title: Phagocyte subsets and lymphocyte clonal deletion behind ineffective immune response to Staphylococcus aureus.
abstract: 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. For instance, certain hypogammaglobulinaemic patients are at increased risk of staphylococcal infections. However, development of effective humoral response may be dampened by converging immune-evasion mechanisms of S. aureus. We hypothesize that B-cell proliferation induced by staphylococcal protein A (SpA) and continuous antigen exposure, without the proper T-cell help and cytokine stimuli, leads to antigen-activated B-cell deletion and anergy. Recent findings suggest an important role of type I neutrophils (PMN-I) and conventionally activated macrophages (M1) against S. aureus, while alternatively activated macrophages (M2) favour biofilm persistence and sepsis. In addition, neutrophil-macrophage cooperation promotes extravasation and activation of neutrophils as well as clearance of bacteria ensnared in neutrophil extracellular traps. Activation of these processes is modulated by cytokines and T cells. Indeed, low CD4(+) T-cell counts represent an important risk factor for skin infections and bacteraemia in patients. Altogether, these observations could lead to the identification of predictive correlates of protection and ways for shifting the balance of the response to the benefit of the host through vaccination.
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Pozzi
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lofano
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soldaini
authors.affiliation: Department of Molecular Medicine, Institute of Biochemistry, 27100 Pavia, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Speziale
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bertholet
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Grandi
authors.affiliation: Novartis Vaccines, Research Center, via Fiorentina 1, 53100 Siena, Italy fabio.bagnoli@novartis.com.
authors.forename: Fabio
authors.initials: F
authors.lastname: Bagnoli
mesh_terms: D017637:Clonal Deletion; D006801:Humans; D057131:Immune Evasion; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D010586:Phagocytes / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology*; D013211:Staphylococcus aureus / Q000276:immunology*
keywords: B cells; Staphylococcus aureus; T cells; correlates of protection; hypogammaglobulinaemia; macrophages; neutrophils; vaccine