RESUMO
Maintaining the correct number of healthy red blood cells (RBCs) is critical for proper oxygenation of tissues throughout the body. Therefore, RBC homeostasis is a tightly controlled balance between RBC production and RBC clearance, through the processes of erythropoiesis and macrophage hemophagocytosis, respectively. However, during the inflammation associated with infectious, autoimmune, or inflammatory diseases this homeostatic process is often dysregulated, leading to acute or chronic anemia. In each disease setting, multiple mechanisms typically contribute to the development of inflammatory anemia, impinging on both sides of the RBC production and RBC clearance equation. These mechanisms include both direct and indirect effects of inflammatory cytokines and innate sensing. Here, we focus on common innate and adaptive immune mechanisms that contribute to inflammatory anemias using examples from several diseases, including hemophagocytic lymphohistiocytosis/macrophage activation syndrome, severe malarial anemia during Plasmodium infection, and systemic lupus erythematosus, among others.
Assuntos
Anemia , Malária , Humanos , Animais , Anemia/complicações , Eritropoese/fisiologia , Eritrócitos , Malária/complicações , MacrófagosRESUMO
Malaria is estimated by the World Health Organization (WHO) to have killed 627,000 individuals worldwide in 2020, with nearly 80% of deaths in African children younger than five. The recent WHO approval of the RTS,S/AS01 vaccine, which targets Plasmodium falciparum pre-erythrocytic stages, provides hope that its use combined with other interventions can help reverse the current malaria resurgence.
Assuntos
Vacinas Antimaláricas , Malária Falciparum , Malária , Criança , Humanos , Lactente , Malária/prevenção & controle , Malária Falciparum/prevenção & controle , Plasmodium falciparumRESUMO
Malaria is a mosquito-borne disease caused by parasites of the obligate intracellular Apicomplexa phylum the most deadly of which, Plasmodium falciparum, prevails in Africa. Malaria imposes a huge health burden on the world's most vulnerable populations, claiming the lives of nearly one million children and pregnant women each year. Although there is keen interest in eradicating malaria, we do not yet have the necessary tools to meet this challenge, including an effective malaria vaccine and adequate vector control strategies. Here we review what is known about the mechanisms at play in immune resistance to malaria in both the human and mosquito hosts at each step in the parasite's complex life cycle with a view toward developing the tools that will contribute to the prevention of disease and death and, ultimately, to the goal of malaria eradication. In so doing, we hope to inspire immunologists to participate in defeating this devastating disease.
Assuntos
Culicidae/imunologia , Interações Hospedeiro-Patógeno/imunologia , Malária/imunologia , Plasmodium/imunologia , Animais , Culicidae/parasitologia , Humanos , Estágios do Ciclo de Vida , Malária/parasitologia , Malária/prevenção & controle , Plasmodium/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/imunologiaRESUMO
All of science takes place amidst a world shaken by uncertainty, social and political upheaval, and challenges to truthful testimony. Just at the moment in which increasing control over biology has been theorized, our social world has become increasingly contentious and its values more divisive. Using the example of gene drives for malaria control to explore the problem of deep uncertainty in biomedical research, I argue that profound uncertainty is an essential feature. Applying the language and presumptions of the discipline of philosophical ethics, I describe three types of uncertainty that raise ethical challenges in scientific research. Rather than mitigate these challenges with excessive precautions and limits on progress, I suggest that researchers can cultivate classic values of veracity, courage, humility, and fidelity in their research allowing science to proceed ethically under conditions of deep uncertainty.
Assuntos
Ética em Pesquisa , Pesquisadores , Incerteza , Sistemas CRISPR-Cas/genética , Epigênese Genética , Genética , Humanos , Malária/genética , Malária/prevenção & controle , RiscoRESUMO
In this issue of Cell, Ma et al. reveal a mechanistic role for PIEZO1 in iron homeostasis through molecular genetic mouse studies. They also demonstrate implications for human iron overload and deficiency syndromes, susceptibility to malarial infection, and red blood cell turnover in persons of African ancestries.
Assuntos
Ferro , Malária , Animais , Eritrócitos , Homeostase , Humanos , Canais Iônicos/genética , CamundongosRESUMO
Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria. Although a standard mRNA vaccine was unable to generate liver Trm or protect against challenge with Plasmodium berghei sporozoites in mice, addition of an agonist that recruits T cell help from type I natural killer T cells under mRNA-vaccination conditions resulted in significant generation of liver Trm cells and effective protection. Moreover, whereas previous exposure of mice to blood-stage infection impaired traditional vaccines based on attenuated sporozoites, mRNA vaccination was unaffected, underlining the potential for such a rational mRNA-based strategy in malaria-endemic regions.
Assuntos
Vacinas Antimaláricas , Malária , Animais , Camundongos , Células T de Memória , Malária/prevenção & controle , Fígado , Plasmodium berghei/genética , Linfócitos T CD8-PositivosRESUMO
Malaria is a prominent vector-borne illness caused by Plasmodium parasites. Therapeutic intervention remains a critical component for disease eradication efforts but is complicated by the emergence of drug resistance. This SnapShot summarizes the human-relevant stages of the P. falciparum life cycle and describes how licensed antimalarials, clinical candidates, and newly emerging compounds target each stage to prevent, treat, or block transmission of malaria. To view this SnapShot, open or download the PDF.
Assuntos
Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Erradicação de Doenças , Resistência a Medicamentos , Humanos , Malária/parasitologia , Malária Falciparum/parasitologia , Plasmodium/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacosRESUMO
Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.
Assuntos
Proteínas de Transporte de Monossacarídeos/ultraestrutura , Plasmodium falciparum/metabolismo , Plasmodium falciparum/ultraestrutura , Proteínas de Protozoários/ultraestrutura , Sequência de Aminoácidos , Animais , Antimaláricos , Transporte Biológico , Glucose/metabolismo , Humanos , Malária , Malária Falciparum/parasitologia , Proteínas de Transporte de Monossacarídeos/química , Proteínas de Transporte de Monossacarídeos/metabolismo , Parasitos , Plasmodium falciparum/genética , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Açúcares/metabolismoRESUMO
Transmission of malaria parasites occurs when a female Anopheles mosquito feeds on an infected host to acquire nutrients for egg development. How parasites are affected by oogenetic processes, principally orchestrated by the steroid hormone 20-hydroxyecdysone (20E), remains largely unknown. Here we show that Plasmodium falciparum development is intimately but not competitively linked to processes shaping Anopheles gambiae reproduction. We unveil a 20E-mediated positive correlation between egg and oocyst numbers; impairing oogenesis by multiple 20E manipulations decreases parasite intensities. These manipulations, however, accelerate Plasmodium growth rates, allowing sporozoites to become infectious sooner. Parasites exploit mosquito lipids for faster growth, but they do so without further affecting egg development. These results suggest that P. falciparum has adopted a non-competitive evolutionary strategy of resource exploitation to optimize transmission while minimizing fitness costs to its mosquito vector. Our findings have profound implications for currently proposed control strategies aimed at suppressing mosquito populations.
Assuntos
Ecdisterona/metabolismo , Interações Hospedeiro-Parasita/fisiologia , Malária Falciparum/parasitologia , Animais , Anopheles/parasitologia , Culicidae , Ecdisterona/fisiologia , Feminino , Células HEK293 , Humanos , Insetos Vetores , Malária/parasitologia , Camundongos , Mosquitos Vetores , Células NIH 3T3 , Oogênese/fisiologia , Plasmodium/metabolismo , Plasmodium falciparum , Esporozoítos , Esteroides/metabolismoRESUMO
Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of the African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro. The existence of a gain-of-function PIEZO1 at such high frequencies is surprising and suggests an association with malaria resistance.
Assuntos
Anemia Hemolítica Congênita/patologia , População Negra/genética , Hidropisia Fetal/patologia , Canais Iônicos/genética , Malária/patologia , Alelos , Anemia Hemolítica Congênita/genética , Animais , Desidratação , Modelos Animais de Doenças , Eritrócitos/citologia , Eritrócitos/metabolismo , Deleção de Genes , Genótipo , Humanos , Hidropisia Fetal/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/deficiência , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais Iônicos/química , Malária/genética , Malária/parasitologia , Malária/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/patogenicidade , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
Plasmodium parasite-specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against Plasmodium takes many years and multiple rounds of infection and cure. Here, we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the germinal center reaction, limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current model describing the role and function of blood-stage Plasmodium-induced plasmablasts but they also reveal new targets and strategies to improve anti-Plasmodium humoral immunity.
Assuntos
Imunidade Humoral , Malária/imunologia , Plasmócitos/metabolismo , Plasmodium falciparum/imunologia , Adolescente , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/metabolismo , Animais , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Anticorpos Antiprotozoários/metabolismo , Antimaláricos/administração & dosagem , DNA de Protozoário/isolamento & purificação , Modelos Animais de Doenças , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Interações Hospedeiro-Parasita/imunologia , Humanos , Malária/sangue , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Nutrientes/metabolismo , Plasmócitos/imunologia , Plasmócitos/parasitologia , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Estudo de Prova de Conceito , Adulto JovemRESUMO
The dynamics of CD4+ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4+ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (TH1) and follicular helper T (TFH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated TH1 and TFH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between TFH and central memory were revealed, with antimalarials modulating these responses and boosting TH1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4+ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations ( http://haquelab.mdhs.unimelb.edu.au/cd4_memory/ ).
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Memória Imunológica , Malária/imunologia , Plasmodium/imunologia , Transcriptoma , Transferência Adotiva , Animais , Antimaláricos/farmacologia , Biomarcadores , Cromatina/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Malária/parasitologia , Malária/terapia , Camundongos , Plasmodium/efeitos dos fármacosRESUMO
Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Leishmania donovani/fisiologia , Leishmaniose Visceral/imunologia , Malária/imunologia , Proteínas de Membrana/metabolismo , Plasmodium/fisiologia , Animais , Células Cultivadas , Citotoxicidade Imunológica , Modelos Animais de Doenças , Exocitose , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Vesículas Secretórias/metabolismoRESUMO
The development of a transmission-blocking vaccine (TBV) against malaria is hampered by poor understanding of functional antibody responses. In this issue of Immunity, Fabra-Garcia et al., Ivanochko et al., and Tang et al. isolate human monoclonal antibodies against the two most promising TBV candidates, Pfs48/45 and Pfs230, and map the epitopes responsible for potent transmission-reducing activity.
Assuntos
Vacinas Antimaláricas , Malária Falciparum , Malária , Humanos , Malária Falciparum/prevenção & controle , Proteínas de Protozoários , Anticorpos Antiprotozoários , Malária/prevenção & controle , Plasmodium falciparum , Antígenos de ProtozoáriosRESUMO
Malaria transmission-blocking vaccines (TBVs) aim to induce antibodies that interrupt malaria parasite development in the mosquito, thereby blocking onward transmission, and provide a much-needed tool for malaria control and elimination. The parasite surface protein Pfs48/45 is a leading TBV candidate. Here, we isolated and characterized a panel of 81 human Pfs48/45-specific monoclonal antibodies (mAbs) from donors naturally exposed to Plasmodium parasites. Genetically diverse mAbs against each of the three domains (D1-D3) of Pfs48/45 were identified. The most potent mAbs targeted D1 and D3 and achieved >80% transmission-reducing activity in standard membrane-feeding assays, at 10 and 2 µg/mL, respectively. Co-crystal structures of D3 in complex with four different mAbs delineated two conserved protective epitopes. Altogether, these Pfs48/45-specific human mAbs provide important insight into protective and non-protective epitopes that can further our understanding of transmission and inform the design of refined malaria transmission-blocking vaccine candidates.
Assuntos
Culicidae , Vacinas Antimaláricas , Malária Falciparum , Malária , Animais , Humanos , Plasmodium falciparum , Culicidae/metabolismo , Proteínas de Protozoários , Anticorpos Monoclonais , Malária Falciparum/prevenção & controle , Anticorpos AntiprotozoáriosRESUMO
Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes. This dichotomy relied on liver stage-dependent activation of Vγ4+ γδ T cells. Subsequent blood stage parasite loads dictated their cytokine profiles, where low parasite loads preferentially expanded IL-17-producing γδ T cells. IL-17 drove extra-medullary erythropoiesis and concomitant reticulocytosis, which protected mice from lethal experimental cerebral malaria (ECM). Adoptive transfer of erythroid precursors could rescue mice from ECM. Modeling of γδ T cell dynamics suggests that this protective mechanism may be key for the establishment of naturally acquired malaria immunity among frequently exposed individuals.
Assuntos
Eritropoese , Malária Cerebral , Animais , Camundongos , Eritrócitos , Interleucina-17 , Fígado/parasitologia , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T gama-delta , MaláriaRESUMO
Sexual differentiation of the malaria parasite is a pre-requisite for transmission from humans to the mosquito vector and has emerged as a target for intervention in eradication efforts. In this issue of Cell, a study from Marti, Clardy, and colleagues (Brancucci et al., 2017) describes a host-derived lipid lysophosphatidylcholine (LysoPC) that regulates sexual commitment.
Assuntos
Malária , Parasitos , Animais , Diferenciação Celular , Humanos , Lisofosfatidilcolinas , Plasmodium falciparum , Diferenciação SexualRESUMO
Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.
Assuntos
Lisofosfatidilcolinas/metabolismo , Malária/parasitologia , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Animais , Feminino , Humanos , Malária/imunologia , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/fisiologia , ReproduçãoRESUMO
Poor biochemical characteristics have severely hampered the development of the promising malaria transmission-blocking vaccine candidate Pfs48/45. In this issue of Immunity, McLeod et al. applied structure-guided vaccine design to transform this protein into a stable, high-producing antigen that elicits exceptional blocking antibodies, renewing its promise as a tool to fight malaria.
Assuntos
Vacinas Antimaláricas , Malária , Anticorpos Antiprotozoários , Humanos , Malária/prevenção & controle , Glicoproteínas de Membrana , Proteínas de ProtozoáriosRESUMO
While searching for new therapeutics against malaria, Lanzavecchia and colleagues discovered that antibodies can be diversified by DNA sequences encoded outside of antibody genes.