Dissecting the Human Response to Systemic Infections.

is a common human commensal and the leading cause of diverse infections. To identify distinctive parameters associated with infection and colonization, we compared the immune and inflammatory responses of patients with a diagnosis of invasive disease to healthy donors. We analyzed the inflammatory responses founding a pattern of distinctive cytokines significantly higher in the patients with invasive disease.

Vaccine Research and Development: The Past, Present and Future, Including Novel Therapeutic Strategies.

is one of the most important human pathogens worldwide. Its high antibiotic resistance profile reinforces the need for new interventions like vaccines in addition to new antibiotics. Vaccine development efforts against have failed so far however, the findings from these human clinical and non-clinical studies provide potential insight for such failures.

-Specific Tissue-Resident Memory CD4 T Cells Are Abundant in Healthy Human Skin.

The skin is an immunocompetent tissue that harbors several kinds of immune cells and a plethora of commensal microbes constituting the skin microbiome. is a prominent skin pathogen that colonizes a large proportion of the human population. We currently have an incomplete understanding of the correlates of protection against infection, however genetic and experimental evidence has shown that CD4 T cells play a key role in orchestrating a protective anti- immune response.

Targeting Skin-Resident Memory T Cells via Vaccination to Combat Staphylococcus aureus Infections.

Tissue-resident memory T cells are important in adaptive immunity against many infections, rendering these cells attractive potential targets in vaccine development. Genetic and experimental evidence highlights the importance of cellular immunity in protection from Staphylococcus aureus skin infections, yet skin-resident memory T cells are, thus far, an untested component of immunity during such infections. Novel methods of generating and sampling vaccine-induced skin memory T cells are paralleled by discoveries of global, skin-wide immunosurveillance.

Human Three-Dimensional Models for Studying Skin Pathogens.

Skin is the most exposed surface of the human body, separating the microbe-rich external environment, from the sterile inner part. When skin is breached or its homeostasis is perturbed, bacterial, fungal and viral pathogens can cause local infections or use the skin as an entry site to spread to other organs. In the last decades, it has become clear that skin provides niches for permanent microbial colonization, and it actively interacts with microorganisms.

Human Organotypic Models for Anti-infective Research.

The use of human organotypic models for biomedical research is experiencing a significant increase due to their biological relevance, the possibility to perform high-throughput analyses, and their cost efficiency. In the field of anti-infective research, comprising the search for novel antipathogenic treatments including vaccines, efforts have been made to reduce the use of animal models. That is due to two main reasons: unreliability of data obtained with animal models and the increasing willingness to reduce the use of animals in research for ethical reasons.

One Dose of Staphylococcus aureus 4C-Staph Vaccine Formulated with a Novel TLR7-Dependent Adjuvant Rapidly Protects Mice through Antibodies, Effector CD4+ T Cells, and IL-17A.

A rapidly acting, single dose vaccine against Staphylococcus aureus would be highly beneficial for patients scheduled for major surgeries or in intensive care units. Here we show that one immunization with a multicomponent S. aureus candidate vaccine, 4C-Staph, formulated with a novel TLR7-dependent adjuvant, T7-alum, readily protected mice from death and from bacterial dissemination, both in kidney abscess and peritonitis models, outperforming alum-formulated vaccine.

MF59- and Al(OH)3-Adjuvanted Staphylococcus aureus (4C-Staph) Vaccines Induce Sustained Protective Humoral and Cellular Immune Responses, with a Critical Role for Effector CD4 T Cells at Low Antibody Titers.

Staphylococcus aureus (S. aureus) is an important opportunistic pathogen that may cause invasive life-threatening infections, like sepsis and pneumonia. Due to the increasing antibiotic resistance, the development of an effective vaccine against S.

Oil-in-Water Emulsion MF59 Increases Germinal Center B Cell Differentiation and Persistence in Response to Vaccination.

Induction of persistent protective immune responses is a key attribute of a successful vaccine formulation. MF59 adjuvant, an oil-in-water emulsion used in human vaccines, is known to induce persistent high-affinity functional Ab titers and memory B cells, but how it really shapes the Ag-specific B cell compartment is poorly documented. In this study, we characterized the Ab- and Ag-specific B cell compartment in wild-type mice immunized with HlaH35L, a Staphylococcus aureus Ag known to induce measurable functional Ab responses, formulated with MF59 or aluminum salts, focusing on germinal centers (GC) in secondary lymphoid organs.

Phagocyte subsets and lymphocyte clonal deletion behind ineffective immune response to Staphylococcus aureus.

Lack of known mechanisms of protection against Staphylococcus aureus in humans is hindering development of efficacious vaccines. Preclinical as well as clinical data suggest that antibodies play an important role against S. aureus.

Vaccine composition formulated with a novel TLR7-dependent adjuvant induces high and broad protection against Staphylococcus aureus.

Both active and passive immunization strategies against Staphylococcus aureus have thus far failed to show efficacy in humans. With the attempt to develop an effective S. aureus vaccine, we selected five conserved antigens known to have different roles in S.

NAD-dependent ADP-ribosylation of the human antimicrobial and immune-modulatory peptide LL-37 by ADP-ribosyltransferase-1.

LL-37 is a cationic peptide belonging to the cathelicidin family that has antimicrobial and immune-modulatory properties. Here we show that the mammalian mono-ADP-ribosyltransferase-1 (ART1), which selectively transfers the ADP-ribose moiety from NAD to arginine residues, ADP-ribosylates LL-37 in vitro. The incorporation of ADP-ribose was first observed by Western blot analysis and then confirmed by MALDI-TOF.

Helicobacter pylori induces activation of human peripheral γδ+ T lymphocytes.

Helicobacter pylori is a gram-negative bacterium that causes gastric and duodenal diseases in humans. Despite a robust antibody and cellular immune response, H. pylori infection persists chronically.

Small molecule Toll-like receptor 7 agonists localize to the MHC class II loading compartment of human plasmacytoid dendritic cells.

TLR7 and TLR8 are intracellular sensors activated by single-stranded RNA species generated during viral infections. Various synthetic small molecules can also activate TLR7 or TLR8 or both through an unknown mechanism. Notably, direct interaction between small molecules and TLR7 or TLR8 has never been shown.

Coligation of the hepatitis C virus receptor CD81 with CD28 primes naive T lymphocytes to acquire type 2 effector function.

Costimuli provide supplementary signals required by naive T cells to become fully activated upon Ag encounter. Tetraspanins are a large family of transmembrane proteins that can costimulate T cells when engaged in vitro. In this study, we describe for the first time that coligation of the tetraspanins CD81, CD82, or CD9 with the costimulatory molecule CD28 in vitro leads to proliferation of naive T cells.

Expression and selective up-regulation of toxin-related mono ADP-ribosyltransferases by pathogen-associated molecular patterns in alveolar epithelial cells.

Mono ADP-ribosyltransferases (ARTs) are a family of enzymes related to bacterial toxins that possess adenosine diphosphate ribosyltransferase activity. We have assessed that A549 constitutively expressed ART1 on the cell surface and shown that lipotheicoic acid (LTA) and flagellin, but not lipopolysaccharide (LPS), peptidoglycan (PG) and poly (I:C), up-regulate ART1 in a time and dose dependent manner. These agonists did not alter the expression of ART3 and ART5 genes.

T cell costimulation by the hepatitis C virus envelope protein E2 binding to CD81 is mediated by Lck.

Binding of the hepatitis C virus (HCV) envelope protein E2 to CD81 provides a costimulatory signal for human T cells. This phenomenon may play a role in liver damage and autoimmune manifestations associated with HCV infection. Here we show that cross-linking of CD81 by HCV E2 induced a calcium flux in T cells that depends on Lck since it was blocked by PP1 and absent in Lck-deficient Jurkat T cells.