RESUMO
Lung transplant remains the primary therapeutic option for patients with end-stage lung disease, but long-term survival rates remain suboptimal compared with other solid organ transplants. Acute cellular rejection (ACR) is a significant challenge in lung transplant recipients, with T cell-mediated mechanisms playing a major role. IL-10 is known for its immunoregulatory function, although its specific role in lung allograft rejection remains unclear. Using the mouse orthotopic lung transplant model, we investigated the role of IL-10 in regulating alloeffector T cell responses. Unexpectedly, we found that IL-10 was not required for early costimulation blockade-induced allograft acceptance. However, IL-10 deficiency or blockade resulted in increased CD4+ T cell numbers, proliferation, graft infiltration, and alloeffector responses. In the absence of IL-10, CD4+ T cell responses predominated over CD8 responses during ACR in contrast to wild-type mice. Type 1 immunity (IFN-γ) responses along with elevated CD4+NKG7+ and CD4+CD107a+ responses predominated during ACR, highlighting a critical regulatory role for IL-10 in modulating CD4+ T cell alloimmune responses. We further demonstrated increased colocalization of NKG7 and CD107a in CD4+ T cells from IL-10-deficient allografts, suggesting coordination in cytotoxic activity. Together, our findings highlight a critical role for IL-10 in regulation of cytotoxic CD4+NKG7+ T cells, an effector population that needs further investigation to elucidate their role in lung allograft rejection.
Assuntos
Aloenxertos , Rejeição de Enxerto , Interleucina-10 , Transplante de Pulmão , Camundongos Endogâmicos C57BL , Animais , Rejeição de Enxerto/imunologia , Camundongos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Aloenxertos/imunologia , Camundongos Knockout , Linfócitos T CD4-Positivos/imunologia , Sobrevivência de Enxerto/imunologia , Camundongos Endogâmicos BALB C , Linfócitos T Citotóxicos/imunologia , Interferon gama/imunologia , Interferon gama/metabolismoRESUMO
Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-α+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4+ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. We also evaluated BAL and lung explant CD4+ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.
Assuntos
COVID-19 , Linfopenia , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Citocinas , Humanos , Infliximab , Leucócitos Mononucleares , Receptores do Fator de Necrose Tumoral , SARS-CoV-2 , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfaRESUMO
While in Northern hemisphere countries, the pandemic H1N1 virus (H1N1pdm) was introduced outside of the typical influenza season, Southern hemisphere countries experienced a single wave of transmission during their 2009 winter season. This provides a unique opportunity to compare the spread of a single virus in different countries and study the factors influencing its transmission. Here, we estimate and compare transmission characteristics of H1N1pdm for eight Southern hemisphere countries/states: Argentina, Australia, Bolivia, Brazil, Chile, New Zealand, South Africa and Victoria (Australia). Weekly incidence of cases and age-distribution of cumulative cases were extracted from public reports of countries' surveillance systems. Estimates of the reproduction numbers, R(0), empirically derived from the country-epidemics' early exponential phase, were positively associated with the proportion of children in the populations (pâ=â0.004). To explore the role of demography in explaining differences in transmission intensity, we then fitted a dynamic age-structured model of influenza transmission to available incidence data for each country independently, and for all the countries simultaneously. Posterior median estimates of R0 ranged 1.2-1.8 for the country-specific fits, and 1.29-1.47 for the global fits. Corresponding estimates for overall attack-rate were in the range 20-50%. All model fits indicated a significant decrease in susceptibility to infection with age. These results confirm the transmissibility of the 2009 H1N1 pandemic virus was relatively low compared with past pandemics. The pattern of age-dependent susceptibility found confirms that older populations had substantial--though partial--pre-existing immunity, presumably due to exposure to heterologous influenza strains. Our analysis indicates that between-country-differences in transmission were at least partly due to differences in population demography.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana/transmissão , Adolescente , Adulto , Fatores Etários , Idoso , Argentina/epidemiologia , Austrália/epidemiologia , Bolívia/epidemiologia , Brasil/epidemiologia , Criança , Pré-Escolar , Chile/epidemiologia , Humanos , Incidência , Lactente , Influenza Humana/epidemiologia , Pessoa de Meia-Idade , Modelos Estatísticos , Nova Zelândia/epidemiologia , Pandemias/estatística & dados numéricos , África do Sul/epidemiologia , Vitória/epidemiologiaRESUMO
Multiple randomized, controlled clinical trials have yielded discordant results regarding the efficacy of convalescent plasma in outpatients, with some showing an approximately 2-fold reduction in risk and others showing no effect. We quantified binding and neutralizing antibody levels in 492 of the 511 participants from the Clinical Trial of COVID-19 Convalescent Plasma in Outpatients (C3PO) of a single unit of COVID-19 convalescent plasma (CCP) versus saline infusion. In a subset of 70 participants, peripheral blood mononuclear cells were obtained to define the evolution of B and T cell responses through day 30. Binding and neutralizing antibody responses were approximately 2-fold higher 1 hour after infusion in recipients of CCP compared with saline plus multivitamin, but levels achieved by the native immune system by day 15 were almost 10-fold higher than those seen immediately after CCP administration. Infusion of CCP did not block generation of the host antibody response or skew B or T cell phenotype or maturation. Activated CD4+ and CD8+ T cells were associated with more severe disease outcome. These data show that CCP leads to a measurable boost in anti-SARS-CoV-2 antibodies but that the boost is modest and may not be sufficient to alter disease course.
Assuntos
COVID-19 , Leucócitos Mononucleares , Humanos , COVID-19/terapia , Soroterapia para COVID-19 , Anticorpos Neutralizantes , Imunidade AdaptativaRESUMO
BACKGROUND: Genetic heterozygosity is increasingly being shown to be a key predictor of fitness in natural populations, both through inbreeding depression, inbred individuals having low heterozygosity, and also through chance linkage between a marker and a gene under balancing selection. One important component of fitness that is often highlighted is resistance to parasites and other pathogens. However, the significance of equivalent loci in human populations remains unclear. Consequently, we performed a case-control study of fatal invasive bacterial disease in Kenyan children using a genome-wide screen with microsatellite markers. METHODS: 148 cases, comprising children aged <13 years who died of invasive bacterial disease, (variously, bacteraemia, bacterial meningitis or neonatal sepsis) and 137 age-matched, healthy children were sampled in a prospective study conducted at Kilifi District Hospital, Kenya. Samples were genotyped for 134 microsatellite markers using the ABI LD20 marker set and analysed for an association between homozygosity and mortality. RESULTS: At five markers homozygosity was strongly associated with mortality (odds ratio range 4.7 - 12.2) with evidence of interactions between some markers. Mortality was associated with different non-overlapping marker groups in Gram positive and Gram negative bacterial disease. Homozygosity at susceptibility markers was common (prevalence 19-49%) and, with the large effect sizes, this suggests that bacterial disease mortality may be strongly genetically determined. CONCLUSION: Balanced polymorphisms appear to be more widespread in humans than previously appreciated and play a critical role in modulating susceptibility to infectious disease. The effect sizes we report, coupled with the stochasticity of exposure to pathogens suggests that infection and mortality are far from random due to a strong genetic basis.
Assuntos
Bacteriemia/genética , Homozigoto , Doenças do Recém-Nascido/genética , Meningites Bacterianas/genética , Repetições de Microssatélites/genética , Análise de Variância , Bacteriemia/mortalidade , Estudos de Casos e Controles , Criança , Pré-Escolar , Intervalos de Confiança , Predisposição Genética para Doença , Infecções por Bactérias Gram-Negativas/genética , Infecções por Bactérias Gram-Negativas/mortalidade , Infecções por Bactérias Gram-Positivas/genética , Infecções por Bactérias Gram-Positivas/mortalidade , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/mortalidade , Quênia/epidemiologia , Meningites Bacterianas/mortalidade , Razão de Chances , Fatores de RiscoRESUMO
Studies of animal populations suggest that low genetic heterozygosity is an important risk factor for infection by a diverse range of pathogens, but relatively little research has looked to see whether similar patterns exist in humans. We have used microsatellite genome screen data for tuberculosis (TB), hepatitis and leprosy to test the hypothesis that inbreeding depression increases risk of infection. Our results indicate that inbred individuals are more common among our infected cases for TB and hepatitis, but only in populations where consanguineous marriages are common. No effect was found either for leprosy, which is thought to be oligogenic, or for hepatitis in Italy where consanguineous marriages are rare. Our results suggest that consanguinity is an important risk factor in susceptibility to infectious diseases in humans.
Assuntos
Doenças Transmissíveis/etiologia , Doenças Transmissíveis/genética , Consanguinidade , Predisposição Genética para Doença , Saúde da Família , Feminino , Genoma , Heterozigoto , Humanos , Masculino , Repetições de Microssatélites , Modelos Biológicos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Risco , Fatores de RiscoRESUMO
To date, coalescent analysis of the Plasmodium falciparum genome sequence has failed to provide a unifying theory regarding the parasite's evolution. While a better understanding of the evolution of the malaria genome will undoubtedly clarify the current controversy, the importance of the parasite's interplay with both the human host and mosquito vector cannot be underestimated. Changes in the population biology or ecology of either one of these species have consequences for malaria transmission and this was never more apparent than in the environmental changes brought about by the advent of agriculture.
Assuntos
Culicidae/parasitologia , Evolução Molecular , Insetos Vetores/parasitologia , Plasmodium falciparum/genética , Agricultura/tendências , Animais , Anopheles/classificação , Anopheles/genética , Humanos , Malária Falciparum/epidemiologia , Malária Falciparum/transmissão , Filogenia , Plasmodium falciparum/isolamento & purificação , Dinâmica PopulacionalAssuntos
Genoma de Protozoário , Tricomoníase/tratamento farmacológico , Trichomonas vaginalis/genética , Animais , Antitricômonas/uso terapêutico , DNA de Protozoário/química , DNA de Protozoário/genética , Humanos , Análise de Sequência de DNA , Tricomoníase/parasitologia , Trichomonas vaginalis/metabolismoRESUMO
A novel influenza A (H1N1) virus has spread rapidly across the globe. Judging its pandemic potential is difficult with limited data, but nevertheless essential to inform appropriate health responses. By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, we make an early assessment of transmissibility and severity. Our estimates suggest that 23,000 (range 6000 to 32,000) individuals had been infected in Mexico by late April, giving an estimated case fatality ratio (CFR) of 0.4% (range: 0.3 to 1.8%) based on confirmed and suspected deaths reported to that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, giving an upper 95% bound on CFR of 0.6%. Thus, although substantial uncertainty remains, clinical severity appears less than that seen in the 1918 influenza pandemic but comparable with that seen in the 1957 pandemic. Clinical attack rates in children in La Gloria were twice that in adults (<15 years of age: 61%; >/=15 years: 29%). Three different epidemiological analyses gave basic reproduction number (R0) estimates in the range of 1.4 to 1.6, whereas a genetic analysis gave a central estimate of 1.2. This range of values is consistent with 14 to 73 generations of human-to-human transmission having occurred in Mexico to late April. Transmissibility is therefore substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics.
Assuntos
Surtos de Doenças , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Saúde Global , Humanos , Influenza Humana/mortalidade , Influenza Humana/transmissão , Influenza Humana/virologia , México/epidemiologia , Dados de Sequência Molecular , ViagemRESUMO
Synergism among mutations can lead to an advantage to sexual reproduction, provided mutation rates are high enough (the mutational deterministic hypothesis). Here we tested the idea that competition for food can increase the advantage to sexual reproduction, perhaps by increasing the synergism among mutations in asexual individuals. We compared the survivorship of sexual and asexual snails (Potamopyrgus antipodarum) under two treatments: starved and fed. We predicted higher mortality for asexual snails when starved, but found that sexual and asexual individuals survived at the same rate, independent of treatment. These results suggest that the distribution of sex in this snail may not be explained by variation in competition among populations.