C5a Enhances Dysregulated Inflammatory and Angiogenic Responses to Malaria In Vitro: Potential Implications for Placental Malaria

Placental malaria (PM) is a leading cause of maternal and infant mortality. Although the accumulation of parasitized erythrocytes (PEs) and monocytes within the placenta is thought to contribute to the pathophysiology of PM, the molecular mechanisms underlying PM remain unclear. Based on the hypothesis that excessive complement activation may contribute to PM, in particular generation of the potent inflammatory peptide C5a, we investigated the role of C5a in the pathogenesis of PM in vitro and in vivo.Using primary human monocytes, the interaction between C5a and malaria in vitro was assessed. CSA- and CD36-binding PEs induced activation of C5 in the presence of human serum. Plasmodium falciparum GPI (pfGPI) enhanced C5a receptor expression (CD88) on monocytes, and the co-incubation of monocytes with C5a and pfGPI resulted in the synergistic induction of cytokines (IL-6, TNF, IL-1beta, and IL-10), chemokines (IL-8, MCP-1, MIP1alpha, MIP1beta) and the anti-angiogenic factor sFlt-1 in a time and dose-dependent manner. This dysregulated response was abrogated by C5a receptor blockade. To assess the potential role of C5a in PM, C5a plasma levels were measured in malaria-exposed primigravid women in western Kenya. Compared to pregnant women without malaria, C5a levels were significantly elevated in women with PM.These results suggest that C5a may contribute to the pathogenesis of PM by inducing dysregulated inflammatory and angiogenic responses that impair placental function

Altered antigen-presenting cells during HIV-1 infection

Purpose of reviewThe purpose of this study is to describe the alterations that HIV-1 induces in antigen-presenting cells (APCs), in vitro, ex vivo and in vivo.Recent findingsHIV-1 disarms several arms of the immune system including APCs. We summarize here recent findings on the impact of the virus on APC.SummaryHIV-1 can invade APC and overall reduce their capacity to present antigens effectively, mostly by reducing their numbers and inducing permanent hyperactivation. This occurs via a combination of alterations; however, the host can counteract, at least in part, some of these defects via restriction factors, autophagy, the production of type I interferon, antiviral cytokines, among others. However, these specific mechanisms of viral evasion from APCs' control lead to a chronic hyperactivation of the immune system implicated in AIDS-related and non-AIDS related pathogenesis. Unfortunately, the current regimens of antiretroviral therapy are unable to dampen sufficiently APC-driven viral-induced immune hyperactivation. Understanding how HIV alters APC will help to tune appropriately both intrinsic immunity and innate immunity, as well as achieve efficient antigen presentation to the adaptive immune system, without inducing a detrimental pervasive hyperactivation of the immune system

Structural effects and lymphocyte activation properties of self-assembled polysaccharide nanogels for effective antigen delivery

Abstract The success of immunotherapeutic vaccines is often limited by their inability to activate the cytotoxic T lymphocyte (CTL)-inducing Th1 pathway. We investigated the ability of self-assembled nanogels (CHP or CH-CDex) to activate this pathway, and characterised them chemically and biologically. Once loaded with antigen (ovalbumin, OVA) their OVA encapsulation and dissociation rates suggested the possibility of effective antigen delivery. The DC2.4 dendritic cell line took up either vaccine time-dependently, but both vaccines required CpG DNA for class I MHC presentation. The nanogel vaccines interacted with RAW264.7, a Balb/c mouse-derived macrophage cell line, and co-localised with lysosomes, suggesting their endocytotic internalization in RAW264.7. Both vaccines activated CTLs better than OVA alone. Unlike OVA alone, the nanogel vaccines induced IgG2a antibody production in mice, whereas the former induced IgG1 antibodies. OVA-nanogel delivery to the draining lymph nodes (DLNs) was higher than that for OVA alone, reaching a deeper medullary area. Furthermore, Langerin+ CD103+ DCs interacted with the nanogel vaccines effectively, which is a subset of cross-presentation DC, in the DLNs. The nanogel vaccines each had good anti-tumour efficacy in OVA tumour-bearing mice compared with the OVA alone. Thus, CHP and CH-CDex nanogels should be investigated further because of the great potential they offer for immunotherapy

Proceedings of the Frontiers of Retrovirology Conference 2016

The emergence of pandemic retroviral infection in small ruminant