Transcriptomic Studies of Malaria: a Paradigm for Investigation of Systemic Host-Pathogen Interactions

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cerebral malaria 5 infectiousdiseases
infectious disease 16 infectiousdiseases
malaria 161 infectiousdiseases
tuberculosis 4 infectiousdiseases
vaccinia 1 infectiousdiseases
yellow fever 1 infectiousdiseases

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cerebral malaria 22985 upregulated (light red) or downregulated (light blue) in each species for uncomplicated disease and for cerebral malaria (CM) or experimental cerebral malaria (ECM). Common functional groups between humans and mice are marked
cerebral malaria 23023 (light blue) in each species for uncomplicated disease and for cerebral malaria (CM) or experimental cerebral malaria (ECM). Common functional groups between humans and mice are marked in boldface type.What Have Transcriptomic
cerebral malaria 47483 points ([69]). Although that study primarily aimed to investigate the pathogenesis of experimental cerebral malaria (ECM), the sequential immune response over time is noteworthy because it varied by organ and by mouse
cerebral malaria 63539 in rodent models with those in humans is challenging (Fig. 3).(i) Cerebral malaria and experimental cerebral malaria .The pathogenesis of human cerebral malaria (CM) has been extensively debated because it is currently
cerebral malaria 63582 challenging (Fig. 3).(i) Cerebral malaria and experimental cerebral malaria.The pathogenesis of human cerebral malaria (CM) has been extensively debated because it is currently impossible to prove the dependency of the
infectious disease 594 analysis of genome-wide RNA expression, is a common approach to investigate host and pathogen processes in infectious disease s. Technical and bioinformatic advances have permitted increasingly thorough analyses of the association
infectious disease 1864 transcriptomic studies of malaria and how these lessons may guide studies of host-pathogen interactions in other infectious disease s. We propose that the potential of transcriptomic studies to improve the understanding of malaria as
infectious disease 11578 depth.The pathogen load is likely to be an important factor in determining the pathogenesis of many infectious disease s but is much harder to quantify as a stimulus for the systemic host response when pathogens are differentially
infectious disease 12822 host-pathogen interactions, lessons learned from malaria studies, and strategies for application to other infectious disease s. We illustrate that the traditional approach of considering variation in the host response to an invariant
infectious disease 13506 technologies over the last 2 decades (Fig. 2) has driven many transcriptomic studies of malaria and other infectious disease s, sometimes with more emphasis on applying new technology than on addressing important biological and
infectious disease 14509 superseded by RNA-seq as the preferred approach for many transcriptomic applications, including studies of infectious disease s.FIG 2Timeline of transcriptomic approaches for infectious diseases. Transcriptomic analysis requires
infectious disease 14576 applications, including studies of infectious diseases.FIG 2Timeline of transcriptomic approaches for infectious disease s. Transcriptomic analysis requires the extraction of RNA from parts of the body such as peripheral blood.
infectious disease 86812 parasite.Biomarkers.Identifying reliable biomarkers can improve diagnosis and the prediction of outcomes of infectious disease s. This is particularly important for malaria because while some individuals living in high-transmission
infectious disease 99610 understanding pathogenesis. This is not unique to malaria research; similar controversies arise for other infectious disease s, such as tuberculosis ([231]), meningococcal disease ([232]), and typhoid ([233]). One way to objectively
infectious disease 104661 for the identification of targets for adjunctive therapies to improve outcomes of malaria and other infectious disease s.Association and causation.Within transcriptomic data sets, it is inevitable that the expressions of
infectious disease 107318 their design. Principles for improving the design of malaria studies will also apply to many other infectious disease s (Table 2). The overarching principle is that if a study is not designed to answer the research question,
infectious disease 107758 track with increasingly complex analytical approaches ([243], [244]).TABLE 2Lessons for the design of infectious disease transcriptomic studiesPhaseChallengeProblemExampleSolutionsDesignDefining study objectivePost hoc specification
infectious disease 112165 highlighted the complexity and challenges of studying host-pathogen interactions in this way. For other infectious disease s, some of these challenges may be even greater. In the next decade, advances in transcriptomics will
infectious disease 114743 results.Mathematical developments will likely facilitate new approaches to studying trajectories of infectious disease s, overcoming the inherent limitation that naturally infected human subjects present only a snapshot
infectious disease 115660 there is a high likelihood that various selection methods applied to transcriptome analyses in any infectious disease will reveal small sets of transcripts as diagnostic or prognostic biomarkers. This has the potential
infectious disease 115822 diagnostic or prognostic biomarkers. This has the potential to revolutionize many aspects of clinical infectious disease practice, if these could be turned into rapid tests administered at the point of care. Currently, commercial
malaria 1340 infections in humans. Here we review the contribution of transcriptomic studies to the understanding of malaria , a parasitic disease which has exerted a major influence on human evolution and continues to cause a
malaria 1492 major influence on human evolution and continues to cause a huge global burden of disease. We consider malaria a paradigm for the transcriptomic assessment of systemic host-pathogen interactions in humans, because
malaria 1777 readily sampled compartment of the body. We illustrate lessons learned from transcriptomic studies of malaria and how these lessons may guide studies of host-pathogen interactions in other infectious diseases.
malaria 1973 infectious diseases. We propose that the potential of transcriptomic studies to improve the understanding of malaria as a disease remains partly untapped because of limitations in study design rather than as a consequence
malaria 4180 genus Plasmodium, which can infect a diverse range of vertebrate hosts. A comprehensive description of malaria epidemiology, biology, immunology, pathogenesis, and treatment is beyond the scope of this text and
malaria 4559 article.Five main species of Plasmodium cause most disease in humans: P. falciparum, P. vivax, P. knowlesi, P. malaria e, and P. ovale. P. falciparum is the major cause of severe malaria, which can result in death, and is
malaria 4626 falciparum, P. vivax, P. knowlesi, P. malariae, and P. ovale. P. falciparum is the major cause of severe malaria , which can result in death, and is the focus of most of the human studies discussed in this article.
malaria 4744 result in death, and is the focus of most of the human studies discussed in this article. The term malaria refers to the disease caused by infection with these parasites, and individuals with asexual-stage parasites
malaria 7958 continue to increase, because of insufficient constraint by the host response or a failure to receive anti malaria treatment, this predisposes an individual to an increasing risk of severe disease manifestations, which
malaria 9380 ready to infect a new human host during a future blood meal ([15]).Individuals in some areas where malaria is highly endemic will be exposed to multiple infectious mosquito bites every day, and cumulative infections
malaria 10332 Paradigm for Transcriptomic Studies of Systemic Host-Pathogen InteractionsClinical manifestations of malaria are due to the asexual blood stage of the parasite, and the host-parasite interactions that cause disease
malaria 11005 numbers of parasites that can be found in human blood, particularly in children with some forms of severe malaria ([26], [27]), can yield abundant parasite RNA, making this a feasible approach. Furthermore, the pathogen
malaria 12109 disease requires evaluation at a much larger scale. Evaluation of host-parasite interactions in blood in malaria through transcriptomic analyses provides a paradigm for understanding the role of systemic host-pathogen
malaria 12379 we aim to describe the contribution that transcriptomic studies have already made to understanding malaria and highlight how new approaches might permit greater insights. We provide an introduction to existing
malaria 12653 these technologies are transforming the depth and richness of transcriptomic data. We then consider malaria as a paradigm for transcriptional analyses of systemic host-pathogen interactions, lessons learned from
malaria 12765 paradigm for transcriptional analyses of systemic host-pathogen interactions, lessons learned from malaria studies, and strategies for application to other infectious diseases. We illustrate that the traditional
malaria 13488 development of these technologies over the last 2 decades (Fig. 2) has driven many transcriptomic studies of malaria and other infectious diseases, sometimes with more emphasis on applying new technology than on addressing
malaria 20272 for example, in the gut of mice infected with whipworm ([63]) and the blood of P. falciparum-infected malaria patients (where about 10% of whole-blood reads mapped to the parasite) ([25]). In contrast, dual RNA-seq
malaria 21270 in vitro and in vivo. Here we focus primarily on those using samples from humans with P. falciparum malaria and animal models of human infection, and we draw upon pivotal in vitro studies, where necessary, to
malaria 21481 give context. Recent reviews have addressed the application of transcriptomics to specific aspects of malaria immunology, vaccinology, and host-parasite interactions ([66][67][68]). We aim to provide a broader
malaria 22595 consistent findings and some clear holes in current knowledge emerge.FIG 3Transcriptomic host response to malaria in humans and mice. Shown is a comparison of selected features of the transcriptional host response
malaria 22706 humans and mice. Shown is a comparison of selected features of the transcriptional host response to malaria in humans (left) and mice (right). Pie charts indicate how frequently each tissue has been studied for
malaria 22994 (light red) or downregulated (light blue) in each species for uncomplicated disease and for cerebral malaria (CM) or experimental cerebral malaria (ECM). Common functional groups between humans and mice are marked
malaria 23032 blue) in each species for uncomplicated disease and for cerebral malaria (CM) or experimental cerebral malaria (ECM). Common functional groups between humans and mice are marked in boldface type.What Have Transcriptomic
malaria 23438 studies of parasite gene expression in vitro ([71], [72]) and in vivo ([23]). Draft genomes of rodent malaria parasites began to be reported at the same time ([73], [74]), and together, these resources opened the
malaria 27584 the clear rationale for these methods to be applied, it is notable that few transcriptomic studies of malaria have used them.Parasite sequestration in the microvasculature is a pathognomonic feature of P. falciparum
malaria 27698 used them.Parasite sequestration in the microvasculature is a pathognomonic feature of P. falciparum malaria ([17], [18]), and the extent of sequestration is one factor that contributes to differences in developmental-stage
malaria 28212 has been to use formalin-fixed paraffin-embedded postmortem tissue blocks from patients who died of malaria , and these specimens enable sequestered parasite gene expression profiles to be obtained from brain
malaria 29093 genome and also produced major improvements in previously fragmented genomes of the common model rodent malaria parasites ([88]). Such a comprehensive annotation is a prerequisite for any attempt to relate quantitative
malaria 31171 global gene expression analysis in vivo identified several different patterns in parasites drawn from malaria patients ([92]), and by analogy to the better-understood biology of Saccharomyces cerevisiae, these
malaria 35157 chabaudi, ∼68 loci in P. knowlesi, ∼1,200 loci in P. cynomolgi and P. vivax, ∼250 loci in P. malaria e, and nearly 2,000 loci in P. ovale ([99], [100], [105], [110], [111]).Transcriptomic studies have revealed
malaria 37696 families, appears upregulated in vivo compared to that in laboratory strains. Among subjects with severe malaria , greater departures from the in vitro transcriptome have been described ([116]), perhaps suggesting
malaria 39690 Naturally occurring immune responses.The complex life cycle of Plasmodium means that the immune response to malaria needs to be understood as a series of responses to spatially, temporally, and antigenically distinct
malaria 40109 challenges for the immune system. Although a huge amount has been learned about immune responses to malaria in both humans and animal models ([120]), most of our understanding comes from reductionist studies,
malaria 40461 important role in and are potential building blocks for an integrated description of immune responses to malaria . It would be ideal to obtain serial samples from all relevant tissues, starting before inoculation by
malaria 41097 piece together a likely sequence of events from limited samples from humans and data from experimental malaria infections in other species.Insights into some of the earliest immune responses to blood-stage parasites
malaria 41268 immune responses to blood-stage parasites in humans come from controlled-infection studies, whereby malaria -naive individuals are infected by a mosquito bite or the inoculation of blood-stage parasites and then
malaria 42509 limited to subjects who developed fever ([124]). Looking slightly later in infection, when previously malaria -naive subjects first developed fever, broadly similar findings were observed by using RNA-seq, although
malaria 42810 profiles from naturally infected individuals at the time of clinical presentation with acute uncomplicated malaria (UM) show many similarities with those of presymptomatic experimentally induced infections ([24], [25],
malaria 43616 less upregulation of interferon responses but greater upregulation of B-cell receptor signaling in malaria -experienced individuals ([125]). Prominent neutrophil-associated signatures were additionally found
malaria 44387 whole blood.Differences between the transcriptional profiles seen in cases of uncomplicated and severe malaria have been less studied. A paired comparison of 5 individuals who first presented with severe malaria
malaria 44488 malaria have been less studied. A paired comparison of 5 individuals who first presented with severe malaria and later returned with an episode of uncomplicated malaria found that IFN pathway and T-cell response
malaria 44548 individuals who first presented with severe malaria and later returned with an episode of uncomplicated malaria found that IFN pathway and T-cell response genes were more highly expressed in the uncomplicated episodes
malaria 44951 difference may be largely a consequence of the lower parasite load at presentation with uncomplicated malaria .Since natural exposure often involves repeated Plasmodium infections, transcriptomic approaches have
malaria 45130 transcriptomic approaches have been used to understand the consequences that one or more episodes of malaria may have on subsequent responses to Plasmodium or other pathogens. Comparison of PBMC transcriptomes
malaria 45316 of PBMC transcriptomes of Malian children 7 days after treatment for the first acute episode of the malaria season with transcriptomes just before the onset of the malaria season revealed the downregulation of
malaria 45380 for the first acute episode of the malaria season with transcriptomes just before the onset of the malaria season revealed the downregulation of inflammatory genes but the upregulation of genes expected to facilitate
malaria 46027 However, there is also abundant evidence that acquisition of immunity is inefficient, and repeated malaria exposure impairs heterologous immune responses and increases susceptibility to other infections ([131],
malaria 46397 transcriptome analysis has been central to defining atypical memory B-cell populations related to chronic malaria infections, which are defective in immunoglobulin production and denoted by the surface expression of
malaria 46646 on the evolution of changes in the blood transcriptome with the progression of infection in animal malaria models, although data available for P. chabaudi infections suggest that there are considerable overlaps
malaria 46820 that there are considerable overlaps with the human blood transcriptome in uncomplicated pediatric malaria ([126], [136], [137]) (Fig. 3). Pathway-level similarities include the upregulation of IFN response,
malaria 47492 ([69]). Although that study primarily aimed to investigate the pathogenesis of experimental cerebral malaria (ECM), the sequential immune response over time is noteworthy because it varied by organ and by mouse
malaria 47695 mouse species. Overall, there were many similarities to the human immune response genes induced by malaria , particularly in spleen, liver, and lung, where Toll-like receptor (TLRs), proinflammatory cytokine,
malaria 48548 interaction between parasites and innate and adaptive immune cells, which control human and rodent malaria infections ([138]). For example, purified CD11c+ splenic dendritic cells (DCs) were examined at different
malaria 48773 during P. yoelii 17XNL-infected BALB/c mice to resolve a controversy surrounding their function in malaria ([139]). At the time of that study, opposing roles had been proposed, with DCs on the one hand enhancing
malaria 49783 contrast to previously described “common” DC maturation signatures, suggesting that DC behavior in malaria may not easily be inferred from that observed in other situations ([139]).Analyses of purified splenic
malaria 49959 ([139]).Analyses of purified splenic CD4 T cells have also contributed to understanding their role in malaria , this time in the lethal P. berghei ANKA model ([142]). In this model, CD4 T cells enhance pathogenicity
malaria 51164 and single-cell sequencing will add further essential detail and complexity to our understanding of malaria immunology in the future.(ii) Vaccine-induced immune responses.Transcriptomic approaches have yielded
malaria 51553 the new discipline of systems vaccinology ([148], [149]). However, the development of a protective malaria vaccine has been an arduous process because a vaccine has to perform considerably better than naturally
malaria 52190 the only vaccine to have achieved licensure and enter into pilot implementation in countries where malaria is endemic is RTS,S/AS01 ([150], [152]). This vaccine has demonstrated only modest efficacy and durability
malaria 55569 characterized.(iii) Gene expression profiles associated with asymptomatic infection.In countries where malaria is endemic, it is common for individuals to have asymptomatic parasitemia ([11], [12]). The likelihood
malaria 56487 sufficient parasitemia to trigger a response and that the set points for such a response may differ between malaria -experienced and previously naive individuals. This concept may be supported by data from a recent study
malaria 57089 the Mossi tribe showed negligible differences. Fulani are well known to have relative protection from malaria ([164]), and the authors of that study speculated that these results might indicate an immune response
malaria 57556 approach, a longitudinal study identified a Vδ2+ subset of γδ T cells as being reduced following chronic malaria exposure, and their gene expression was investigated ([165]). Interestingly, their basal expression
malaria 59936 distress, and severe anemia ([167], [168]). The pathogenesis of the clinical and laboratory features of malaria is incompletely understood, and this is especially so for the progression from uncomplicated to severe
malaria 60047 incompletely understood, and this is especially so for the progression from uncomplicated to severe malaria ([13]). Although transcriptomic approaches have the ability to broaden our understanding of the changes
malaria 60505 animal models have frequently been used to try to provide an understanding of the pathogenesis of severe malaria . However, the interpretation of the results generated in these models is dependent on understanding
malaria 60845 groups.The most common models use inbred strains of mice of specified ages and sexes. Unlike natural malaria infections in humans, the outcome of these models tends to be extremely consistent for any given combination
malaria 62173 disentangle expression differences associated with the genetic background from those causing severe malaria . Furthermore, features that are critical for valid comparisons in models with different mouse or parasite
malaria 63192 date comparing human gene expression from organs such as brain or lung in severe and uncomplicated malaria cases (Fig. 3). In contrast, relatively few animal studies have investigated gene expression in blood
malaria 63514 Thus, synthesis of findings in rodent models with those in humans is challenging (Fig. 3).(i) Cerebral malaria and experimental cerebral malaria.The pathogenesis of human cerebral malaria (CM) has been extensively
malaria 63548 models with those in humans is challenging (Fig. 3).(i) Cerebral malaria and experimental cerebral malaria .The pathogenesis of human cerebral malaria (CM) has been extensively debated because it is currently
malaria 63591 (Fig. 3).(i) Cerebral malaria and experimental cerebral malaria.The pathogenesis of human cerebral malaria (CM) has been extensively debated because it is currently impossible to prove the dependency of the
malaria 64309 misclassified as CM. A relatively common and specific feature of CM that is not present in false CM is malaria l retinopathy, which colocalizes with the sequestration of parasites in the retinal blood vessels ([181],
malaria 64590 has become apparent that coma in some children without retinopathy is also at least partly caused by malaria ([182], [183], [186]).(a) Host response.Few studies have compared the human or mouse blood transcriptomes
malaria 64733 response.Few studies have compared the human or mouse blood transcriptomes between CM and uncomplicated malaria ([129], [170], [171]) or between severe malaria phenotypes ([187]). In Malawian children initially treated
malaria 64781 mouse blood transcriptomes between CM and uncomplicated malaria ([129], [170], [171]) or between severe malaria phenotypes ([187]). In Malawian children initially treated for CM and subsequently reattending with
malaria 64906 ([187]). In Malawian children initially treated for CM and subsequently reattending with an uncomplicated malaria episode, paired analyses of whole blood showed a striking upregulation of type I interferon-associated
malaria 65068 striking upregulation of type I interferon-associated gene expression at presentation with uncomplicated malaria compared to the episode of severe malaria ([129]). Differential type I interferon responses were also
malaria 65110 interferon-associated gene expression at presentation with uncomplicated malaria compared to the episode of severe malaria ([129]). Differential type I interferon responses were also a feature detected in a larger study comparing
malaria 66360 complement, Toll-like receptor, and cytotoxic-T-cell genes than those in 5 children with uncomplicated malaria ([171]). Many of these findings parallel those for the blood transcriptome in ECM, obtained from comparisons
malaria 67376 associated with other neurodegenerative diseases between 7 children with CM and 8 with uncomplicated malaria suggested that protein aggregation pathways may be activated and important in CM ([170]).In contrast
malaria 71740 ([22], [138]). Splenic gene expression has been investigated in both ECM and non-ECM severe rodent malaria models. Consistent with findings for other tissues, erythropoiesis genes were suppressed as ECM progressed
malaria 73630 this have been rather inconclusive. Targeted analysis of the var transcriptome revealed that severe malaria (both CM and severe anemia) was associated with high expression levels of var genes encoding PfEMP1
malaria 73954 consistent with previous functional analyses highlighting the importance of this interaction in severe malaria ([193], [194]).Analysis of P. falciparum isolates from 58 Malawian CM patients revealed considerable
malaria 74410 Subsequent combination of those data with additional gene expression data from subjects with uncomplicated malaria suggested that CM-associated parasites might show increased expression levels of genes that modify cytoadhesion
malaria 74939 find any significant residual differences between groups with severe (including CM) and uncomplicated malaria ([82]).Parasite gene expression in ECM has also been examined by using custom microarrays, but at that
malaria 75786 these differences to the already complex patterns of organ-specific host gene expression.(ii) Other malaria phenotypes.CM is the most studied severe malaria phenotype, but other life-threatening manifestations
malaria 75835 of organ-specific host gene expression.(ii) Other malaria phenotypes.CM is the most studied severe malaria phenotype, but other life-threatening manifestations include severe anemia and respiratory distress
malaria 76137 hyperventilation to raise the blood pH by the exhalation of more carbon dioxide ([13]). In adults, malaria -associated respiratory distress often represents true lung pathology with a picture similar to those
malaria 76381 respiratory distress syndrome ([12]). Severe anemia is probably the most common severe manifestation of malaria in very-high-transmission settings ([13]). If prompt blood transfusion and antimalarial treatment are
malaria 76468 manifestation of malaria in very-high-transmission settings ([13]). If prompt blood transfusion and anti malaria l treatment are available, the mortality rate can be low ([195]). Malaria in pregnancy is a special case
malaria 77028 include lung and liver pathology ([197]).(a) Host response.Fever is one of the key clinical features of malaria , but there is great variation in the temperatures at the time of clinical presentation among individuals
malaria 77728 and lysosome-related ([25]) genes has been significantly associated with body temperature in acute malaria , while in PBMCs, heat shock proteins, interleukin-8 (a chemokine that promotes neutrophil chemotaxis),
malaria 78254 [169]). The potential for the correlation of gene expression with clinical and laboratory features of malaria pathogenesis has not yet been fully exploited.Pathogenicity-associated whole-blood host transcriptional
malaria 79362 mouse data onto patterns of gene expression from a cross-sectional study of subjects with uncomplicated malaria ([126]). This novel approach may represent an important advance because it is almost impossible to examine
malaria 79541 it is almost impossible to examine sequential gene expression in humans with untreated symptomatic malaria , but consequently, robust validation is also challenging.In other mouse models, analysis of the spleen
malaria 80633 of genes in the spleen, mostly related to T-cell function ([200]).Individuals living in areas where malaria transmission is common develop immunity through repeated infection, and many become clinically immune
malaria 81720 parasites isolated from the placenta ([80], [201], [202]).Human gene expression in the placentas of malaria -infected women showed considerable perturbation, with distinct patterns related to both infection status
malaria 82761 studies examining parasite transcriptomes in association with the pathogenesis of noncerebral severe malaria . Dual RNA-seq revealed 126 parasite genes significantly associated with high fever, with the strongest
malaria 83808 parasite gene expression levels has been performed with a small number of adults with noncerebral severe malaria (predominantly subjects with renal impairment) versus those with uncomplicated malaria by using a custom
malaria 83895 noncerebral severe malaria (predominantly subjects with renal impairment) versus those with uncomplicated malaria by using a custom microarray designed to identify a broader repertoire of genes from variant gene families
malaria 84233 differentially expressed, with a notable downregulation of genes associated with host cell entry in severe malaria as well as enrichment for metabolic processes and RNA splicing and the differential expression of a
malaria 84472 antigens ([205]). The generalizability of these findings remains to be determined.In pregnancy-associated malaria , transcriptomic analyses of parasites from placental malaria have found modest numbers of differentially
malaria 84533 be determined.In pregnancy-associated malaria, transcriptomic analyses of parasites from placental malaria have found modest numbers of differentially expressed genes other than var2csa, many of which are thought
malaria 84891 var2csa, additional mechanisms of the host-parasite interaction may also play a role in susceptibility to malaria in pregnancy.(c) Host-pathogen interaction.The association between host gene expression and parasite
malaria 85990 one study to date, which used dual RNA-seq to analyze whole blood from uncomplicated P. falciparum malaria cases in Indonesia ([25]). Host innate immune response genes were negatively correlated with parasite
malaria 86868 diagnosis and the prediction of outcomes of infectious diseases. This is particularly important for malaria because while some individuals living in high-transmission settings will have parasitemia, which is
malaria 87036 settings will have parasitemia, which is not the cause of their illness, others will definitely have malaria but despite antimalarial treatment may develop severe disease, and others will have coinfections with
malaria 87060 parasitemia, which is not the cause of their illness, others will definitely have malaria but despite anti malaria l treatment may develop severe disease, and others will have coinfections with malaria and bacterial
malaria 87146 but despite antimalarial treatment may develop severe disease, and others will have coinfections with malaria and bacterial pathogens, both of which require treatment ([11], [27], [28], [132]). Identifying these
malaria 87615 allowing accurate sample size calculations and the use of less-severe endpoints. Given the complexity of malaria pathogenesis, biomarker discovery may provide more than just a disease indicator but also greater insight
malaria 88275 the biomarker predicts the outcome of interest. Most transcriptomic biomarker discovery studies of malaria have not met this standard of evidence; nonetheless, they suggest that robust biomarkers might be found
malaria 88418 evidence; nonetheless, they suggest that robust biomarkers might be found in the future.(i) Diagnosis of malaria .Since we already have good tools to detect Plasmodium using microscopy, point-of-care antigen tests,
malaria 88625 tests, and even PCR-based parasite detection ([11]), the utility of transcriptomics for the diagnosis of malaria may not be obvious. Gene expression signatures can be derived to distinguish diseases that have similar
malaria 89084 form the basis of a rapid test to guide initial clinical management ([210], [211]). In a country where malaria is endemic, any such test would need to be able to distinguish malaria from other febrile illnesses,
malaria 89155 ([210], [211]). In a country where malaria is endemic, any such test would need to be able to distinguish malaria from other febrile illnesses, and so a gene expression signature of malaria would be essential. One
malaria 89231 be able to distinguish malaria from other febrile illnesses, and so a gene expression signature of malaria would be essential. One of the first transcriptomic studies of malaria suggested that this would be
malaria 89302 gene expression signature of malaria would be essential. One of the first transcriptomic studies of malaria suggested that this would be feasible because unsupervised clustering was able to largely separate febrile
malaria 89417 suggested that this would be feasible because unsupervised clustering was able to largely separate febrile malaria from other acute febrile illness ([24]). Clusters were particularly separated based on neutrophil-related
malaria 90945 be considered candidate biomarkers. C1Q was also identified as a putative biomarker of severe human malaria in a pilot study of 10 Malian children ([171]). Seven other candidate markers were all related to the
malaria 91334 been investigated by transcriptomic profiling of parasites taken from children with CM, uncomplicated malaria , and asymptomatic malaria ([212]). Among them, only the comparison between CM and asymptomatic malaria
malaria 91360 transcriptomic profiling of parasites taken from children with CM, uncomplicated malaria, and asymptomatic malaria ([212]). Among them, only the comparison between CM and asymptomatic malaria found differentially expressed
malaria 91437 malaria, and asymptomatic malaria ([212]). Among them, only the comparison between CM and asymptomatic malaria found differentially expressed genes, 99 of which were upregulated and 135 of which were downregulated
malaria 92003 ([212]).(iii) Markers of parasite drug resistance.Resistance to antimicrobial agents, including anti malaria l drugs, is a growing problem ([213], [214]). Widespread resistance could set back many of the gains
malaria 92119 is a growing problem ([213], [214]). Widespread resistance could set back many of the gains made by malaria control initiatives over the last decade ([11], [214]). Artemisinin and its derivatives are the mainstay
malaria 92239 initiatives over the last decade ([11], [214]). Artemisinin and its derivatives are the mainstay of anti malaria l treatment globally, and emerging resistance is starting to spread from foci in Southeast Asia ([11],
malaria 92545 transcriptomic study of 1,043 P. falciparum clinical isolates from 13 regions of Southeast Asia and Africa where malaria is endemic ([216]). The identification of genes significantly associated with the parasite clearance
malaria 93240 falciparum, is implicated in the induction of type I interferons ([127]). The role of type I interferons in malaria has been enigmatic because of conflicting data from animal models indicating roles in both protection
malaria 95246 leukocyte populations in blood, yet there has been disproportionately little investigation of their role in malaria . Higher neutrophil-associated gene expression levels are a consistent feature of analyses of whole-blood
malaria 95823 proportions of neutrophils in blood.Relative neutrophilia is frequently described in human cases of malaria ([221], [222]), particularly in association with severe disease and high-level parasitemia, whereas
malaria 95969 association with severe disease and high-level parasitemia, whereas this is not always the case in rodent malaria models. However, differences in neutrophil counts are not the only explanation. In cases of retinopathy-positive
malaria 96800 elevated circulating levels of their granule proteins are detected in cases of severe and uncomplicated malaria ([221], [224]). Many neutrophil granule proteins can be damaging to host tissues, and it is tempting
malaria 97024 that this indicates a pathogenic mechanism in humans. Female C57BL/6 mice, which are commonly used in malaria research, have among the lowest circulating neutrophil counts of all mouse strains ([225]). Although
malaria 97204 mouse strains ([225]). Although neutrophil mobilization from bone marrow has been described for rodent malaria ([226], [227]), neutrophil counts in peripheral blood can go up or down ([226][227][228]), possibly
malaria 97784 subpopulations ([229], [230]). Despite this, additional evidence supports the roles of neutrophils in malaria -induced lung and liver injury ([220], [228]) and of a neutrophil subpopulation in ECM ([227]). The prominence
malaria 97958 subpopulation in ECM ([227]). The prominence of neutrophil-related gene expression in human cases of malaria clearly indicates that more work is needed to understand exactly what these cells contribute to both
malaria 98587 expression detected between different in vivo situations ([117], [216]), including those under anti malaria l drug pressure, suggest that the in vivo variation can be both substantial and responsive to the within-host
malaria 99349 are animal models and human disease?Although it is clear that there are differences between severe malaria in animal models and human disease ([172], [180], [197]), there is no agreed way to quantify the importance
malaria 99554 importance of the differences or similarities for understanding pathogenesis. This is not unique to malaria research; similar controversies arise for other infectious diseases, such as tuberculosis ([231]), meningococcal
malaria 100843 involvement of the highly polymorphic var, rif, and stevor multigene families in the pathogenesis of severe malaria is attracting increasing interest ([19], [236]), but accurately determining the expression levels of
malaria 102702 protection or pathogenesis. Ideally, we would like to investigate much more specific in vivo interactions in malaria (Fig. 1), for example, mosquito saliva, sporozoites, and skin; Kupffer cells, hepatocytes, and sporozoites;
malaria 103538 from comparisons of different clinical phenotypes. To better understand the pathogenesis of severe malaria , there is a clear need for a dual RNA-seq analysis comparing cases of severe and uncomplicated malaria.
malaria 103641 malaria, there is a clear need for a dual RNA-seq analysis comparing cases of severe and uncomplicated malaria . Deeper insights may be gained from comparisons of subjects with discrete phenotypes of severe malaria,
malaria 103744 malaria. Deeper insights may be gained from comparisons of subjects with discrete phenotypes of severe malaria , such as severe anemia, acidosis/hyperlactatemia, and CM. Comparisons between subjects with malaria
malaria 103844 malaria, such as severe anemia, acidosis/hyperlactatemia, and CM. Comparisons between subjects with malaria and subjects with asymptomatic infection, matched for parasite loads, may be particularly helpful to
malaria 104352 disease may be ineffective because the damage has already been done. There are notably no studies of malaria examining gene expression profiles associated with recovery from severe disease, during the first few
malaria 104495 associated with recovery from severe disease, during the first few days after the initiation of anti malaria l treatment, and such studies may be much more informative for the identification of targets for adjunctive
malaria 104643 more informative for the identification of targets for adjunctive therapies to improve outcomes of malaria and other infectious diseases.Association and causation.Within transcriptomic data sets, it is inevitable
malaria 105238 different biological phenotypes of the outcome of interest. For example, comparisons of uncomplicated malaria with each of the different phenotypes of severe malaria (hyperlactatemia, CM, and severe anemia) may
malaria 105294 interest. For example, comparisons of uncomplicated malaria with each of the different phenotypes of severe malaria (hyperlactatemia, CM, and severe anemia) may reveal gene expression common to all severe phenotypes
malaria 106263 samples. A seminal example is the use of the protective effect of sickle-cell trait against developing malaria to demonstrate that malaria causes susceptibility to bacterial infections in humans ([242]). A similar
malaria 106291 the use of the protective effect of sickle-cell trait against developing malaria to demonstrate that malaria causes susceptibility to bacterial infections in humans ([242]). A similar approach might be employed
malaria 107184 treatments in clinical trials.Lessons for Study Design and AnalysisIt is clear that many studies on malaria had suboptimal elements in their design. Principles for improving the design of malaria studies will
malaria 107272 studies on malaria had suboptimal elements in their design. Principles for improving the design of malaria studies will also apply to many other infectious diseases (Table 2). The overarching principle is that
malaria 108631 interest may influence the association between gene expression and outcomeLikelihood of symptomatic malaria or asymptomatic parasitemia is influenced by age, prior exposure, and parasite loadCollect data on known
malaria 109728 certain features of study designHigher type I interferon response gene expression levels in uncomplicated malaria than in severe malaria (Is it protective?)Compare graded outcomes for gene expression “dose-response”
malaria 109751 designHigher type I interferon response gene expression levels in uncomplicated malaria than in severe malaria (Is it protective?)Compare graded outcomes for gene expression “dose-response” relationships; use
malaria 111139 confounders cannot be achievedAdjustment for parasite load in comparison of cases of severe and uncomplicated malaria Logistic and linear regression models can be implemented in many transcriptomic analysis toolsDiscovery
malaria 111521 predictionWhich combination of transcripts best predicts clinical deterioration in a child with uncomplicated malaria Apply variable selection algorithms to a training data set; confirm with a separate test data set; validate
malaria 112017 availableTRANSCRIPTOMICS IN FUTURE HOST-PATHOGEN RESEARCHFifteen years of transcriptomic studies of malaria have brought many insights but also highlighted the complexity and challenges of studying host-pathogen
tuberculosis 88826 have similar clinical presentations, such as distinguishing bacterial from viral infection ([208]) or tuberculosis from nontuberculous infection ([209]), demonstrating a proof of principle that each disease has a unique
tuberculosis 99639 not unique to malaria research; similar controversies arise for other infectious diseases, such as tuberculosis ([231]), meningococcal disease ([232]), and typhoid ([233]). One way to objectively identify similarities
tuberculosis 100050 will be comparisons of blood transcriptomes between humans and rodent models, as has been tried for tuberculosis ([231]), but comparisons with other tissues will also be needed for a complete understanding ([234]).
tuberculosis 112620 streptococcal infections; establishing the mechanisms underlying clearance, latency, or progression in tuberculosis ; and defining protective and harmful host-pathogen interactions in emerging infections, such as Ebola
vaccinia 54878 from two other studies with the vaccine antigen, using either two doses of RTS,S followed by modified vaccinia virus Ankara (MVA)-vectored CSP or two doses of DNA multiple-epitope thrombospondin-related adhesive
yellow fever 51381 particular success in identifying vaccine-induced protective immune responses for viral infections such as yellow fever and influenza ([146], [147]), catalyzing the development of the new discipline of systems vaccinology

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