Immunity against the pre-erythrocytic stages of malaria is the most promising, as it is strong and fully sterilizing. Yet, the underlying immune effectors against the human Plasmodium falciparum pre-erythrocytic stages remain surprisingly poorly known and have been little explored, which in turn prevents any rational vaccine progress. Evidence that has been gathered in vitro and in vivo, in higher primates and in humans, is reviewed here, emphasizing the significant role of IFN-, either as a critical immune mediator or at least as a valuable surrogate marker of protection. One may hope that these results will trigger investigations in volunteers immunized either by optimally irradiated or over-irradiated sporozoites, to quickly delineate better surrogates of protection, which are essential for the development of a successful malaria vaccine. © 2011 Perlaza et al; licensee BioMed Central Ltd.

Copyright © 2015 Ben Haij et al. We recently reported that the human immunodeficiency virus type-1 (HIV-1) Tat protein induced the expression of programmed death ligand-1 (PD-L1) on dendritic cells (DCs) through a TLR4 pathway. However, the underlying mechanisms by which HIV-1 Tat protein induces the abnormal hyper-activation of the immune system seen in HIV-1 infected patients remain to be fully elucidated. In the present study, we report that HIV-1 Tat protein induced the production of significant amounts of the pro-inflammatory IL-6 and IL-8 cytokines by DCs and monocytes from both healthy and HIV-1 infected patients. Such production was abrogated in the presence of anti-TLR4 blocking antibodies or soluble recombinant TLR4-MD2 as a decoy receptor, suggesting TLR4 was recruited by Tat protein. Tat-induced murine IL-6 and CXCL1/KC a functional homologue of human IL-8 was abolished in peritoneal macrophages derived from TLR4 KO but not from Wt mice, confirming the involvement of the TLR4 pathway. Furthermore, the recruitment of TLR4-MD2-CD14 complex by Tat protein was demonstrated by the activation of TLR4 downstream pathways including NF-κB and SOCS-1 and by down-modulation of cell surface TLR4 by endocytosis in dynamin and lipid-raft-dependent manners. Collectively, these findings demonstrate, for the first time, that HIV-1 Tat interacts with TLR4-MD2-CD14 complex and activates the NF-κB pathway, leading to overproduction of IL-6 and IL-8 pro-inflammatory cytokines by myeloid cells from both healthy and HIV-1 infected patients. This study reveals a novel mechanism by which HIV-1, via its early expressed Tat protein, hijacks the TLR4 pathway, hence establishing abnormal hyper-activation of the immune system.

Dendritic cells (DCs) and airway epithelial cells (AECs) are in close proximity, and AECs secrete factors such as retinoic acid which induce tolerance in DCs at homeostasis. However, the question remains as to how DCs in the lung are able to respond to pathogens in the immunosuppressive environment. Using an in vitro human myeloid DC (mDC)-AEC co-culture system, we demonstrate that AECs induced several gene changes in the mDCs cultured with AECs compared to the mDCs not cultured with AECs. Analysis revealed that several chemokine genes were altered. These chemokine genes could serve to attract neutrophils, natural killer (NK) T as well as T helper type 1 (Th1)/Th2 cells to the airways. Genes priming lipid and major histocompatibility complex (MHC) class II antigen presentation were also up-regulated, along with certain anti-microbial protein genes. In addition, the expression and function of pathogen-sensing Toll-like receptors (TLRs) as well as Nod-like receptors (NLRs) and their downstream signalling molecules were up-regulated in mDCs cultured with AECs. Moreover, murine mucosal DCs from the lung expressed significantly higher levels of TLRs and NLRs compared to peripheral DCs from the spleen. These results indicate that AECs prime mDCs to enhance their immunogenicity, which could be one of the mechanisms that compensates for the immunosuppressive mucosal environment.

Purpose: Using CJLAT, a chimeric herpes simplex virus (HSV-1) that produces a high incidence of herpes stromal keratitis (HSK) in latently infected rabbits, and in vivo confocal microscopy (CM), we characterized the cellular events that precede the development of HSK. Methods: Thirty days after infection, in vivo CM was performed daily for 10 days and then weekly for up to 80 days after infection. Results: We detected 3 types of subclinical corneal lesions before HSK was clinically apparent: (1) small epithelial erosions; (2) regenerating epithelium overlying small cell infiltrates within the basal epithelial cell layer; and (3) dendritic-like cells within the basal epithelial layer overlying stromal foci containing infiltrating cells. Sequential in vivo CM observations suggested that subclinical foci resolved over time but were larger and more abundant with CJLAT than with wild-type HSV-1 McKrae. Active HSK was observed only with CJLAT and was initially associated with a large epithelial lesion overlying stromal immune cell infiltrates. Conclusions: These results suggest that replication in the cornea of reactivated virus from the trigeminal ganglia produces epithelial lesions, which recruit immune cell infiltrates into the basal epithelial layer and anterior stroma. The virus is usually cleared rapidly eliminating viral antigens before the arrival of the immune cells, which disperse. However, if the virus is not cleared rapidly, or if an additional reactivation results in an additional round of virus at the same site before the immune cells disperse, then the immune cells are stimulated and may induce an immunopathological response leading to the development of HSK.

Background: Herpes simplex virus type 2 (HSV-2), the mostfrequent cause of genital ulcer disease (GUD), has been shown to play a moreimportant role than any other sexually transmitted infections (STIs) in drivingHIV prevalence in Africa. In turn, HIV-1 infection leads to more frequent HSV-2reactivations and shedding. The exact immune mechanisms involved in thisvirological negative immuno-synergy are unknown. In the present study we soughtto assess whether HIV co-infection would affects HSV-specific T cell immunity.Methods: Nineteen HSV peptides, derived from HSV-2glycoproteins gB and gD, were used to analyze the frequency and the magnitudeof HSV-2-specific IFN-γ-producing CD4⁺ and CD8⁺ T cellresponses in 30 HSV-2 seropositive patients and 17 HSV-2 seronegativeindividuals in a cohort of heterosexual Senegalese HIV-discordant couples,using ELISpot assay. HIV RNA viral load has been run for HIV infected subjects and CD4 count ran for all subjects using a flow cytometry method..Results: The magnitude and frequency HSV-2-specific Tcell responses was compared between 21 HSV-2 co-infected with HIV-1 and 9 HSV-2mono-infected individuals. A significantly higher magnitude of IFN-γ-producingT cell responses were observed in HSV-2 infected patients compared toseronegative individuals (median, 61 vs. 0 spots/10⁶ PBMC, P= 0.001). Moreover, twenty-four (80%) out of 30 HSV-2 seropositive patientsshowed significant HSV-2-specific IFN-γ-producing T cell responses comparedwith only 6 (35%) out of 17 HSV-2 negative subjects (P < 0.001). TheHSV-2 mono-infected patients showed significantly higher magnitude ofHSV-2-specific T cell responses compared to HSV/HIV co-infected patients(median, 140 vs. 42 spots/10⁶ PBMC, P = 0.024).Conclusions: Our finding suggest that co-infection with HIV-1 inHSV-2-infected patients might be associated with reduced HSV-2 cellular immuneresponses. However, the interaction between HIV and HSV-2 appears complex, andprecise longitudinal studies will be required to dissect their exact temporalrelationship.