The innate immune system is the oldest protection strategy that is conserved across all organisms. Although having an unspecific action, it is the first and fastest defense mechanism against pathogens. Development of predominantly the adaptive immune system takes place after birth. However, some key components of the innate immune system evolve during the prenatal period of life, which endows the newborn with the ability to mount an immune response against pathogenic invaders directly after birth. Undoubtedly, the crosstalk between maternal immune cells, antibodies, dietary antigens, and microbial metabolites originating from the maternal microbiota are the key players in preparing the neonate’s immunity to the outer world. Birth represents the biggest substantial environmental change in life, where the newborn leaves the protective amniotic sac and is exposed for the first time to a countless variety of microbes. Colonization of all body surfaces commences, including skin, lung, and gastrointestinal tract, leading to the establishment of the commensal microbiota and the maturation of the newborn immune system, and hence lifelong health. Pregnancy, birth, and the consumption of breast milk shape the immune development in coordination with maternal and newborn microbiota. Discrepancies in these fine-tuned microbiota interactions during each developmental stage can have long-term effects on disease susceptibility, such as metabolic syndrome, childhood asthma, or autoimmune type 1 diabetes. In this review, we will give an overview of the recent studies by discussing the multifaceted emergence of the newborn innate immune development in line with the importance of maternal and early life microbiota exposure and breast milk intake.
Listeria monocytogenes (LM) has been proposed as vaccine vector in various cancers and infectious diseases since LM induces a strong immune response. In this study, we developed a novel and safe LM-based vaccine vector platform, by engineering a triple attenuated mutant (Lm3Dx) (ΔactA, ΔinlA, ΔinlB) of the wild-type LM strain JF5203 (CC 1, phylogenetic lineage I). We demonstrated the strong attenuation of Lm3Dx while maintaining its capacity to selectively infect antigen-presenting cells (APCs) in vitro. Furthermore, as proof of concept, we introduced the immunodominant Neospora caninum (Nc) surface antigen NcSAG1 into Lm3Dx. The NcSAG1 protein was expressed by Lm3Dx_SAG1 during cellular infection. To demonstrate safety of Lm3Dx_SAG1 in vivo, we vaccinated BALB/C mice by intramuscular injection. Following vaccination, mice did not suffer any adverse effects and only sporadically shed bacteria at very low levels in the feces (<100 CFU/g). Additionally, bacterial load in internal organs was very low to absent at day 1.5 and 4 following the 1st vaccination and at 2 and 4 weeks after the second boost, independently of the physiological status of the mice. Additionally, vaccination of mice prior and during pregnancy did not interfere with pregnancy outcome. However, Lm3Dx_SAG1 was shed into the milk when inoculated during lactation, although it did not cause any clinical adverse effects in either dams or pups. Also, we have indications that the vector persists more days in the injected muscle of lactating mice. Therefore, impact of physiological status on vector dynamics in the host and mechanisms of milk shedding requires further investigation. In conclusion, we provide strong evidence that Lm3Dx is a safe vaccine vector in non-lactating animals. Additionally, we provide first indications that mice vaccinated with Lm3Dx_SAG1 develop a strong and Th1-biased immune response against the Lm3Dx-expressed neospora antigen. These results encourage to further investigate the efficiency of Lm3Dx_SAG1 to prevent and treat clinical neosporosis.
The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.
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