5 research outputs found
Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78
The pre- and postnatal environment may represent a window of opportunity for allergy and asthma prevention, and the hygiene hypothesis implies that microbial agents may play an important role in this regard. Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis, maternal (prenatal) microbial exposure, and the involvement of Toll-like receptor (TLR) signaling in prenatal protection from asthma. Maternal intranasal exposure to A. lwoffii F78 protected against the development of experimental asthma in the progeny. Maternally, A. lwoffii F78 exposure resulted in a transient increase in lung and serum proinflammatory cytokine production and up-regulation of lung TLR messenger RNA. Conversely, suppression of TLRs was observed in placental tissue. To investigate further, the functional relevance of maternal TLR signaling was tested in TLR2/3/4/7/9â/â knockout mice. The asthma-preventive effect was completely abolished in heterozygous offspring from A. lwoffii F78âtreated TLR2/3/4/7/9â/â homozygous mother mice. Furthermore, the mild local and systemic inflammatory response was also absent in these A. lwoffii F78âexposed mothers. These data establish a direct relationship between maternal bacterial exposures, functional maternal TLR signaling, and asthma protection in the progeny
Egg- or cell culture-derived hemagglutinin mutations impair virus stability and antigen content of inactivated influenza vaccines
Egg-derived viruses are the only available seed material for influenza vaccine production. Vaccine manufacturing is done in embryonated chicken eggs, MDCK or Vero cells. In order to contribute to efficient production of influenza vaccines, we investigate whether the quality of inactivated vaccines is influenced by the propagation substrate. We demonstrate that H3N2 egg-derived seed viruses (A/Brisbane/10/07, IVR147, and A/Uruguay/716/07) triggered the hemagglutinin (HA) conformational change under less acidic conditions (0.2-0.6 pH units) than antigenically similar primary isolates. This phenotype was associated with HA1 (A138S, L194P) and HA2 (D160N) substitutions, and strongly related to decreased virus stability towards acidic pH and elevated temperature. The subsequent propagation of H3N2 and H1N1 egg-derived seed viruses in MDCK and Vero cells induced HA2 N50K (H1N1) and D160E (H3N2) mutations, improving virus growth in cell culture but further impairing virus stability. The prevention of the loss or recovery of stability was possible by cultivation at acidified conditions. Viruses carrying less stable HAs are more sensitive for HA conformational change during concentration, purification and storage. This results in decreased detectable HA antigen content - the main potency marker for inactivated influenza vaccines. Thus, virus stability can be a useful marker for predicting the manufacturing scope of seed viruses
Veryâlowâcarbohydrate diet enhances human Tâcell immunity through immunometabolic reprogramming
Abstract Veryâlowâcarbohydrate diet triggers the endogenous production of ketone bodies as alternative energy substrates. There are as yet unproven assumptions that ketone bodies positively affect human immunity. We have investigated this topic in an in vitro model using primary human T cells and in an immunoânutritional intervention study enrolling healthy volunteers. We show that ketone bodies profoundly impact human Tâcell responses. CD4+, CD8+, and regulatory Tâcell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling. Our data suggest a veryâlowâcarbohydrate diet as a clinical tool to improve human Tâcell immunity. Rethinking the value of nutrition and dietary interventions in modern medicine is required