Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 237
Filtrar
2.
Nature ; 621(7977): 196-205, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37612507

RESUMO

Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.


Assuntos
Envelhecimento Saudável , Hialuronan Sintases , Ácido Hialurônico , Longevidade , Ratos-Toupeira , Animais , Camundongos , Ácido Hialurônico/biossíntese , Ácido Hialurônico/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/prevenção & controle , Camundongos Transgênicos , Ratos-Toupeira/genética , Longevidade/genética , Longevidade/imunologia , Longevidade/fisiologia , Hialuronan Sintases/genética , Hialuronan Sintases/metabolismo , Envelhecimento Saudável/genética , Envelhecimento Saudável/imunologia , Envelhecimento Saudável/fisiologia , Transgenes/genética , Transgenes/fisiologia , Transcriptoma , Neoplasias/genética , Neoplasias/prevenção & controle , Estresse Oxidativo , Gerociência , Rejuvenescimento/fisiologia
3.
Nature ; 614(7949): 762-766, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36653453

RESUMO

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1-3. To provide immunity, transiently stimulated CD8+ T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits. We activated mouse T cells in vivo using acute heterologous prime-boost-boost vaccinations4, transferred expanded cells to new mice, and then repeated this process iteratively. Over 10 years (greatly exceeding the mouse lifespan)5 and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells required sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 1040-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can cause T cell proliferative senescence, functional exhaustion and death6. We found that although iterative acute stimulations also induced sustained expression and epigenetic remodelling of common exhaustion markers (including PD1, which is also known as PDCD1, and TOX) in the cells, they could still proliferate, execute antimicrobial functions and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, cancer and ageing, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan.


Assuntos
Divisão Celular , Senescência Celular , Longevidade , Ativação Linfocitária , Linfócitos T , Animais , Camundongos , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Memória Imunológica , Longevidade/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Linfócitos T/citologia , Linfócitos T/imunologia , Senescência Celular/imunologia , Senescência Celular/fisiologia , Imunização Secundária , Vacinação , Transferência Adotiva , Fatores de Tempo , Infecções/imunologia , Doença Crônica , Epigênese Genética
4.
Elife ; 112022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35129436

RESUMO

Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune-repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune-repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences. Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B-cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system.


Assuntos
Diversidade de Anticorpos/imunologia , Fundulidae/imunologia , Imunossenescência/imunologia , Imunidade Adaptativa/imunologia , Envelhecimento/imunologia , Animais , Linfócitos B/imunologia , Humanos , Longevidade/imunologia , Microbiota/imunologia , Modelos Animais
5.
J Immunol ; 208(5): 1085-1098, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35101890

RESUMO

The development of long-lived immune memory cells against pathogens is critical for the success of vaccines to establish protection against future infections. However, the mechanisms governing the long-term survival of immune memory cells remain to be elucidated. In this article, we show that the maintenance mitochondrial homeostasis by autophagy is critical for restricting metabolic functions to protect IgG memory B cell survival. Knockout of mitochondrial autophagy genes, Nix and Bnip3, leads to mitochondrial accumulation and increases in oxidative phosphorylation and fatty acid synthesis, resulting in the loss of IgG+ memory B cells in mice. Inhibiting fatty acid synthesis or silencing necroptosis gene Ripk3 rescued Nix-/-Bnip3-/- IgG memory B cells, indicating that mitochondrial autophagy is important for limiting metabolic functions to prevent cell death. Our results suggest a critical role for mitochondrial autophagy in the maintenance of immunological memory by protecting the metabolic quiescence and longevity of memory B cells.


Assuntos
Imunoglobulina G/imunologia , Memória Imunológica/imunologia , Células B de Memória/imunologia , Mitocôndrias/metabolismo , Mitofagia/fisiologia , Transferência Adotiva , Animais , Ácidos Graxos/biossíntese , Homeostase/fisiologia , Longevidade/imunologia , Proteínas de Membrana/genética , Células B de Memória/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Necroptose/genética , Fosforilação Oxidativa , Interferência de RNA , RNA Interferente Pequeno/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
6.
Nat Immunol ; 23(2): 303-317, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34949833

RESUMO

Antigen-specific memory CD4+ T cells can persist and confer rapid and efficient protection from microbial reinfection. However, the mechanisms underlying the long-term maintenance of the memory CD4+ T cell pool remain largely unknown. Here, using a mouse model of acute infection with lymphocytic choriomeningitis virus (LCMV), we found that the serine/threonine kinase complex mammalian target of rapamycin complex 2 (mTORC2) is critical for the long-term persistence of virus-specific memory CD4+ T cells. The perturbation of mTORC2 signaling at memory phase led to an enormous loss of virus-specific memory CD4+ T cells by a unique form of regulated cell death (RCD), ferroptosis. Mechanistically, mTORC2 inactivation resulted in the impaired phosphorylation of downstream AKT and GSK3ß kinases, which induced aberrant mitochondrial reactive oxygen species (ROS) accumulation and ensuing ferroptosis-causative lipid peroxidation in virus-specific memory CD4+ T cells; furthermore, the disruption of this signaling cascade also inhibited glutathione peroxidase 4 (GPX4), a major scavenger of lipid peroxidation. Thus, the mTORC2-AKT-GSK3ß axis functions as a key signaling hub to promote the longevity of virus-specific memory CD4+ T cells by preventing ferroptosis.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Ferroptose/imunologia , Memória Imunológica/imunologia , Longevidade/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Alvo Mecanístico do Complexo 2 de Rapamicina/imunologia , Animais , Glicogênio Sintase Quinase 3 beta/imunologia , Peroxidação de Lipídeos/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos/métodos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/imunologia
7.
PLoS Comput Biol ; 17(12): e1009714, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34932551

RESUMO

Hosts diverge widely in how, and how well, they defend themselves against infection and immunopathology. Why are hosts so heterogeneous? Both epidemiology and life history are commonly hypothesized to influence host immune strategy, but the relationship between immune strategy and each factor has commonly been investigated in isolation. Here, we show that interactions between life history and epidemiology are crucial for determining optimal immune specificity and sensitivity. We propose a demographically-structured population dynamics model, in which we explore sensitivity and specificity of immune responses when epidemiological risks vary with age. We find that variation in life history traits associated with both reproduction and longevity alters optimal immune strategies-but the magnitude and sometimes even direction of these effects depends on how epidemiological risks vary across life. An especially compelling example that explains previously-puzzling empirical observations is that depending on whether infection risk declines or rises at reproductive maturity, later reproductive maturity can select for either greater or lower immune specificity, potentially illustrating why studies of lifespan and immune variation across taxa have been inconclusive. Thus, the sign of selection on the life history-immune specificity relationship can be reversed in different epidemiological contexts. Drawing on published life history data from a variety of chordate taxa, we generate testable predictions for this facet of the optimal immune strategy. Our results shed light on the causes of the heterogeneity found in immune defenses both within and among species and the ultimate variability of the relationship between life history and immune specificity.


Assuntos
Interações Hospedeiro-Parasita/imunologia , Modelos Biológicos , Parasitos , Doenças Parasitárias , Animais , Evolução Biológica , Humanos , Longevidade/imunologia , Parasitos/imunologia , Parasitos/patogenicidade , Doenças Parasitárias/epidemiologia , Doenças Parasitárias/imunologia , Doenças Parasitárias/parasitologia , Dinâmica Populacional , Reprodução
8.
Genesis ; 59(12): e23454, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34664387

RESUMO

In the recent past, Caenorhabditis elegans has emerged as one of the leading nematode models for studying host-microbe interactions on molecular, cellular, or organismal levels. In general, morphological and functional similarities of the gut of C. elegans with respect to that of human has brought in speculations on the study of the intestinal microbiota. On the other hand, probiotics have proved their efficacy in metabolism, development, and pathogenesis thereby inducing an immune response in C. elegans. Nurturing C. elegans with probiotics has led to immunomodulatory effects in the intestinal microbiota, proposing C. elegans as one of the in vivo screening criteria to select potential probiotic bacteria for host health-promoting factors. The major prospect of these probiotics is to exert longevity toward the host in diverse environmental conditions. The extent of research on probiotic metabolism has shed light on mechanisms of the immunomodulatory effect exerted by the nematode model. This review discusses various aspects of the effects of probiotics in improving the health and mechanisms involved in conferring immunity in C. elegans.


Assuntos
Caenorhabditis elegans/microbiologia , Microbioma Gastrointestinal/imunologia , Imunidade Inata/imunologia , Probióticos , Animais , Caenorhabditis elegans/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Longevidade/imunologia
9.
Cell Rep ; 36(8): 109564, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34433065

RESUMO

Studies investigating whether there is a causative link between the gut microbiota and lifespan have largely been restricted to invertebrates or to mice with a reduced lifespan because of a genetic deficiency. We investigate the effect of early-life antibiotic exposure on otherwise healthy, normal chow-fed, wild-type mice, monitoring these mice for more than 700 days in comparison with untreated control mice. We demonstrate the emergence of two different low-diversity community types, post-antibiotic microbiota (PAM) I and PAM II, following antibiotic exposure. PAM II but not PAM I mice have impaired immunity, increased insulin resistance, and evidence of increased inflammaging in later life as well as a reduced lifespan. Our data suggest that differences in the composition of the gut microbiota following antibiotic exposure differentially affect host health and longevity in later life.


Assuntos
Antibacterianos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Longevidade/imunologia , Animais , Longevidade/efeitos dos fármacos , Camundongos
10.
J Gerontol A Biol Sci Med Sci ; 76(10): 1775-1783, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34396395

RESUMO

Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people.


Assuntos
COVID-19 , Peptídeos e Proteínas de Sinalização Intercelular , Longevidade/imunologia , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/imunologia , Linhagem Celular , Citocinas/sangue , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Inflamação/sangue , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Itália/epidemiologia , Masculino , Prognóstico , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
11.
J Immunol ; 207(6): 1616-1626, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34452932

RESUMO

The evolutionarily conserved immune deficiency (IMD) signaling pathway shields Drosophila against bacterial infections. It regulates the expression of antimicrobial peptides encoding genes through the activation of the NF-κB transcription factor Relish. Tight regulation of the signaling cascade ensures a balanced immune response, which is otherwise highly harmful. Several phosphorylation events mediate intracellular progression of the IMD pathway. However, signal termination by dephosphorylation remains largely elusive. Here, we identify the highly conserved protein phosphatase 4 (PP4) complex as a bona fide negative regulator of the IMD pathway. RNA interference-mediated gene silencing of PP4-19c, PP4R2, and Falafel, which encode the catalytic and regulatory subunits of the phosphatase complex, respectively, caused a marked upregulation of bacterial-induced antimicrobial peptide gene expression in both Drosophila melanogaster S2 cells and adult flies. Deregulated IMD signaling is associated with reduced lifespan of PP4-deficient flies in the absence of any infection. In contrast, flies overexpressing this phosphatase are highly sensitive to bacterial infections. Altogether, our results highlight an evolutionarily conserved function of PP4c in the regulation of NF-κB signaling from Drosophila to mammals.


Assuntos
Proteínas de Drosophila/deficiência , Drosophila melanogaster/enzimologia , Drosophila melanogaster/imunologia , Imunidade Inata , NF-kappa B/metabolismo , Fosfoproteínas Fosfatases/deficiência , Transdução de Sinais/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Expressão Gênica , Inativação Gênica , Longevidade/genética , Longevidade/imunologia , Fosfoproteínas Fosfatases/genética , Interferência de RNA , Transdução de Sinais/genética , Regulação para Cima/genética
12.
Front Immunol ; 12: 677036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177919

RESUMO

Dendritic cells are the antigen presenting cells that process antigens effectively and prime the immune system, a characteristic that have gained them the spotlights in recent years. B cell antigen presentation, although less prominent, deserves equal attention. B cells select antigen experienced CD4 T cells to become memory and initiate an orchestrated genetic program that maintains memory CD4 T cells for life of the individual. Over years of research, we have demonstrated that low levels of antigens captured by B cells during the resolution of an infection render antigen experienced CD4 T cells into a quiescent/resting state. Our studies suggest that in the absence of antigen, the resting state associated with low-energy utilization and proliferation can help memory CD4 T cells to survive nearly throughout the lifetime of mice. In this review we would discuss the primary findings from our lab as well as others that highlight our understanding of B cell antigen presentation and the contributions of the MHC Class II accessory molecules to this outcome. We propose that the quiescence induced by the low levels of antigen presentation might be a mechanism necessary to regulate long-term survival of CD4 memory T cells and to prevent cross-reactivity to autoantigens, hence autoimmunity.


Assuntos
Apresentação de Antígeno , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Memória Imunológica , Longevidade/imunologia , Animais , Antígenos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos
13.
PLoS Genet ; 17(6): e1009600, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34166401

RESUMO

Animals and plants need to defend themselves from pathogen attack. Their defences drive innovation in virulence mechanisms, leading to never-ending cycles of co-evolution in both hosts and pathogens. A full understanding of host immunity therefore requires examination of pathogen virulence strategies. Here, we take advantage of the well-studied innate immune system of Caenorhabditis elegans to dissect the action of two virulence factors from its natural fungal pathogen Drechmeria coniospora. We show that these two enterotoxins have strikingly different effects when expressed individually in the nematode epidermis. One is able to interfere with diverse aspects of host cell biology, altering vesicle trafficking and preventing the key STAT-like transcription factor STA-2 from activating defensive antimicrobial peptide gene expression. The second increases STA-2 levels in the nucleus, modifies the nucleolus, and, potentially as a consequence of a host surveillance mechanism, causes increased defence gene expression. Our results highlight the remarkably complex and potentially antagonistic mechanisms that come into play in the interaction between co-evolved hosts and pathogens.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/imunologia , Enterotoxinas/genética , Hypocreales/patogenicidade , Imunidade Inata , Fatores de Transcrição STAT/genética , Esporos Fúngicos/patogenicidade , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/imunologia , Coevolução Biológica , Transporte Biológico , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Proteínas de Caenorhabditis elegans/imunologia , Enterotoxinas/metabolismo , Epiderme/imunologia , Epiderme/metabolismo , Epiderme/microbiologia , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Hypocreales/crescimento & desenvolvimento , Longevidade/genética , Longevidade/imunologia , Fatores de Transcrição STAT/imunologia , Transdução de Sinais , Esporos Fúngicos/crescimento & desenvolvimento , Vesículas Transportadoras/metabolismo , Virulência , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
14.
PLoS Genet ; 17(6): e1009612, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34143770

RESUMO

Wolbachia is one of the most prevalent bacterial endosymbionts, infecting approximately 40% of terrestrial arthropod species. Wolbachia is often a reproductive parasite but can also provide fitness benefits to its host, as, for example, protection against viral pathogens. This protective effect is currently being applied to fight arboviruses transmission by releasing Wolbachia-transinfected mosquitoes. Titre regulation is a crucial aspect of Wolbachia biology. Higher titres can lead to stronger phenotypes and fidelity of transmission but can have a higher cost to the host. Since Wolbachia is maternally transmitted, its fitness depends on host fitness, and, therefore, its cost to the host may be under selection. Understanding how Wolbachia titres are regulated and other aspects of Wolbachia biology has been hampered by the lack of genetic tools. Here we developed a forward genetic screen to identify new Wolbachia over-proliferative mutant variants. We characterized in detail two new mutants, wMelPop2 and wMelOctoless, and show that the amplification or loss of the Octomom genomic region lead to over-proliferation. These results confirm previous data and expand on the complex role of this genomic region in the control of Wolbachia proliferation. Both new mutants shorten the host lifespan and increase antiviral protection. Moreover, we show that Wolbachia proliferation rate in Drosophila melanogaster depends on the interaction between Octomom copy number, the host developmental stage, and temperature. Our analysis also suggests that the life shortening and antiviral protection phenotypes of Wolbachia are dependent on different, but related, properties of the endosymbiont; the rate of proliferation and the titres near the time of infection, respectively. We also demonstrate the feasibility of a novel and unbiased experimental approach to study Wolbachia biology, which could be further adapted to characterize other genetically intractable bacterial endosymbionts.


Assuntos
Drosophila melanogaster/microbiologia , Genoma Bacteriano , Longevidade/imunologia , Simbiose/genética , Wolbachia/genética , Animais , Carga Bacteriana , Dicistroviridae/crescimento & desenvolvimento , Dicistroviridae/patogenicidade , Drosophila melanogaster/imunologia , Drosophila melanogaster/virologia , Feminino , Edição de Genes/métodos , Ilhas Genômicas , Masculino , Fenótipo , Wolbachia/crescimento & desenvolvimento , Wolbachia/metabolismo
15.
Fish Shellfish Immunol ; 112: 1-7, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33588083

RESUMO

Larval lake sturgeon, Acipenser fulvescens, reared in hatcheries for stock enhancement of wild populations may be susceptible to early opportunistic bacterial infection. Thus, we examined survival and whole-body mRNA expression of both stress- and immune-related genes (MyD88, IL-1ß, StAR, GR1, and HSP70) in 30 days post fertilization larval lake sturgeon following immune challenge with lipopolysaccharides (LPS). Larval sturgeon were exposed to 0, 25, 50, 100, 150, and 200 µg ml-1 LPS and sampled after 30 min, 4 h, and 48 h. Mortality was zero in 0 and 25 µg ml-1 LPS; 37.5% in 50 µg ml-1 LPS and 100% in the higher concentrations. Expression of MyD88 and StAR mRNA were positively correlated and increased with time in the 50 µg ml-1 LPS treatment. There was an influence of both treatment and time on IL-1ß mRNA, with expression 10-fold higher than controls after 4 h. Expression of HSP70 mRNA was suppressed within 30 min of 50 µg ml-1 LPS exposure and remained so throughout the time course. Correlated mRNA expression of GR1 with MyD88, StAR and IL-1ß suggests a potential relationship between the innate immune and glucocorticoid responses of larval lake sturgeon during this early developmental stage. Data presented suggest that larval lake sturgeon largely responded with predicted changes in gene expression of immune related and stress response genes following LPS challenge. This study provides a foundation for future research examining the effects of hatchery and naturally occurring stressors on the immune responses of larval lake sturgeon.


Assuntos
Proteínas de Peixes/genética , Peixes/fisiologia , Expressão Gênica/imunologia , Imunidade Inata/genética , Lipopolissacarídeos/farmacologia , Longevidade , Animais , Relação Dose-Resposta a Droga , Proteínas de Peixes/metabolismo , Peixes/genética , Peixes/imunologia , Longevidade/imunologia , Estresse Fisiológico/imunologia
16.
Int J Biol Macromol ; 172: 223-230, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33453252

RESUMO

Microsporidia are obligate single-celled eukaryote parasites. Microsporidian infection can cause large economic losses to beneficial insects such as silkworms and honey bees. Identification of resistance biomacromolecules and breeding of transgenic lines resistant to the microsporidian Nosema bombycis are important for disease management. We previously used transcriptome analysis to identify a guanylate binding protein family BmAtlastin-n gene that was significantly upregulated after Nosema bombycis infection, and we determined that the molecule was highly expressed in resistance-related tissues such as the midgut, fat body and the epidermis. The transgenic silkworm line overexpressing BmAtlastin-n biomolecules had economic characters similar to those of non-transgenic lines. The transgenic OE-BmAtlastin-n lines had significantly improved survival after microspore infection. We used RT-PCR and H&E staining to show that the number of spores in the transgenic lines was significantly lower than in the control lines. In this study, we identified a BmAtlastin-n macromolecule with resistance to N. bombycis and developed a transgenic line. The results improved understanding of the GBP protein family and provided biomacromolecule material for the treatment and prevention of microsporidia.


Assuntos
Bombyx/genética , Resistência à Doença/genética , Proteínas de Ligação ao GTP/genética , Interações Hospedeiro-Patógeno/genética , Proteínas de Insetos/genética , Nosema/patogenicidade , Animais , Animais Geneticamente Modificados , Bombyx/imunologia , Bombyx/microbiologia , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/imunologia , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Engenharia Genética/métodos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Interações Hospedeiro-Patógeno/imunologia , Proteínas de Insetos/imunologia , Longevidade/genética , Longevidade/imunologia , Nosema/crescimento & desenvolvimento , Plasmídeos/química , Plasmídeos/metabolismo , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/imunologia , Esporos Fúngicos/crescimento & desenvolvimento , Esporos Fúngicos/patogenicidade , Transcrição Gênica
17.
Int J Mol Sci ; 21(23)2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33255339

RESUMO

The complexity of the human immune system is exacerbated by age-related changes to immune cell functionality. Many of these age-related effects remain undescribed or driven by mechanisms that are poorly understood. γδ T cells, while considered an adaptive subset based on immunological ontogeny, retain both innate-like and adaptive-like characteristics. This T cell population is small but mighty, and has been implicated in both homeostatic and disease-induced immunity within tissues and throughout the periphery. In this review, we outline what is known about the effect of age on human peripheral γδ T cells, and call attention to areas of the field where further research is needed.


Assuntos
Envelhecimento/imunologia , Imunidade Inata/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Humanos , Longevidade/imunologia
18.
Sci Rep ; 10(1): 20862, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257786

RESUMO

Inflammatory signaling is thought to modulate the neurodegenerative cascade in amyotrophic lateral sclerosis (ALS). We have previously shown that expression of Interleukin-10 (IL-10), a classical anti-inflammatory cytokine, extends lifespan in the SOD1-G93A mouse model of familial ALS. Here we test whether co-expression of the decoy chemokine receptor M3, that can scavenge inflammatory chemokines, augments the efficacy of IL-10. We found that recombinant adeno-associated virus (AAV)-mediated expression of IL-10, alone, or in combination with M3, resulted in modest extension of lifespan relative to control SOD1-G93A cohort. Interestingly neither AAV-M3 alone nor AAV-IL-10 + AAV-M3 extend survival beyond that of the AAV-IL-10 alone cohort. Focused transcriptomic analysis revealed induction of innate immunity and phagocytotic pathways in presymptomatic SOD1-G93A mice expressing IL-10 + M3 or IL-10 alone. Further, while IL-10 expression increased microglial burden, the IL-10 + M3 group showed lower microglial burden, suggesting that M3 can successfully lower microgliosis before disease onset. Our data demonstrates that over-expression of an anti-inflammatory cytokine and a decoy chemokine receptor can modulate inflammatory processes in SOD1-G93A mice, modestly delaying the age to paralysis. This suggests that multiple inflammatory pathways can be targeted simultaneously in neurodegenerative disease and supports consideration of adapting these approaches to treatment of ALS and related disorders.


Assuntos
Esclerose Lateral Amiotrófica/imunologia , Imunomodulação/imunologia , Interleucina-10/imunologia , Longevidade/imunologia , Animais , Dependovirus/imunologia , Modelos Animais de Doenças , Feminino , Imunidade Inata/imunologia , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Microglia/imunologia , Doenças Neurodegenerativas/imunologia , Fagocitose/imunologia , Transdução de Sinais/imunologia , Superóxido Dismutase-1/imunologia
19.
Int J Mol Sci ; 21(19)2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32998388

RESUMO

Aging is the most relevant risk factor for cardiovascular diseases which are the main cause of mortality in industrialized countries. In this context, there is a progressive loss of cardiovascular homeostasis that translates in illness and death. The study of long living individuals (LLIs), which show compression of morbidity toward the end of their life, is a valuable approach to find the key to delay aging and postpone associate cardiovascular events. A contribution to the age-related decline of cardiovascular system (CVS) comes from the immune system; indeed, it is dysfunctional during aging, a process described as immunosenescence and comprises the combination of several processes overpowering both innate and adaptative immune system. We have recently discovered a longevity-associated variant (LAV) in bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4), which is a secreted protein able to enhance endothelial function through endothelial nitric oxide synthase (eNOS) activation and capable to protect from hypertension, atherosclerosis, diabetic cardiopathy, frailty, and inflammaging. Here, we sum up the state of the art of the mechanisms involved in the main pathological processes related to CVD (atherosclerosis, aging, diabetic cardiopathy, and frailty) and shed light on the therapeutic effects of LAV-BPIFB4 in these contexts.


Assuntos
Aterosclerose/genética , Cardiomiopatias Diabéticas/genética , Fragilidade/genética , Hipertensão/genética , Imunossenescência/genética , Longevidade/genética , Fosfoproteínas/genética , Imunidade Adaptativa , Fatores Etários , Animais , Aterosclerose/imunologia , Aterosclerose/prevenção & controle , Cardiomiopatias Diabéticas/imunologia , Cardiomiopatias Diabéticas/prevenção & controle , Fragilidade/imunologia , Fragilidade/prevenção & controle , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Terapia Genética/métodos , Humanos , Hipertensão/imunologia , Hipertensão/prevenção & controle , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intercelular , Longevidade/imunologia , Camundongos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/imunologia , Fosfoproteínas/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Fatores de Risco
20.
J Exp Zool A Ecol Integr Physiol ; 333(10): 820-828, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33075211

RESUMO

Longevity patterns in most vertebrates suggest that females benefit most from maintenance investment. A reversed longevity pattern in loggerhead musk turtles (Sternotherus minor) allowed us to test trade-offs between maintenance and survivorship. We tested the hypothesis that the sex with greater longevity has greater maintenance than the sex with shorter longevity. We also compared the following parameters between sexes: Bactericidal ability (BA) and heterophil:lymphocyte ratios (HLR). Baseline blood samples were collected from turtles in the field; a subset of turtles was returned to a laboratory for experiments of acquired immune responses to sheep red blood cells (SRBC). We found no support for the original hypothesis of reversal in sex-dependent immune trade-offs (difference between sex SRBC titers: p = .102; interaction between treatment and sex: p = .177; difference between treatments: p < .001; effect of sex on BA: p = .830; effect of sex on HLR: p = .717). However, we did find support for sex-dependent differences in immunity in the relationship between HLR and body condition (BCI) (effect of BCI on HLR: p = .015). In field conditions, we found that males with higher body condition indices express stressed phenotypes more than males with lower body condition indices (p = .002). However, females expressed similar stress loads across all body conditions (p = .900). Testosterone concentrations were assayed in free-living turtles and were not related to any of the immune parameters. Our results suggest that the immune systems play an important role in balancing sex-specific responses to different selective pressures in S. minor.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Tartarugas/imunologia , Animais , Atividade Bactericida do Sangue , Feminino , Testes de Hemaglutinação , Contagem de Leucócitos , Longevidade/imunologia , Masculino , Fatores Sexuais , Testosterona/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...