- Email: [email protected]
Combating malaria: the devil is in the molecular details
Editorial
Breaking barriers: a leap ahead in Plasmodium biology
Combating malaria: the devil is in the molecular details R. Lynn Sherrer Editor, Trends in Parasitology
Malaria remains a scourge, especially for children, and the landscape of controlling the disease, much less eradicating it, is still daunting. In 2007, Bill and Melinda Gates called on global leaders to embrace ‘an audacious goal – to reach a day when no human being has malaria, and no mosquito on earth is carrying it.’ Although malaria eradication is unlikely to be around the corner, enormous strides have been made in understanding both Plasmodium biology and that of its mosquito vector, Anopheles. The year 2012 marks the 10th anniversary of the publication of the genomic sequences of both Plasmodium falciparum and Anopheles gambiae, which have contributed enormously to our understanding of these organisms. This Trends in Parasitology Special Issue – ‘Breaking Barriers: A Leap Ahead in Plasmodium Biology’ – was inspired by the 2012 fourth Molecular Approaches to Malaria (MAM) conference, which was recently held in the beautiful setting of Lorne on the southern coast of Australia. This conference brought together all facets of malaria biology, and the quality of the science presented was outstanding – what follows is but a brief glimpse. We will begin with the mosquito vector, an essential element of the Plasmodium parasite life cycle. Although insecticides and bed net use are crucial in controlling malaria, reducing or blocking transmission of the parasites from mosquitoes to the human host is an area of intense interest. Sinden et al. explain transmission biology and discuss the pros and cons of different laboratory assays that measure transmission. Understanding the interaction between the parasites and their vectors is also essential. Some parasites alter the behavior of their hosts to increase their transmission, and Cator et al. explore the possibility that Plasmodium parasites manipulate the behavior of mosquitoes to benefit parasite transmission. Moving into the host, dynamic and high-resolution imaging by Dixon et al. has literally given insight into how and why P. falciparum gametocytes undergo a striking change in shape during maturation: whereas the rigidity of early-stage gametocytes probably aids sequestration at sites of low blood-flow, late-stage gametocytes are flexible and are able to circulate in the bloodstream, bypassing mechanical filtering mechanisms in the spleen of the host. Interestingly, a similar process may offer protection from malaria in individuals who have hemoglobinopathies (such as sickle cell disease and a- and b-thalassemia). Cytoadhesion of infected erythrocytes within the bloodstream, avoiding passage through the spleen (and filtering mechanisms), is associated with pathology of malaria. Cyrklaff et al. Corresponding author: Sherrer, R.L. ([email protected]).
describe the impaired cytoadhesion phenotype of infected sickle cell and a-thalassemic erythrocytes due to host actin remodeling, which allows bypass of splenic filtering. Genomic and proteomic analysis of Plasmodium species continues to expand our understanding at the molecular level, and this will assist the discovery of new drug targets. Improvement in genomic technologies has allowed Hoeijmakers et al. to probe epigenetic mechanisms that regulate chromatin structure and affect the development and survival of Plasmodium within the human host. Jones et al. review post-translational modification at the proteomic level, discussing the importance of palmitoylation – the addition of a lipid moiety to cysteine residues of targeted proteins – in Plasmodium biology. The necessity and importance of genomic studies is further highlighted by discussion of the chloroquine resistance transporter (PfCRT) by Ecker et al. Chloroquine was the drug of choice for P. falciparum malaria for years; unfortunately, widespread drug-resistance emerged, although studies of PfCRT are still useful in picking apart the details of antimalarial drug resistance. What is particularly disturbing is that mutations at multiple residues of PfCRT alter parasite susceptibility to a wide range of antimalarial drugs, emphasizing the need to continue screening for the appearance of novel pfcrt alleles. Chloroquine resistance has now become a problem in treating Plasmodium vivax, the often ‘overlooked’ humaninfectious Plasmodium species. The transmission dynamics of P. vivax differ from those of P. falciparum because it can form a dormant liver stage whereby recurrence of disease can occur long after the initial infection; this makes the infection difficult to control. Price et al. address the complications in analyzing antimalarial resistance of P. vivax, one aspect of which is the problematic in vitro culture of the parasite, a mainstay of studying drug susceptibility for falciparum malaria. On the upside, recent genome-wide diversity and sequence data from multiple field isolates will hopefully assist in understanding drug resistance as it has for P. falciparum infection. Last, but not least, of course, we turn to drug and vaccine development. Experimentally induced blood-stage malaria infection (IBSM) with P. falciparum, which entails direct intravenous inoculation of infected erythrocytes into human volunteers, had to overcome ethical, safety, and technical challenges for use. Engwerda et al. inform us of the value of such clinical studies: uncovering many aspects of malaria, including pathogenesis, immunity, and vaccine and drug efficacy, which could facilitate next-generation drug design and immune studies.
1471-4922/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2012.08.010 Trends in Parasitology, November 2012, Vol. 28, No. 11
455
Editorial Within this Special Issue, a grand leap forward in understanding Plasmodium biology stemming from sequencing of the P. falciparum genome is obvious. Many of the new techniques that have contributed to our ever-increasing knowledge – such as the significant advances in understanding drug resistance – spring from this point. Other techniques, such as the improved imaging that you will read about in the coming pages, bring us a much greater understanding of how the parasite survives and replicates within the human host. What techniques will come next? Perhaps eradication is an audacious goal at this point in time, but let us hope that the next decade brings as many advances in Plasmodium and vector biology as has the past one.
456
Trends in Parasitology November 2012, Vol. 28, No. 11
I would like to offer my sincerest gratitude to the authors and reviewers of the Opinions and Reviews herein. Additional thanks are to the MAM 2012 Conference organizers, Jake Baum and Kevin Saliba, for organizing a stimulating and excellent conference. I hope you, the reader, enjoy these vignettes arising from the exciting advances presented at MAM 2012. All those able to attend the next MAM in 2016 are encouraged to do so! I look forward to hearing your opinions and feedback about this issue in particular, and Trends in Parasitology in general; please keep them coming ([email protected]).
Breaking barriers: a leap ahead in Plasmodium biology
Combating malaria: the devil is in the molecular details R. Lynn Sherrer Editor, Trends in Parasitology
Malaria remains a scourge, especially for children, and the landscape of controlling the disease, much less eradicating it, is still daunting. In 2007, Bill and Melinda Gates called on global leaders to embrace ‘an audacious goal – to reach a day when no human being has malaria, and no mosquito on earth is carrying it.’ Although malaria eradication is unlikely to be around the corner, enormous strides have been made in understanding both Plasmodium biology and that of its mosquito vector, Anopheles. The year 2012 marks the 10th anniversary of the publication of the genomic sequences of both Plasmodium falciparum and Anopheles gambiae, which have contributed enormously to our understanding of these organisms. This Trends in Parasitology Special Issue – ‘Breaking Barriers: A Leap Ahead in Plasmodium Biology’ – was inspired by the 2012 fourth Molecular Approaches to Malaria (MAM) conference, which was recently held in the beautiful setting of Lorne on the southern coast of Australia. This conference brought together all facets of malaria biology, and the quality of the science presented was outstanding – what follows is but a brief glimpse. We will begin with the mosquito vector, an essential element of the Plasmodium parasite life cycle. Although insecticides and bed net use are crucial in controlling malaria, reducing or blocking transmission of the parasites from mosquitoes to the human host is an area of intense interest. Sinden et al. explain transmission biology and discuss the pros and cons of different laboratory assays that measure transmission. Understanding the interaction between the parasites and their vectors is also essential. Some parasites alter the behavior of their hosts to increase their transmission, and Cator et al. explore the possibility that Plasmodium parasites manipulate the behavior of mosquitoes to benefit parasite transmission. Moving into the host, dynamic and high-resolution imaging by Dixon et al. has literally given insight into how and why P. falciparum gametocytes undergo a striking change in shape during maturation: whereas the rigidity of early-stage gametocytes probably aids sequestration at sites of low blood-flow, late-stage gametocytes are flexible and are able to circulate in the bloodstream, bypassing mechanical filtering mechanisms in the spleen of the host. Interestingly, a similar process may offer protection from malaria in individuals who have hemoglobinopathies (such as sickle cell disease and a- and b-thalassemia). Cytoadhesion of infected erythrocytes within the bloodstream, avoiding passage through the spleen (and filtering mechanisms), is associated with pathology of malaria. Cyrklaff et al. Corresponding author: Sherrer, R.L. ([email protected]).
describe the impaired cytoadhesion phenotype of infected sickle cell and a-thalassemic erythrocytes due to host actin remodeling, which allows bypass of splenic filtering. Genomic and proteomic analysis of Plasmodium species continues to expand our understanding at the molecular level, and this will assist the discovery of new drug targets. Improvement in genomic technologies has allowed Hoeijmakers et al. to probe epigenetic mechanisms that regulate chromatin structure and affect the development and survival of Plasmodium within the human host. Jones et al. review post-translational modification at the proteomic level, discussing the importance of palmitoylation – the addition of a lipid moiety to cysteine residues of targeted proteins – in Plasmodium biology. The necessity and importance of genomic studies is further highlighted by discussion of the chloroquine resistance transporter (PfCRT) by Ecker et al. Chloroquine was the drug of choice for P. falciparum malaria for years; unfortunately, widespread drug-resistance emerged, although studies of PfCRT are still useful in picking apart the details of antimalarial drug resistance. What is particularly disturbing is that mutations at multiple residues of PfCRT alter parasite susceptibility to a wide range of antimalarial drugs, emphasizing the need to continue screening for the appearance of novel pfcrt alleles. Chloroquine resistance has now become a problem in treating Plasmodium vivax, the often ‘overlooked’ humaninfectious Plasmodium species. The transmission dynamics of P. vivax differ from those of P. falciparum because it can form a dormant liver stage whereby recurrence of disease can occur long after the initial infection; this makes the infection difficult to control. Price et al. address the complications in analyzing antimalarial resistance of P. vivax, one aspect of which is the problematic in vitro culture of the parasite, a mainstay of studying drug susceptibility for falciparum malaria. On the upside, recent genome-wide diversity and sequence data from multiple field isolates will hopefully assist in understanding drug resistance as it has for P. falciparum infection. Last, but not least, of course, we turn to drug and vaccine development. Experimentally induced blood-stage malaria infection (IBSM) with P. falciparum, which entails direct intravenous inoculation of infected erythrocytes into human volunteers, had to overcome ethical, safety, and technical challenges for use. Engwerda et al. inform us of the value of such clinical studies: uncovering many aspects of malaria, including pathogenesis, immunity, and vaccine and drug efficacy, which could facilitate next-generation drug design and immune studies.
1471-4922/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pt.2012.08.010 Trends in Parasitology, November 2012, Vol. 28, No. 11
455
Editorial Within this Special Issue, a grand leap forward in understanding Plasmodium biology stemming from sequencing of the P. falciparum genome is obvious. Many of the new techniques that have contributed to our ever-increasing knowledge – such as the significant advances in understanding drug resistance – spring from this point. Other techniques, such as the improved imaging that you will read about in the coming pages, bring us a much greater understanding of how the parasite survives and replicates within the human host. What techniques will come next? Perhaps eradication is an audacious goal at this point in time, but let us hope that the next decade brings as many advances in Plasmodium and vector biology as has the past one.
456
Trends in Parasitology November 2012, Vol. 28, No. 11
I would like to offer my sincerest gratitude to the authors and reviewers of the Opinions and Reviews herein. Additional thanks are to the MAM 2012 Conference organizers, Jake Baum and Kevin Saliba, for organizing a stimulating and excellent conference. I hope you, the reader, enjoy these vignettes arising from the exciting advances presented at MAM 2012. All those able to attend the next MAM in 2016 are encouraged to do so! I look forward to hearing your opinions and feedback about this issue in particular, and Trends in Parasitology in general; please keep them coming ([email protected]).