Innate Immune Response to Dengue Virus: Toll-like Receptors and Antiviral Response.

Dengue is a mosquito-borne viral disease caused by the dengue virus (DENV1-4). The clinical manifestations range from asymptomatic to life-threatening dengue hemorrhagic fever (DHF) and/or Dengue Shock Syndrome (DSS). Viral and host factors are related to the clinical outcome of dengue, although the disease pathogenesis remains uncertain. The innate antiviral response to DENV is implemented by a variety of immune cells and inflammatory mediators. Blood monocytes, dendritic cells (DCs) and tissue macrophages are the main target cells of DENV infection. These cells recognize pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs). Pathogen recognition is a critical step in eliciting the innate immune response. Toll-like receptors (TLRs) are responsible for the innate recognition of pathogens and represent an essential component of the innate and adaptive immune response. Ten different TLRs are described in humans, which are expressed in many different immune cells. The engagement of TLRs with viral PAMPs triggers downstream signaling pathways leading to the production of inflammatory cytokines, interferons (IFNs) and other molecules essential for the prevention of viral replication. Here, we summarize the crucial TLRs' roles in the antiviral innate immune response to DENV and their association with viral pathogenesis.

Complement-Mediated Differential Immune Response of Human Macrophages to Sporothrix Species Through Interaction With Their Cell Wall Peptidorhamnomannans.

In this study, the human immune response mechanisms against Sporothrix brasiliensis and Sporothrix schenckii, two causative agents of human and animal sporotrichosis, were investigated. The interaction of S. brasiliensis and S. schenckii with human monocyte-derived macrophages (hMDMs) was shown to be dependent on the thermolabile serum complement protein C3, which facilitated the phagocytosis of Sporothrix yeast cells through opsonization. The peptidorhamnomannan (PRM) component of the cell walls of these two Sporothrix yeasts was found to be one of their surfaces exposed pathogen-associated molecular pattern (PAMP), leading to activation of the complement system and deposition of C3b on the Sporothrix yeast surfaces. PRM also showed direct interaction with CD11b, the specific component of the complement receptor-3 (CR3). Furthermore, the blockade of CR3 specifically impacted the interleukin (IL)-1ß secretion by hMDM in response to both S. brasiliensis and S. schenckii, suggesting that the host complement system plays an essential role in the inflammatory immune response against these Sporothrix species. Nevertheless, the structural differences in the PRMs of the two Sporothrix species, as revealed by NMR, were related to the differences observed in the host complement activation pathways. Together, this work reports a new PAMP of the cell surface of pathogenic fungi playing a role through the activation of complement system and via CR3 receptor mediating an inflammatory response to Sporothrix species.

Phagocytosis: Our Current Understanding of a Universal Biological Process.

Phagocytosis is a cellular process for ingesting and eliminating particles larger than 0.5 µm in diameter, including microorganisms, foreign substances, and apoptotic cells. Phagocytosis is found in many types of cells and it is, in consequence an essential process for tissue homeostasis. However, only specialized cells termed professional phagocytes accomplish phagocytosis with high efficiency. Macrophages, neutrophils, monocytes, dendritic cells, and osteoclasts are among these dedicated cells. These professional phagocytes express several phagocytic receptors that activate signaling pathways resulting in phagocytosis. The process of phagocytosis involves several phases: i) detection of the particle to be ingested, ii) activation of the internalization process, iii) formation of a specialized vacuole called phagosome, and iv) maturation of the phagosome to transform it into a phagolysosome. In this review, we present a general view of our current understanding on cells, phagocytic receptors and phases involved in phagocytosis.

Induction of innate immune response in whiteleg shrimp (Litopenaeus vannamei) embryos.

The immune response of commercially relevant marine invertebrates has been extensively studied, in search of new disease-control strategies. Immune training is considered a novel approach that could help improve resistance to different pathogens. Here, we stimulated the white shrimp (Litopenaeus vannamei) during embryo development by exposure to heat-killed bacteria and evaluated their effect on hatching, larval development, and the expression of immune-related genes. In addition, we evaluated its impact on the response of shrimp nauplii during a challenge with Vibrio parahaemolyticus. We observed that the percentage of hatching and the resistance to bacterial infection increased due to the treatment of embryos with heat-killed cells of Vibrio and Bacillus. Apparently different stimuli could generate a differential pattern of gene expression, e.g., Vibrio induced a strong effector immune response whereas Bacillus elicited a protective immune profile. In addition, each response was triggered by molecular patterns detected in the environment. The results obtained in this study provide new insights for immune training to improve shrimp farming.

Bacterial RNA Contributes to the Down-Modulation of MHC-II Expression on Monocytes/Macrophages Diminishing CD4+ T Cell Responses.

Brucella abortus, the causative agent of brucellosis, displays many resources to evade T cell responses conducive to persist inside the host. Our laboratory has previously showed that infection of human monocytes with B. abortus down-modulates the IFN-γ-induced MHC-II expression. Brucella outer membrane lipoproteins are structural components involved in this phenomenon. Moreover, IL-6 is the soluble factor that mediated MHC-II down-regulation. Yet, the MHC-II down-regulation exerted by lipoproteins was less marked than the one observed as consequence of infection. This led us to postulate that there should be other components associated with viable bacteria that may act together with lipoproteins in order to diminish MHC-II. Our group has recently demonstrated that B. abortus RNA (PAMP related to pathogens' viability or vita-PAMP) is involved in MHC-I down-regulation. Therefore, in this study we investigated if B. abortus RNA could be contributing to the down-regulation of MHC-II. This PAMP significantly down-modulated the IFN-γ-induced MHC-II surface expression on THP-1 cells as well as in primary human monocytes and murine bone marrow macrophages. The expression of other molecules up-regulated by IFN-γ (such as co-stimulatory molecules) was stimulated on monocytes treated with B. abortus RNA. This result shows that this PAMP does not alter all IFN-γ-induced molecules globally. We also showed that other bacterial and parasitic RNAs caused MHC-II surface expression down-modulation indicating that this phenomenon is not restricted to B. abortus. Moreover, completely degraded RNA was also able to reproduce the phenomenon. MHC-II down-regulation on monocytes treated with RNA and L-Omp19 (a prototypical lipoprotein of B. abortus) was more pronounced than in monocytes stimulated with both components separately. We also demonstrated that B. abortus RNA along with its lipoproteins decrease MHC-II surface expression predominantly by a mechanism of inhibition of MHC-II expression. Regarding the signaling pathway, we demonstrated that IL-6 is a soluble factor implicated in B. abortus RNA and lipoproteins-triggered MHC-II surface down-regulation. Finally, CD4+ T cells functionality was affected as macrophages treated with these components showed lower antigen presentation capacity. Therefore, B. abortus RNA and lipoproteins are two PAMPs that contribute to MHC-II down-regulation on monocytes/macrophages diminishing CD4+ T cell responses.

Platelet TLR4 at the crossroads of thrombosis and the innate immune response.

Platelet TLR-4 activation by pathogen- or damage-associated molecular pattern molecules triggers pro-thrombotic, proinflammatory, and pro-coagulant effector responses. Moreover, platelet TLR4 has a prominent role as a sensor of high lipopolysaccharide circulating levels during sepsis and in the clearance of pathogens mediated by neutrophils. This review presents evidence pointing to TLR4 as a bridge connecting thrombosis and innate immunity.

Helminth Infections: Recognition and Modulation of the Immune Response by Innate Immune Cells.

The survival of helminths in the host over long periods of time is the result of a process of adaptation or dynamic co-evolution between the host and the parasite. However, infection with helminth parasites causes damage to the host tissues producing the release of danger signals that induce the recruitment of various cells, including innate immune cells such as macrophages (Mo), dendritic cells (DCs), eosinophils, basophils, and mast cells. In this scenario, these cells are able to secrete soluble factors, which orchestrate immune effector mechanisms that depend on the different niches these parasites inhabit. Here, we focus on recent advances in the knowledge of excretory-secretory products (ESP), resulting from helminth recognition by DCs and Mo. Phagocytes and other cells types such as innate lymphocyte T cells 2 (ILC2), when activated by ESP, participate in an intricate cytokine network to generate innate and adaptive Th2 responses. In this review, we also discuss the mechanisms of innate immune cell-induced parasite killing and the tissue repair necessary to assure helminth survival over long periods of time.

PAMP-DAMPs interactions mediates development and progression of multiple sclerosis.

Multiple sclerosis (MS) is a disease presumably associated with chronic immune stimulation promoted by either pathogens or autoimmune processes. It has been hypothesized that MS could be the result of previous viral infections rendering a permanent immune stimulation that could be triggered by molecular similarities, or by modulating the antigens expression of major histocompatibility complex (MHC) on target cells, which in turn act as super antigens. During immune stimulation occurs the recruitment of immunological cells, resulting in local tissue damage and leading to the release of damage- associated molecular patterns (DAMPs), which also act as inflammation inducers. Recently, it has been proposed that the association between pathogen-associated molecular patterns (PAMPs) with DAMPs constitutes an additional level of immune regulation. The properties of DAMPs to act as carriers of PAMPs and their role as enhancers or inhibitors of PAMPs could play a role during inflammatory responses triggered by infections. Here, we focused this review in outcomes which support the hypothesis that particular PAMP-DAMPs interactions could regulated the relapse and progressive disability observed in multiple sclerosis.