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1.
Function (Oxf) ; 5(3): zqae009, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38706961

RESUMO

Global prevalence of hypertension is on the rise, burdening healthcare, especially in developing countries where infectious diseases, such as malaria, are also rampant. Whether hypertension could predispose or increase susceptibility to malaria, however, has not been extensively explored. Previously, we reported that hypertension is associated with abnormal red blood cell (RBC) physiology and anemia. Since RBC are target host cells for malarial parasite, Plasmodium, we hypothesized that hypertensive patients with abnormal RBC physiology are at greater risk or susceptibility to Plasmodium infection. To test this hypothesis, normotensive (BPN/3J) and hypertensive (BPH/2J) mice were characterized for their RBC physiology and subsequently infected with Plasmodium yoelii (P. yoelii), a murine-specific non-lethal strain. When compared to BPN mice, BPH mice displayed microcytic anemia with RBC highly resistant to osmotic hemolysis. Further, BPH RBC exhibited greater membrane rigidity and an altered lipid composition, as evidenced by higher levels of phospholipids and saturated fatty acid, such as stearate (C18:0), along with lower levels of polyunsaturated fatty acid like arachidonate (C20:4). Moreover, BPH mice had significantly greater circulating Ter119+ CD71+ reticulocytes, or immature RBC, prone to P. yoelii infection. Upon infection with P. yoelii, BPH mice experienced significant body weight loss accompanied by sustained parasitemia, indices of anemia, and substantial increase in systemic pro-inflammatory mediators, compared to BPN mice, indicating that BPH mice were incompetent to clear P. yoelii infection. Collectively, these data demonstrate that aberrant RBC physiology observed in hypertensive BPH mice contributes to an increased susceptibility to P. yoelii infection and malaria-associated pathology.


Assuntos
Eritrócitos , Hipertensão , Malária , Plasmodium yoelii , Animais , Malária/imunologia , Malária/parasitologia , Malária/complicações , Malária/sangue , Malária/fisiopatologia , Camundongos , Eritrócitos/parasitologia , Eritrócitos/metabolismo , Suscetibilidade a Doenças , Masculino , Anemia/parasitologia , Modelos Animais de Doenças , Hemólise
3.
Infect Immun ; 92(5): e0011324, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38624215

RESUMO

Malaria, one of the major infectious diseases in the world, is caused by the Plasmodium parasite. Plasmodium antigens could modulate the inflammatory response by binding to macrophage membrane receptors. As an export protein on the infected erythrocyte membrane, Plasmodium surface-related antigen (SRA) participates in the erythrocyte invasion and regulates the immune response of the host. This study found that the F2 segment of P. yoelii SRA activated downstream MAPK and NF-κB signaling pathways by binding to CD68 on the surface of the macrophage membrane and regulating the inflammatory response. The anti-PySRA-F2 antibody can protect mice against P. yoelii, and the pro-inflammatory responses such as IL-1ß, TNF-α, and IL-6 after infection with P. yoelii are attenuated. These findings will be helpful for understanding the involvement of the pathogenic mechanism of malaria with the exported protein SRA.


Assuntos
Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Macrófagos , Malária , Plasmodium yoelii , Plasmodium yoelii/imunologia , Animais , Camundongos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Malária/imunologia , Malária/parasitologia , Antígenos CD/metabolismo , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígenos de Diferenciação Mielomonocítica/imunologia , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/metabolismo , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Humanos , Feminino , Antígenos de Superfície/imunologia , Antígenos de Superfície/metabolismo , Ligação Proteica , Transdução de Sinais , NF-kappa B/metabolismo , NF-kappa B/imunologia , Membrana Celular/metabolismo , Membrana Celular/imunologia , Inflamação/imunologia , Inflamação/metabolismo
4.
J Immunol ; 212(9): 1467-1478, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38477614

RESUMO

Development of Plasmodium-specific humoral immunity is critically dependent on CD4 Th cell responses and germinal center (GC) reactions during blood-stage Plasmodium infection. IL-21, a cytokine primarily produced by CD4 T cells, is an essential regulator of affinity maturation, isotype class-switching, B cell differentiation, and maintenance of GC reactions in response to many infection and immunization models. In models of experimental malaria, mice deficient in IL-21 or its receptor IL-21R fail to develop memory B cell populations and are not protected against secondary infection. However, whether sustained IL-21 signaling in ongoing GCs is required for maintaining GC magnitude, organization, and output is unclear. In this study, we report that CD4+ Th cells maintain IL-21 expression after resolution of primary Plasmodium yoelii infection. We generated an inducible knockout mouse model that enabled cell type-specific and timed deletion of IL-21 in peripheral, mature CD4 T cells. We found that persistence of IL-21 signaling in active GCs had no impact on the magnitude of GC reactions or their capacity to produce memory B cell populations. However, the memory B cells generated in the absence of IL-21 exhibited reduced recall function upon challenge. Our data support that IL-21 prevents premature cellular dissolution within the GC and promotes stringency of selective pressures during B cell fate determination required to produce high-quality Plasmodium-specific memory B cells. These data are additionally consistent with a temporal requirement for IL-21 in fine-tuning humoral immune memory responses during experimental malaria.


Assuntos
Linfócitos T CD4-Positivos , Interleucinas , Malária , Plasmodium , Animais , Camundongos , Linfócitos B , Linfócitos T CD4-Positivos/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Malária/imunologia , Células B de Memória/imunologia , Camundongos Endogâmicos C57BL , Plasmodium/imunologia
5.
Parasitology ; 151(4): 380-389, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38361461

RESUMO

Naturally acquired immunity to the different types of malaria in humans occurs in areas of endemic transmission and results in asymptomatic infection of peripheral blood. The current study examined the possibility of naturally acquired immunity in Bornean orangutans, Pongo pygmaeus, exposed to endemic Plasmodium pitheci malaria. A total of 2140 peripheral blood samples were collected between January 2017 and December 2022 from a cohort of 135 orangutans housed at a natural forested Rescue and Rehabilitation Centre in West Kalimantan, Indonesia. Each individual was observed for an average of 4.3 years during the study period. Blood samples were examined by microscopy and polymerase chain reaction for the presence of plasmodial parasites. Infection rates and parasitaemia levels were measured among age groups and all 20 documented clinical malaria cases were reviewed to estimate the incidence of illness and risk ratios among age groups. A case group of all 17 individuals that had experienced clinical malaria and a control group of 34 individuals having an event of >2000 parasites µL−1 blood but with no outward or clinical sign of illness were studied. Immature orangutans had higher-grade and more frequent parasitaemia events, but mature individuals were more likely to suffer from clinical malaria than juveniles. The case orangutans having patent clinical malaria were 256 times more likely to have had no parasitaemia event in the prior year relative to asymptomatic control orangutans. The findings are consistent with rapidly acquired immunity to P. pitheci illness among orangutans that wanes without re-exposure to the pathogen.


Assuntos
Doenças dos Símios Antropoides , Malária , Plasmodium , Pongo pygmaeus , Animais , Malária/epidemiologia , Malária/imunologia , Malária/parasitologia , Plasmodium/imunologia , Indonésia/epidemiologia , Pongo pygmaeus/parasitologia , Masculino , Feminino , Doenças dos Símios Antropoides/parasitologia , Doenças dos Símios Antropoides/epidemiologia , Parasitemia/veterinária , Parasitemia/epidemiologia , Parasitemia/parasitologia , Incidência
6.
Parasitol Res ; 122(11): 2513-2524, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37707607

RESUMO

CD103 is an important marker of tissue-resident memory T cells (TRM) which play important roles in fighting against infection. However, the immunological characteristics of CD103+ T cells are not thoroughly elucidated in the liver of mouse infected with Plasmodium. Six- to eight-week-old C57BL/6 mice were infected with Plasmodium yoelii nigeriensis NSM. Mice were sacrificed on 12-16 days after infection and the livers were picked out. Sections of the livers were stained, and serum aspartate aminotransferase (AST) and alanine transaminase (ALT) levels were measured. Moreover, lymphocytes in the liver were isolated, and the expression of CD103 was determined by using qPCR. The percentage of CD103 on different immune cell populations was dynamically observed by using flow cytometry (FCM). In addition, the phenotype and cytokine production characteristics of CD103+CD8+ Tc cell were analyzed by using flow cytometry, respectively. Erythrocyte stage plasmodium infection could result in severe hepatic damage, a widespread inflammatory response and the decrease of CD103 expression on hepatic immune cells. Only CD8+ Tc and γδT cells expressed higher levels of CD103 in the uninfected state.CD103 expression in CD8+ Tc cells significantly decreased after infection. Compared to that of CD103- CD8+ Tc cells, CD103+ CD8+ Tc cells from the infected mice expressed lower level of CD69, higher level of CD62L, and secreted more IL-4, IL-10, IL-17, and secreted less IFN-γ. CD103+CD8+ Tc cells might mediate the hepatic immune response by secreting IL-4, IL-10, and IL-17 except IFN-γ in the mice infected with the erythrocytic phase plasmodium, which could be involved in the pathogenesis of severe liver damage resulted from the erythrocytic phase plasmodium yoelii nigeriensis NSM infection.


Assuntos
Malária , Plasmodium yoelii , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Interleucina-10/metabolismo , Interleucina-17 , Interleucina-4 , Fígado , Malária/imunologia , Malária/metabolismo , Camundongos Endogâmicos C57BL
8.
Front Immunol ; 14: 1140426, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36993971

RESUMO

Introduction: This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP). Methods: In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation. Results: We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. Conclusion: These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.


Assuntos
Glicólise , Malária , Receptores Purinérgicos P2X7 , Células Th1 , Animais , Camundongos , Camundongos Endogâmicos C57BL , Receptores Purinérgicos P2X7/metabolismo , Células Th1/citologia , Células Th1/metabolismo , Diferenciação Celular , Plasmodium chabaudi , Malária/imunologia , Trifosfato de Adenosina , Adenosina Trifosfatases , Mitocôndrias/metabolismo , Proteínas com Domínio T/metabolismo , Fosforilação Oxidativa , Transdução de Sinais , Células Cultivadas
9.
Curr Med Chem ; 30(39): 4450-4465, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36748809

RESUMO

Although the burden of malaria has been successfully controlled globally, this disease remains a major public health issue. To date, neither existing drugs nor vaccines against malaria are sufficient in eliminating malaria worldwide. To achieve the eradication of malaria by 2040, effective interventions targeting all Plasmodium species are urgently needed. As the cornerstone of vaccine design, immune memory serves a significant role in the host's defense against Plasmodium infections. It has long been considered that innate immunity is non-specific and lacks immunologic memory. However, emerging evidence has suggested that innate immunity can be trained following exposure of the body to infectious agents, such as Plasmodium or its products, which, in turn, promotes the onset of a type of memory in innate immune cells. The above "trained" innate immune cells, whose phenotype is modified in response to epigenetic modifications, metabolic recombination, or cytokine secretion, exhibit differential pathophysiology after the exposure of the body to a pathogen. In addition, Plasmodium-infected red blood cells and other host cells can secrete exosomes that contain conserved parasite-specific information, such as proteins, RNA, non-coding RNA molecules, and nucleic acids. These molecules can act as stimuli for promoting the establishment of "trained" innate immunity against malaria, thereby altering the onset and progression of the parasitic disease. A deeper understanding of the role of exosomes in the development of "trained" innate immunity during Plasmodium infection could provide novel therapeutic and prevention strategies against malaria infections.


Assuntos
Imunidade Inata , Malária , Plasmodium , Plasmodium/imunologia , Malária/imunologia , Malária/terapia , Vesículas Extracelulares/imunologia , Humanos , Animais , Vacinas Antimaláricas/imunologia
10.
Nature ; 611(7936): 563-569, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36352220

RESUMO

Malaria infection involves an obligatory, yet clinically silent liver stage1,2. Hepatocytes operate in repeating units termed lobules, exhibiting heterogeneous gene expression patterns along the lobule axis3, but the effects of hepatocyte zonation on parasite development at the molecular level remain unknown. Here we combine single-cell RNA sequencing4 and single-molecule transcript imaging5 to characterize the host and parasite temporal expression programmes in a zonally controlled manner for the rodent malaria parasite Plasmodium berghei ANKA. We identify differences in parasite gene expression in distinct zones, including potentially co-adaptive programmes related to iron and fatty acid metabolism. We find that parasites develop more rapidly in the pericentral lobule zones and identify a subpopulation of periportally biased hepatocytes that harbour abortive infections, reduced levels of Plasmodium transcripts and parasitophorous vacuole breakdown. These 'abortive hepatocytes', which appear predominantly with high parasite inoculum, upregulate immune recruitment and key signalling programmes. Our study provides a resource for understanding the liver stage of Plasmodium infection at high spatial resolution and highlights the heterogeneous behaviour of both the parasite and the host hepatocyte.


Assuntos
Regulação da Expressão Gênica , Hepatócitos , Fígado , Malária , Parasitos , Plasmodium berghei , Análise de Célula Única , Animais , Hepatócitos/citologia , Hepatócitos/imunologia , Hepatócitos/metabolismo , Hepatócitos/parasitologia , Fígado/anatomia & histologia , Fígado/citologia , Fígado/imunologia , Fígado/parasitologia , Malária/genética , Malária/imunologia , Malária/parasitologia , Parasitos/genética , Parasitos/imunologia , Parasitos/metabolismo , Plasmodium berghei/genética , Plasmodium berghei/imunologia , Plasmodium berghei/metabolismo , Imagem Individual de Molécula , Análise de Sequência de RNA , Ferro/metabolismo , Ácidos Graxos/metabolismo , Transcrição Gênica , Genes de Protozoários/genética , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia
11.
Parasite Immunol ; 44(12): e12952, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36131528

RESUMO

Severe malaria occurs most in young children but is poorly understood due to the absence of a developmentally-equivalent rodent model to study the pathogenesis of the disease. Though functional and quantitative deficiencies in innate response and a biased T helper 1 (Th1) response are reported in newborn pups, there is little information available about this intermediate stage of the adaptive immune system in murine neonates. To fill this gap in knowledge, we have developed a mouse model of severe malaria in young mice using 15-day old mice (pups) infected with Plasmodium chabaudi. We observe similar parasite growth pattern in pups and adults, with a 60% mortality and a decrease in the growth rate of the surviving young mice. Using a battery of behavioral assays, we observed neurological symptoms in pups that do not occur in infected wildtype adults. CD4+ T cells were activated and differentiated to an effector T cell (Teff) phenotype in both adult and pups. However, there were relatively fewer and less terminally differentiated pup CD4+ Teff than adult Teff. Interestingly, despite less activation, the pup Teff expressed higher T-bet than adults' cells. These data suggest that Th1 cells are functional in pups during Plasmodium infection but develop slowly.


Assuntos
Linfócitos T CD4-Positivos , Malária , Plasmodium chabaudi , Animais , Camundongos , Linfócitos T CD4-Positivos/imunologia , Malária/complicações , Malária/imunologia , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Modelos Animais de Doenças , Doenças do Sistema Nervoso/etiologia
12.
Front Immunol ; 13: 942862, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091043

RESUMO

The morbidity and mortality of malaria are still high. Programmed cell death-1(PD-1) is an important co-inhibitory factor and CD8 T cells with PD-1 were reported to be exhausted cells. It remains unknown what the role of CD4 T cells expressing PD-1 is and what the upstream regulating molecules of PD-1 in CD4 T cells are. The C57BL/6 mice were injected with Plasmodium yoelii (P. yoelii) in this study. Expressions of PD-1, activation markers, and cytokines were tested. The differentially expressed genes between PD-1+/- CD4 T cells were detected by microarray sequencing. Western blot, chromatin immunoprecipitation (ChIP), siRNA, hypoxia inducible factor-1α (HIF-1α) inducer and inhibitor were used to explore PD-1's upstream molecules, respectively. The proportions of PD-1+ CD4 T cells increased post P. yoelii infection. PD-1+ CD4 T cells expressed more activated surface markers and could produce more cytokines. Nuclear factor of activated T cells 1 (NFATc1) was found to be a key transcription factor to induce PD-1 expression after infection. Both the inducer and the inhibitor of HIF-1α could change the expressions of NFATc1 and PD-1 in vivo and in vitro, respectively. Taken together, P. yoelii infection induced NFATc1 expression by HIF-1α. The highly expressed NFATc1 entered the nucleus and initiated PD-1 expression. PD-1+ CD4 T cells appeared to be more activated and could secrete more cytokines to regulate the host's immune responses against malaria.


Assuntos
Linfócitos T CD4-Positivos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Malária , Fatores de Transcrição NFATC , Plasmodium yoelii , Receptor de Morte Celular Programada 1 , Animais , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Malária/genética , Malária/imunologia , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais
13.
Proc Natl Acad Sci U S A ; 119(35): e2209729119, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35994647

RESUMO

Glutaminyl cyclase (QC) modifies N-terminal glutamine or glutamic acid residues of target proteins into cyclic pyroglutamic acid (pGlu). Here, we report the biochemical and functional analysis of Plasmodium QC. We show that sporozoites of QC-null mutants of rodent and human malaria parasites are recognized by the mosquito immune system and melanized when they reach the hemocoel. Detailed analyses of rodent malaria QC-null mutants showed that sporozoite numbers in salivary glands are reduced in mosquitoes infected with QC-null or QC catalytically dead mutants. This phenotype can be rescued by genetic complementation or by disrupting mosquito melanization or phagocytosis by hemocytes. Mutation of a single QC-target glutamine of the major sporozoite surface protein (circumsporozoite protein; CSP) of the rodent parasite Plasmodium berghei also results in melanization of sporozoites. These findings indicate that QC-mediated posttranslational modification of surface proteins underlies evasion of killing of sporozoites by the mosquito immune system.


Assuntos
Aminoaciltransferases , Culicidae , Malária , Processamento de Proteína Pós-Traducional , Esporozoítos , Aminoaciltransferases/imunologia , Animais , Culicidae/imunologia , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Malária/genética , Malária/imunologia , Malária/parasitologia , Plasmodium berghei/genética , Plasmodium berghei/imunologia , Processamento de Proteína Pós-Traducional/imunologia , Proteínas de Protozoários/imunologia , Esporozoítos/imunologia
14.
J Leukoc Biol ; 112(5): 1115-1135, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35657097

RESUMO

Memory B cells (MBCs) are essential for maintaining long-term humoral immunity to infectious organisms, including Plasmodium. MBCs are a heterogeneous population whose function can be dictated by isotype or expression of particular surface proteins. Here, aided by antigen-specific B-cell tetramers, MBC populations were evaluated to discern their phenotype and function in response to infection with a nonlethal strain of P. yoelii. Infection of mice with P. yoelii 17X resulted in 2 predominant MBC populations: somatically hypermutated isotype-switched (IgM- ) and IgM+ MBCs that coexpressed CD73 and CD80 that produced antigen-specific antibodies in response to secondary infection. Rechallenge experiments indicated that IgG-producing cells dominated the recall response over the induction of IgM-secreting cells, with both populations expanding with similar timing during the secondary response. Furthermore, using ZsGreen1 expression as a surrogate for activation-induced cytidine deaminase expression alongside CD73 and CD80 coexpression, ZsGreen1+ CD73+ CD80+ IgM+ , and IgM- MBCs gave rise to plasmablasts that secreted Ag-specific Abs after adoptive transfer and infection with P. yoelii. Moreover, ZsGreen1+ CD73+ CD80+ IgM+ and IgM- MBCs could differentiate into B cells with a germinal center phenotype after adoptive transfer. A third population of B cells (ZsGreen1- CD73- CD80- IgM- ) that is apparent after infection responded poorly to reactivation in vitro and in vivo, indicating that these cells do not represent a canonical population of MBCs. Together these data indicated that MBC function is not defined by immunoglobulin isotype, nor does coexpression of key surface markers limit the potential fate of MBCs after recall.


Assuntos
Memória Imunológica , Malária , Células B de Memória , Animais , Camundongos , Antígeno B7-1 , Citidina Desaminase , Centro Germinativo , Imunoglobulina G , Imunoglobulina M , Células B de Memória/imunologia , Plasmodium yoelii , Malária/imunologia
15.
Adv Sci (Weinh) ; 9(22): e2103701, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35635376

RESUMO

Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) play critical roles in the innate immunity against infectious diseases and are required to link pathogen DNA sensing to immune responses. However, the mechanisms by which cGAS-STING-induced cytokines suppress the adaptive immune response against malaria infections remain poorly understood. Here, cGAS-STING signaling is identified to play a detrimental role in regulating anti-malaria immunity. cGAS or STING deficiency in mice markedly prolongs mouse survival during lethal malaria Plasmodium yoelii nigeriensis N67C infections by reducing late interleukin (IL)-6 production. Mechanistically, cGAS/STING recruits myeloid differentiation factor 88 (MyD88) and specifically induces the p38-dependent signaling pathway for late IL-6 production, which, in turn, expands CD11b+ Ly6Chi proinflammatory monocytes to inhibit immunity. Moreover, the blockage or ablation of the cGAS-STING-MyD88-p38-IL-6 signaling axis or the depletion of CD11b+ Ly6Chi proinflammatory monocytes provides mice a significant survival benefit during N67C and other lethal malaria-strain infections. Taken together, these findings identify a previously unrecognized detrimental role of cGAS-STING-MyD88-p38 axis in infectious diseases through triggering the late IL-6 production and proinflammatory monocyte expansion and provide insight into how targeting the DNA sensing pathway, dysregulated cytokines, and proinflammatory monocytes enhances immunity against infection.


Assuntos
Malária , Monócitos , Animais , DNA , Interleucina-6/metabolismo , Malária/imunologia , Malária/mortalidade , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Monócitos/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo
16.
Front Immunol ; 13: 795463, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35197971

RESUMO

Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral 'TRM-like' cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM-like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach.


Assuntos
Vacinas Antimaláricas/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Vetores Genéticos , Hepatócitos/imunologia , Humanos , Imunidade Celular , Memória Imunológica/imunologia , Fígado/imunologia , Malária/imunologia , Plasmodium/imunologia , Esporozoítos/imunologia , Transcriptoma , Vacinação
17.
Nat Commun ; 13(1): 976, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35190534

RESUMO

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period (n = 5642 blood specimens, n = 3814 children ages 1-59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger.


Assuntos
Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Mortalidade da Criança , Imunoglobulina G/sangue , Administração Massiva de Medicamentos , Infecções por Campylobacter/sangue , Infecções por Campylobacter/imunologia , Infecções por Campylobacter/mortalidade , Infecções por Campylobacter/prevenção & controle , Criança , Pré-Escolar , Criptosporidiose/sangue , Criptosporidiose/imunologia , Criptosporidiose/mortalidade , Criptosporidiose/parasitologia , Farmacorresistência Bacteriana , Infecções por Escherichia coli/sangue , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/mortalidade , Infecções por Escherichia coli/prevenção & controle , Seguimentos , Giardíase/sangue , Giardíase/imunologia , Giardíase/mortalidade , Giardíase/parasitologia , Humanos , Imunoglobulina G/imunologia , Lactente , Malária/sangue , Malária/imunologia , Malária/mortalidade , Malária/parasitologia , Níger/epidemiologia , População Rural/estatística & dados numéricos , Infecções por Salmonella/sangue , Infecções por Salmonella/imunologia , Infecções por Salmonella/mortalidade , Infecções por Salmonella/prevenção & controle
18.
Malar J ; 21(1): 32, 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35109868

RESUMO

BACKGROUND: Regulatory T cells are known to play a key role to counter balance the protective immune response and immune mediated pathology. However, the role of naturally occurring regulatory cells CD4+CD25+Foxp3+ in malaria infection during the disease pathogenesis is controversial. Beside this, ICOS molecule has been shown to be involved in the development and function of regulatory T cell enhance IL-10 production. Therefore, possible involvement of the ICOS dependent regulatory CD4+ICOS+Foxp3+ T cells in resistance/susceptibility during malaria parasite is explored in this study. METHODS: 5 × 105 red blood cells infected with non-lethal and lethal parasites were inoculated in female Balb/c mice by intra-peritoneal injection. Infected or uninfected mice were sacrificed at early (3rd day post infection) and later stage (10th day post infection) of infection. Harvested cells were analysed by using flow cytometer and serum cytokine by Bioplex assay. RESULTS: Thin blood films show that percentages of parasitaemia increases with disease progression in infections with the lethal malaria parasite and mice eventually die by day 14th post-infection. Whereas in case of non-lethal malaria parasite, parasitaemia goes down by 7th day post infection and gets cleared within 13th day. The number of CD4+ ICOS+ T cells increases in lethal infection with disease progression. Surprisingly, in non-lethal parasite, ICOS expression decreases after day 7th post infection as parasitaemia goes down. The frequency of CD4+ICOS+FoxP3+ Tregs was significantly higher in lethal parasitic infection as compared to the non-lethal parasite. The level of IL-12 cytokine was remarkably higher in non-lethal infection compared to the lethal infection. In contrast, the level of IL-10 cytokines was higher in lethal parasite infection compared to the non-lethal parasite. CONCLUSION: Taken together, these data suggest that lethal parasite induce immunosuppressive environment, protecting from host immune responses and help the parasite to survive whereas non-lethal parasite leads to low frequencies of Treg cells seldom impede immune response that allow the parasite to get self-resolved.


Assuntos
Malária/etiologia , Linfócitos T Reguladores/fisiologia , Animais , Antígenos CD4/fisiologia , Citocinas/análise , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/fisiologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/fisiologia , Interleucina-10/análise , Malária/diagnóstico , Malária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Parasitemia/diagnóstico , Parasitemia/parasitologia , Fragmentos de Peptídeos/fisiologia , Plasmodium berghei , Plasmodium chabaudi , Plasmodium yoelii , Organismos Livres de Patógenos Específicos , Baço/citologia
19.
Front Immunol ; 13: 801120, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154114

RESUMO

An increase in mast cells (MCs) and MCs mediators has been observed in malaria-associated bacteremia, however, the role of these granulocytes in malarial immunity is poorly understood. Herein, we studied the role of mouse MC protease (Mcpt) 4, an ortholog of human MC chymase, in malaria-induced bacteremia using Mcpt4 knockout (Mcpt4-/-) mice and Mcpt4+/+ C57BL/6J controls, and the non-lethal mouse parasite Plasmodium yoelii yoelii 17XNL. Significantly lower parasitemia was observed in Mcpt4-/- mice compared with Mcpt4+/+ controls by day 10 post infection (PI). Although bacterial 16S DNA levels in blood were not different between groups, increased intestinal permeability to FITC-dextran and altered ileal adherens junction E-cadherin were observed in Mcpt4-/- mice. Relative to infected Mcpt4+/+ mice, ileal MC accumulation in Mcpt4-/- mice occurred two days earlier and IgE levels were higher by days 8-10 PI. Increased levels of circulating myeloperoxidase were observed at 6 and 10 days PI in Mcpt4+/+ but not Mcpt4-/- mice, affirming a role for neutrophil activation that was not predictive of parasitemia or bacterial 16S copies in blood. In contrast, early increased plasma levels of TNF-α, IL-12p40 and IL-3 were observed in Mcpt4-/- mice, while levels of IL-2, IL-10 and MIP1ß (CCL4) were increased over the same period in Mcpt4+/+ mice, suggesting that the host response to infection was skewed toward a type-1 immune response in Mcpt4-/- mice and type-2 response in Mcpt4+/+ mice. Spearman analysis revealed an early (day 4 PI) correlation of Mcpt4-/- parasitemia with TNF-α and IFN-γ, inflammatory cytokines known for their roles in pathogen clearance, a pattern that was observed in Mcpt4+/+ mice much later (day 10 PI). Transmission success of P. y. yoelii 17XNL to Anopheles stephensi was significantly higher from infected Mcpt4-/- mice compared with infected Mcpt4+/+ mice, suggesting that Mcpt4 also impacts transmissibility of sexual stage parasites. Together, these results suggest that early MCs activation and release of Mcpt4 suppresses the host immune response to P. y. yoelii 17XNL, perhaps via degradation of TNF-α and promotion of a type-2 immune response that concordantly protects epithelial barrier integrity, while limiting the systemic response to bacteremia and parasite transmissibility.


Assuntos
Anopheles/parasitologia , Permeabilidade da Membrana Celular/imunologia , Quimases/genética , Quimases/imunologia , Interações Hospedeiro-Parasita/imunologia , Malária/imunologia , Mastócitos/enzimologia , Plasmodium yoelii/imunologia , Animais , Feminino , Íleo/citologia , Íleo/patologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismo
20.
Infect Genet Evol ; 98: 105210, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35031509

RESUMO

γδ T cells are thymus derived heterogeneous and unconventional T- lymphocyte expressing TCR γ (V γ9) and TCRδ (Vδ2) chain and play an important role in connecting innate and adaptive armaments of immune response. These cells can recognize wide ranges of antigens even without involvement of major histocompatibility complex and exert their biological functions by cytotoxicity or activating various types of immune cells. In recent past, γδ T cells have emerged as an important player during protozoa infection and rapidly expand after exposure with them. They have also been widely studied in vaccine induced immune response against many bacterial and protozoan infections with improved clinical outcome. In this review, we will discuss the various roles of γδ T cells in immunity against malaria and leishmaniasis, the two important protozoan diseases causing significant mortality and morbidity throughout the world.


Assuntos
Imunidade Inata , Linfócitos Intraepiteliais/imunologia , Leishmaniose/imunologia , Malária/imunologia , Humanos
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