Group A Streptococcus emm3 strains induce early macrophage cell death.

Group A Streptococcus (GAS) infections present high morbidity and mortality rates and consequently remain a significant health problem. The emm3 isolates induce more severe pathologies than all others. In this study, we tested, on a collection of invasive and non-invasive emm3 clinical isolates, whether in that genotype the invasive status of the strains affects the innate immune response. We show that phagocytosis is dependent on the invasiveness of the isolates. Interestingly, all emm3 isolates compromise macrophage integrity, already noticeable 1 h after infection. Inflammatory modulators (IL-6, TNF-α and IFN-ß) are nevertheless detected during at least 6 h post-infection. This is a likely consequence of the macrophages not being all infected. The efficient and rapid induction of macrophage death could explain the virulence of the emm3 strains.

Srr2, a multifaceted adhesin expressed by ST-17 hypervirulent Group B Streptococcus involved in binding to both fibrinogen and plasminogen.

The Group B Streptococcus (GBS) 'hypervirulent' ST-17 clone is strongly associated with invasive neonatal meningitis. Comparative genome analyses revealed that the serine-rich repeat (Srr) glycoprotein Srr2 is a cell wall-anchored protein specific for ST-17 strains, the non-ST-17 isolates expressing Srr1. Here, we unravel the binding capacity of GBS Srr proteins to relevant components of the host fibrinolysis pathway. We demonstrate that: (i) Srr2 binds plasminogen and plasmin whereas Srr1 does not; (ii) the ability of ST-17 strains to bind fibrinogen reflects a high level surface display of Srr2 combined with a higher affinity of Srr2 than Srr1 to bind this ligand; and (iii) Srr2 binding to host plasma proteins results in the formation of bacterial aggregates that are efficiently endocytosed by phagocytes. Importantly, we show that Srr2 increased bacterial survival to phagocytic killing and bacterial persistence in a murine model of meningitis. We conclude that Srr2 is a multifaceted adhesin used by the ST-17 clone to hijack ligands of the host coagulation system, thereby contributing to bacterial dissemination and invasiveness, and ultimately to meningitis.

Loss of TLR3 aggravates CHIKV replication and pathology due to an altered virus-specific neutralizing antibody response.

RNA-sensing toll-like receptors (TLRs) mediate innate immunity and regulate anti-viral response. We show here that TLR3 regulates host immunity and the loss of TLR3 aggravates pathology in Chikungunya virus (CHIKV) infection. Susceptibility to CHIKV infection is markedly increased in human and mouse fibroblasts with defective TLR3 signaling. Up to 100-fold increase in CHIKV load was observed in Tlr3-/- mice, alongside increased virus dissemination and pro-inflammatory myeloid cells infiltration. Infection in bone marrow chimeric mice showed that TLR3-expressing hematopoietic cells are required for effective CHIKV clearance. CHIKV-specific antibodies from Tlr3-/- mice exhibited significantly lower in vitro neutralization capacity, due to altered virus-neutralizing epitope specificity. Finally, SNP genotyping analysis of CHIKF patients on TLR3 identified SNP rs6552950 to be associated with disease severity and CHIKV-specific neutralizing antibody response. These results demonstrate a key role for TLR3-mediated antibody response to CHIKV infection, virus replication and pathology, providing a basis for future development of immunotherapeutics in vaccine development.

Neutrophils: neglected players in viral diseases.

Increasing evidence has shown that neutrophils are able to crosstalk with various immune cells and have paradoxical roles in pathogen infections. However, the role of neutrophils in viral infections remains poorly defined. Here, the various roles that neutrophils play in viral infections and in host immunity are discussed. Various activation mechanisms of neutrophils following virus interactions and the consequences that affect disease pathogenesis are also addressed. Such knowledge not only could be used in the development of tools for clinical management but would also value-add to the current understanding of innate immunity in viral infections and disease pathogenesis.

Leishmania donovani promastigotes evade the antimicrobial activity of neutrophil extracellular traps.

Upon their recruitment to a site of infection and their subsequent activation, neutrophils release DNA and a subset of their granule content to form filamentous structures, known as neutrophil extracellular traps, which capture and kill microorganisms. In this study, we show that Leishmania promastigotes induced the rapid release of neutrophil extracellular traps from human neutrophils and were trapped by these structures. The use of Leishmania mutants defective in the biosynthesis of either lipophosphoglycan or GP63 revealed that these two major surface promastigote virulence determinants were not responsible for inducing the release of the surface protease neutrophil extracellular traps. We also demonstrate that this induction was independent of superoxide production by neutrophils. Finally, in contrast to wild-type Leishmania donovani promastigotes, mutants defective in lipophosphoglycan biosynthesis were highly susceptible to the antimicrobial activity of neutrophil extracellular traps. Altogether, our data suggest that neutrophil extracellular traps may contribute to the containment of L. donovani promastigotes at the site of inoculation, thereby facilitating their uptake by mononuclear phagocytes.