The need for highly effective vaccines that induce robust and long-lasting immunity has never been more apparent. However, for reasons that are still poorly understood, immune responses to ...vaccination are highly variable between different individuals and different populations. Furthermore, vaccine immunogenicity is frequently suboptimal in the very populations who are at most risk from infectious disease, including infants, the elderly, and those living in low-income and middle-income countries. Although many factors have the potential to influence vaccine immunogenicity and therefore vaccine effectiveness, increasing evidence from clinical studies and animal models now suggests that the composition and function of the gut microbiota are crucial factors modulating immune responses to vaccination. In this Review, we synthesize this evidence, discuss the immunological mechanisms that potentially mediate these effects and consider the potential of microbiota-targeted interventions to optimize vaccine effectiveness.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious respiratory virus which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. It is increasingly ...clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms for many months after infection, a condition referred to as "long COVID", post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. However, despite the plethora of research on COVID-19, relatively little is known about the molecular underpinnings of these long-term effects.
We have undertaken an integrated analysis of immune responses in blood at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 patients recovering from mild, moderate, severe, or critical COVID-19 in comparison to healthy uninfected controls. Twenty-one of these patients were referred to a long COVID clinic and > 50% reported ongoing symptoms more than 6 months post-infection.
Anti-Spike and anti-RBD IgG responses were largely stable up to 24 wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper, and regulatory T cells) in convalescent individuals compared to healthy controls, which were most strongly evident at 12 and 16 wpi. RNA sequencing revealed significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection. We also uncovered significant differences in the transcriptome at 24 wpi of convalescents who were referred to a long COVID clinic compared to those who were not.
Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.
We investigated the properties of leishmania exosomes with respect to influencing innate and adaptive immune responses. Exosomes from Leishmania donovani modulated human monocyte cytokine responses ...to IFN-γ in a bimodal fashion by promoting IL-10 production and inhibiting that of TNF-α. Moreover, these vesicles were inhibitory with respect to cytokine responses (IL-12p70, TNF-α, and IL-10) by human monocyte-derived dendritic cells. Exosomes from wild-type (WT) L. donovani failed to prime monocyte-derived dendritic cells to drive the differentiation of naive CD4 T cells into IFN-γ-producing Th1 cells. In contrast, vesicles from heat shock protein (HSP)100(-/-) L. donovani showed a gain-of-function and proinflammatory phenotype and promoted the differentiation of naive CD4 lymphocytes into Th1 cells. Proteomic analysis showed that exosomes from WT and HSP100(-/-) leishmania had distinct protein cargo, suggesting that packaging of proteins into exosomes is dependent in part on HSP100. Treatment of C57BL/6 mice with WT L. donovani exosomes prior to challenge with WT organisms exacerbated infection and promoted IL-10 production in the spleen. In contrast, HSP100(-/-) exosomes promoted spleen cell production of IFN-γ and did not adversely affect hepatic parasite burdens. Furthermore, the proparasitic properties of WT exosomes were not species specific because BALB/c mice exposed to Leishmania major exosomes showed increased Th2 polarization and exacerbation of disease in response to infection with L. major. These findings demonstrate that leishmania exosomes are predominantly immunosuppressive. Moreover, to our knowledge, this is the first evidence to suggest that changes in the protein cargo of exosomes may influence the impact of these vesicles on myeloid cell function.
BackgroundActivating mutations in KRAS frequently occur in colorectal cancer (CRC) patients, leading to resistance to EGFR-targeted therapies.MethodsTo better understand the cellular reprogramming ...which occurs in mutant KRAS cells, we have undertaken a systems-level analysis of four CRC cell lines which express either wild type (wt) KRAS or the oncogenic KRASG13D allele (mtKRAS).ResultsRNAseq revealed that genes involved in ribosome biogenesis, mRNA translation and metabolism were significantly upregulated in mtKRAS cells. Consistent with the transcriptional data, protein synthesis and cell proliferation were significantly higher in the mtKRAS cells. Targeted metabolomics analysis also confirmed the metabolic reprogramming in mtKRAS cells. Interestingly, mtKRAS cells were highly transcriptionally responsive to EGFR activation by TGFα stimulation, which was associated with an unexpected downregulation of genes involved in a range of anabolic processes. While TGFα treatment strongly activated protein synthesis in wtKRAS cells, protein synthesis was not activated above basal levels in the TGFα-treated mtKRAS cells. This was likely due to the defective activation of the mTORC1 and other pathways by TGFα in mtKRAS cells, which was associated with impaired activation of PKB signalling and a transient induction of AMPK signalling.ConclusionsWe have found that mtKRAS cells are substantially rewired at the transcriptional, translational and metabolic levels and that this rewiring may reveal new vulnerabilities in oncogenic KRAS CRC cells that could be exploited in future.
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.
Display omitted
•Analysis of aged mice exposed to antibiotics in the pre-weaning period•Microbiota community type following antibiotics affects host health in later life•PAM II mice have increased insulin resistance, inflammaging, and reduced lifespan
Lynn et al. expose mice to antibiotics in early life and then monitor these mice for more than 700 days. The study reveals that differences in the composition of the gut microbiota following antibiotic exposure differentially affects host immunity, metabolism, and longevity in later life.
Abstract
Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is ...poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRAS
G13D
) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRAS
G13D
(mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
Compassionate conservation is based on the ethical position that actions taken to protect biodiversity should be guided by compassion for all sentient beings. Critics argue that there are 3 core ...reasons harming animals is acceptable in conservation programs: the primary purpose of conservation is biodiversity protection; conservation is already compassionate to animals; and conservation should prioritize compassion to humans. We used argument analysis to clarify the values and logics underlying the debate around compassionate conservation. We found that objections to compassionate conservation are expressions of human exceptionalism, the view that humans are of a categorically separate and higher moral status than all other species. In contrast, compassionate conservationists believe that conservation should expand its moral community by recognizing all sentient beings as persons. Personhood, in an ethical sense, implies the individual is owed respect and should not be treated merely as a means to other ends. On scientific and ethical grounds, there are good reasons to extend personhood to sentient animals, particularly in conservation. The moral exclusion or subordination of members of other species legitimates the ongoing manipulation and exploitation of the living worlds, the very reason conservation was needed in the first place. Embracing compassion can help dismantle human exceptionalism, recognize nonhuman personhood, and navigate a more expansive moral space.
Reconocimiento de la Calidad de Persona en los Animales dentro de la Conservación Compasiva
Resumen
La conservación compasiva está basada en la posición ética que parte de que las acciones tomadas para proteger a la biodiversidad deberían estar dirigidas por la compasión por todos los seres sintientes. Los críticos de esta postura argumentan que hay tres razones nucleares por las que el daño a los animales es aceptable dentro de los programas de conservación: el principal motivo de la conservación es la protección de la biodiversidad; la conservación ya es compasiva con los animales; y la conservación debería priorizar la compasión hacia los humanos. Usamos un análisis de argumentos para aclarar los valores y la lógica subyacentes al debate en torno a la conservación compasiva. Encontramos que el rechazo a la conservación compasiva es una expresión de la excepcionalidad humana, la visión de que los humanos están en un nivel categóricamente separado y de mayor moral que todas las demás especies. Por el contrario, los conservacionistas compasivos creen que la conservación debería expandir su comunidad moral al reconocer a todos los seres sintientes como personas. La calidad de persona, en un sentido ético, implica que el individuo merece respeto y no debería ser tratado solamente como un medio para otros fines. Si hablamos desde fundamentos científicos y éticos, existen muy buenas razones para extender la calidad de persona a todos los animales sintientes, particularmente en la conservación. La exclusión moral o la subordinación de los miembros de otras especies justifica la continua manipulación y explotación de los seres vivos, la justa razón por la que necesitamos de la conservación desde el principio. La aceptación de la compasión nos puede ayudar a desmantelar la excepcionalidad humana, a reconocer la calidad de persona no humana y a navegar un espacio moral más expansivo.
摘要
同情心保护基于这样一种伦理立场, 即生物多样性保护行动的指导原则应为对众生的同情心。而批评者认为在保护项目中可以接受对动物的伤害, 其三个核心原因是:保护的主要目的是保护生物多样性;保护动物已经是同情心的体现;保护应该优先考虑对人类的同情心。本研究使用了论点分析来阐明关于同情心保护的辩论背后的价值和逻辑。我们发现, 对同情心保护的反对是人类例外论的表现, 这种观点认为人类独立于其它所有物种且拥有更高的道德地位。相比之下, 同情心保护主义者则认为, 在保护中应承认众生与人类平等的存在, 以扩大其道德共同体的范围。在伦理意义上, 人格性意味着个体应该被尊重, 而不应该仅仅被当作达到其它目的的手段。而从科学和伦理的角度来看, 我们有充分的理由将人格性扩展到有感知能力的动物身上, 特别是在保护当中。对其它物种的道德排斥或从属化导致了人们长期以来对生命世界操纵和剥削的合法化, 而这也正是目前需要进行保护的首要原因。积极拥抱同情心可以帮助消除人类例外论, 认识到非人类生命的人格性, 并导向更广阔的道德空间。 【翻译: 胡怡思; 审校: 聂永刚】
Article Impact Statement: The debate about compassionate conservation is about whether to recognize nonhuman personhood.
In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, ...such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes.
PDF
