TLR

responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.

Improving the immunogenicity of subunit vaccines, in particular skewing of the immune response towards Th1 type immunity, is crucial for the development of effective vaccines against intracellular infections and for the development of anti-cancer vaccines. Small molecule TLR7/8 agonist hold high potential for this purpose, but suffer from an undesirable pharmacokinetic profile, resulting in systemic inflammatory responses. An effective solution to this problem is covalent ligation to a larger carrier. Here, a degradable nanogel carrier containing a covalently linked imidazoquinoline (IMDQ) TLR7/8 agonist is explored as adjuvant for vaccination against the respiratory syncytial virus (RSV). In vitro and in vivo experiments in mice provide a solid rational base for preferring nanogels over soluble polymers as IMDQ carrier in terms of cellular uptake and lymph node accumulation.

The cardiovascular effects of probiotics Lactobacillus fermentum CECT5716 (LC40), or L. coryniformis CECT5711 (K8) plus L. gasseri CECT5714 (LC9) (1:1) in spontaneously hypertensive rats (SHR) were evaluated. Ten Wistar Kyoto rats (WKY) and thirty SHR were randomly assigned to four groups (n = 10): a control WKY group, a control SHR groups, a SHR group treated with LC40, and a SHR treated with K8/K8 group for 5 weeks (at dose of 3.3×10(10) colony-forming units/units in drinking water). Long-term administration of probiotics reduced systolic blood pressure. The consumption of K8/K8 mixture significantly reduced the cardiac and renal hypertrophy. Both groups of probiotics reversed the impaired aortic endothelium-dependent relaxation to acetylcholine observed in SHR. They also abolished the increased aortic superoxide levels by reducing the increased toll-like receptor-4 mRNA levels and NADPH oxidase activity found in SHR. K8/K8 consumption also increased endothelial nitric oxide synthase phosphorylation. Probiotics treatments induced a change in the caecum microbiota of SHR, with higher counts of the Lactobacillus spp. cluster, and lower counts of Bacteriodes spp. and Clostridium spp. Probiotics exert cardiovascular protective effects in genetic hypertension related to the improvement of vascular pro-oxidative and pro-inflammatory status. This article is protected by copyright. All rights reserved.

The innate immune system senses invading microorganisms by a phylogenetically conserved family of proteins--TLRs. They are expressed in several types of cells that represent a route of entry of pathogens into the host organism and that can contribute to protection against infection. Except for cells of the immune system, TLRs are present in epithelial cells of the skin, respiratory, intestinal, and genitourinary tracts that form the first protective barrier to invading pathogens. Polarized regulation of TLR expression in epithelial cells explains why pathogenic but not commensal bacteria elicit inflammatory responses. TLR-induced intracellular signalling pathways show remarkable complexity: apart from a common signalling pathway, additional signalling pathways specific for each of the TLRs are responsible for a fine tuning of the immune response, thus securing effective pathogen-directed biological responses.