bhatt et al.1 estimate that 68% of the large reduction in clinical cases of malaria in Africa between 2000 and 2015 is attributable to the use of insecticide-impregnated bednets.
were also replaced with artemisinin-based combination therapies (ACTs) in 79 countries by the end of 2013. Bhatt et al. set out to model the impact of these interventions since 2000, collating the largest global published and unpublished data set ever analysed. They were not able to use the number of deaths from malaria for this modelling, because the quantity and quality of these data in different African settings were inadequate. A more accessible measure was the prevalence rate of malaria parasites in children between the ages of 2 and 10, and so the authors used the number of clinical cases of malaria averted, rather than deaths averted, as the output indicator. The collaborating researchers, who include members of some of the world’s best disease-modelling groups, used three independent malaria-transmission models to generate counterfactual geospatial maps — that is, they estimated what the malaria parasite prevalence rates would have been without each intervention. The authors estimate that 663 million
1 9 8 | NAT U R E | VO L 5 2 6 | 8 O C T O B E R 2 0 1 5
© 2015 Macmillan Publishers Limited. All rights reserved
clinical cases of malaria were averted between 2000 and 2015 (Fig. 1). Most of this improvement (68%) was due to bednets, with 22% resulting from ACTs and 10% from indoor residual spraying. Although these numbers are influenced by the timing, speed and scale on which each intervention was introduced, the massive impact of the mosquito-control interventions will come as a surprise to many who believe that improvements have primarily been driven by the introduction of ACTs2. Over the same 15-year period, malaria infection rates have halved, with threequarters of this improvement occurring in the past decade. Although this massive improvement in malaria control should be applauded, the study provides a timely warning against complacency. The rate of improvement slowed to 5% per year in 2013, and malaria is an infectious disease that could easily resurge. As we move from the era of the United Nations’ Millennium Development Goals, which set the targets for malaria and child-mortality reduction that instigated much of this activity, to the
NEWS & VIEWS RESEARCH Sustainable Development Goals, which are more oriented towards improving health systems and health services, we need to maintain and enhance malaria-control activities. The target of universal bednet coverage for at-risk populations is still a distant dream, nets distributed before 2012 now need replacing, and all three interventions are increasingly threatened by the development of mosquito resistance to the insecticides or parasite resistance to the drugs. ACT drug resistance is already well documented in southeast Asia, and would be catastrophic if it spread widely in Africa3. However, the greatest threat may come from the rapid increases in pyrethroid resistance that have occurred in the two main African malaria-vector mosquito species4. Drug resistance is detected rapidly, because health workers and patients can immediately recognize a failing treatment. But it is less
obvious when mosquitoes fail to respond to insecticides, and resistance will already be widespread in a mosquito population before there is an associated increase in the numbers of malaria cases and deaths. An international effort is already in place to try to stem the movement of ACT-resistant malaria parasites from Asia to Africa, and a more proactive approach is now needed for insecticide resistance. The urgency of this is underscored by the improved understanding that Bhatt and colleagues have provided of the crucial role that vector control has had in reducing malaria over the past decade, and, by extrapolation, of the role it will need to have if we are to eliminate the disease. A healthy portfolio of new antimalarial drugs and insecticides is under development, driven in particular by product-development partnerships coordinated by two non-profit
MOLECUL AR B IO LO GY
Mediating transcription and RNA export The finding that the Mediator protein complex contributes to messenger RNA export from the nucleus in yeast adds to a growing list of roles for the complex in regulating transcriptional processes. J O N AT H A N D . R U B I N & D Y L A N J . TA ATJ E S
G
ene transcription is fundamental to all major physiological processes, and defects in its regulation underlie myriad human diseases. Transcription culminates in the export of messenger RNA transcripts from the nucleus to the cytoplasm, where they are translated into proteins. In a paper in Cell, Schneider et al.1 use a combination of structural and cell biology, biochemistry, yeast genetics and transcript analyses to describe how this process is regulated by cooperation between the mRNA export machinery and Mediator — a large, multi-subunit protein complex best known for regulating the activity of the enzyme RNA polymerase II (pol II) during the early stages of transcription2. Many factors converge on nascent mRNA transcripts to facilitate their export from the nucleus. One such factor, the TREX-2 protein complex, regulates export through interactions with other complexes, including pol II and the nuclear pore complex (NPC)3, which acts as a gateway for cellular components to exit the nucleus and enter the cytoplasm. However, the mechanisms by which TREX-2 acts are uncertain. Schneider et al. investigated TREX-2 in the brewer’s yeast Saccharomyces cerevisiae. In yeast
cells lacking the TREX-2 subunit Sac3, the composition of the Mediator complex changed. Specifically, components of the Mediator ‘Cdk8
organizations, the Medicines for Malaria Venture and the Innovative Vector Control Consortium. But substantial development, financial, regulatory and policy hurdles are impeding the roll-out of these agents. If we can overcome these, stay ahead of the ‘arms race’ of parasite and mosquito resistance, develop an effective vaccine to reduce transmission and optimally deploy these interventions, then no child need die from malaria. ■ Janet Hemingway is at the Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK. e-mail: [email protected] 1. Bhatt, S. et al. Nature 526, 207–211 (2015). 2. Taylor Bright, A. & Winzeler, E. A. Nature 498, 446–447 (2013). 3. White, N. J. et al. Lancet 353, 1965–1967 (1999). 4. Hemingway, J. et al. Lancet http://dx.doi.org/ 10.1016/S0140-6736(15)00417-1 (2015).
kinase’ module failed to associate with the rest of the complex. The authors demonstrated that TREX-2 physically associates with Mediator, and that this association depends on Sac3 and a Mediator subunit implicated in the activation of transcription, Med31. A series of experiments then showed a functional interdependence between Mediator and TREX-2. In yeast, genes that are in the process of being transcribed associate with the NPC, presumably to facilitate mRNA export to the cytoplasm4. Schneider and colleagues demonstrated that, like Sac3, Med31 is required for gene targeting to the NPC, implying that Mediator is involved in mRNA export (Fig. 1). However, in contrast to cells lacking Sac3, mRNA export seemed normal in cells lacking
5′ DNA
Transcription initiation factor Med31
AAAA NPC
TREX-2 Mediator
mRNA Cytoplasm
Cdk8 module
Nucleus
3′ DNA
Figure 1 | Complex interactions in messenger RNA export. Following gene transcription, mRNAs are polyadenylated (adenine (A) bases are added to the 3ʹ end of the transcript). Factors involved in the export of mRNA from the nucleus, such as the TREX-2 protein complex, can associate with the mRNA. Schneider et al.1 report that mRNA export is regulated by interactions between TREX-2 and another protein complex, Mediator. In yeast, the Mediator–TREX-2 interaction seems to stabilize Mediator’s association with its Cdk8 kinase module — possibly through the TREX-2 subunit Sac3 (not shown) and a subunit of Mediator called Med31. Mediator–TREX-2 interactions help to ensure that genes undergoing transcription are close to the nuclear pore complex (NPC), thereby facilitating mRNA export to the cytoplasm. Gene–NPC interactions are also needed to maintain a function called transcriptional memory, which depends on the formation of a looped gene architecture (only the 5ʹ and 3ʹ ends of a DNA loop are shown) that also seems to be facilitated by Mediator7,13. 8 O C T O B E R 2 0 1 5 | VO L 5 2 6 | NAT U R E | 1 9 9
© 2015 Macmillan Publishers Limited. All rights reserved
