Modulation of innate immune responses by hantaviruses

Hantavirus infection can cause hantavirus cardiopulmonary syndrome or hemorrhagic fever with renal syndrome depending on the virus species involved. The determinants for the virus species specific virulence in humans are unclear. Successful infection is a conditio sine qua non for the virulence of a virus and it is well-known that the innate interferon (IFN) system generally plays a decisive role to prevent establishment of an infection. The importance of the IFN system is underscored by the fact that viruses have developed an amazing number of different escape mechanisms to enable replication in face of the antiviral host response. Interestingly, pathogenic hantaviruses escape induction of innate antiviral responses in the early phase of the infection, which are elicited in a pronounced manner by nonpathogenic hantaviruses in vitro. This differential response might be important for the pathogenicity of hantaviruses in humans. This review aims to summarize the current knowledge about the interaction between hantaviruses and the innate IFN system. Detailed characterization of the cellular sensors and pathways that lead to activation of the IFN system on one side and the viral escape mechanisms on the other might help to develop novel vaccination strategies and therapeutic approaches.     

Induction and direction of immune responses by vaccine adjuvants

Successful vaccination against infectious or neoplastic disease programs the host's immune system, in a multistep process, to generate an efficient defense and memory response. Conditioning of immune responses to nonreplicating, poorly immunogenic antigens generally requires the help of an adjuvant. The present review attempts to classify vaccine adjuvants functionally, according to recently proposed, mutually exclusive concepts of immunity induction. These include the geographical concept of immune reactivity and the theory of depot effect. Both emphasize the importance of antigen delivery and localization to the lymph node in time after immunization. Other concepts stress the importance of key signals, such as "infectious nonself" or "danger," which influence the activation state of the antigen-presenting cell (APC) and, hence, its capacity to prime na?ve T cells. The nature of adjuvant-induced immune responses is discussed in relation to each concept.     

Regulation of innate immune responses by rabies virus

Rabies virus(RABV) is an infectious and neurotropic pathogen that causes rabies and infects humans and almost all warm-blooded animals, posing a great threat to people and public safety. It is well known that innate immunity is the critical first line of host defense against viral infection. It monitors the invading pathogens by recognizing the pathogen-associated molecular patterns and danger-associated molecular patterns through pattern-recognition receptors, leading to the production of type ...     

Activation of innate immune responses by IL-2-expressing Salmonella typhimurium is independent of Toll-like receptor 4

We previously demonstrated that an attenuated strain of Salmonella enterica serovar Typhimurium, engineered to express IL-2 (strain GIDIL2), is cleared more rapidly than its parental, non-cytokine-expressing, strain (designated BRD509) from the reticuloendothelial system of susceptible BALB/c mice. This early clearance correlated with the induction of a strong innate immune response within a few hours of administration of GIDIL2 organisms. In the present study, we wished to assess the contribution of LPS recognition to GIDIL2-induced immune responses using Toll-like receptor 4 (TLR4) mutant C3H/HeJ mice. In contrast to LPS responder mice, both BRD509 and GIDIL2 strains persisted at higher levels in LPS non-responder animals. However, the GIDIL2 bacterial loads in the peritoneal cavity and spleen, recovered over a period of 21 days post infection, were consistently lower than the corresponding CFUs of the BRD509 strain. Direct evidence for the induction of innate immunity was shown by demonstrating increased NK cell cytotoxicity, NOS2 gene expression, and nitric oxide synthesis by peritoneal cells obtained as early as 2h after infection with GIDIL2, but not BRD509, organisms. Unlike BALB/c mice, however, these responses failed to afford any protection against virulent challenge in C3H/HeJ mice. Taken together, our data demonstrate that despite the induction of innate immune responses by IL2-expressing organisms, this was not sufficient to induce protection in TLR4 mutant mice.     

Regulation of frontline antibody responses by innate immune signals

Mature B cells generate protective immunity by undergoing immunoglobulin (Ig) class switching and somatic hypermutation, two Ig gene-diversifying processes that usually require cognate interactions with T cells that express CD40 ligand. This T-cell-dependent pathway provides immunological memory but is relatively slow to occur. Thus, it must be integrated with a faster, T-cell-independent pathway for B-cell activation through CD40 ligand-like molecules that are released by innate immune cells in response to microbial products. Here, we discuss recent advances in our understanding of the interplay between the innate immune system and B cells, particularly “frontline” B cells located in the marginal zone of the spleen and in the intestine.     

Mechanisms of innate immune responses mediated by Toll-like receptors

The innate immune response is thought to be a rapid and nonclonal host defense. The recent discovery of Toll-like receptors (TLRs) and analyses of their physiological roles have established the notion that TLRs play a central role in innate immunity. Accumulating evidence suggests that individual TLRs recognize distinct ligands derived from bacterial components to generate specific cellular immune responses. In this review, we delineate the relationships between TLRs and microbial components, the TLR-mediated signaling pathways mainly based on cytoplasmic adaptor molecules containing Toll/interleukin-1R domains, the mechanism of TLR-mediated gene expression, and the involvement of TLRs in septic shock, including up-to-date observations.     

Riboflavin in innate and acquired immune responses

Objective and Design: Riboflavin, also known as vitamin B2, is a micronutrient with a key role in maintaining human health. It has also been shown to enhance host resistance to bacterial infections in mice. The aim of this study was to assess the role of vitamin B2 treatment in inflammatory conditions. Subjects and Methods: Three models of inflammatory states were assessed. One of them encompasses neutrophil mediated but T cell/macrophage independent cutaneous inflammation. Another one is delayed type hypersensitivity reaction (DTH), a T cell/macrophage dependent but neutrophil independent inflammatory response. The third one is collagen- induced arthritis, having components from both of the above described reactions. Mice were treated with vitamin B2, administered by peritoneal injections, throughout the course of the experiments. Results: The granulocyte dependent reaction to olive oil was significantly reduced in vitamin B2 treated mice. In contrast, DTH reactivity and collagen II arthritis were not affected by the treatment. Conclusion: Riboflavin administration affects neutrophil migration but does not alter acquired immune responsiveness. Received 20 April 2005; returned for revision 9 June 2005; returned for final revision 29 June 2005; accepted by M. Parnham 5 July 2005     

Roles of Toll-like receptors in innate immune responses

Innate immunity recognizes invading micro-organisms and triggers a host defence response. However, the molecular mechanism for innate immune recognition was unclear. Recently, a family of Toll-like receptors (TLRs) was identified, and crucial roles for these receptors in the recognition of microbial components have been elucidated. The TLR family consists of 10 members and will be expanding. Each TLR distinguishes between specific patterns of microbial components to provoke innate immune responses. The activation of innate immunity then leads to the development of antigen-specific adaptive immunity. Thus, TLRs control both innate and adaptive immune responses.     

Toll样受体在先天性免疫反应中的作用

先天性免疫识别侵袭的微生物,引起宿主防御反应.然而,先天性免疫识别的分子机制还不清楚.最近,有人发现了Toll样受体家族(TLRs),并阐明了这些受体在微生物识别中的主要作用.TLR基因家族包括11个成员,也可能更多.每种引起TLR先天性免疫反应的微生物类型各不相同.先天性免疫的激活引起特定抗原获得性免疫的发展.因此,TLRs控制先天性免疫反应和获得性免疫反应.     

Tailoring the immune response by targeting C-type lectin receptors on alveolar macrophages using "pathogen-like" amphiphilic polyanhydride nanoparticles

C-type lectin receptors (CLRs) offer unique advantages for tailoring immune responses. Engagement of CLRs regulates antigen presenting cell (APC) activation and promotes delivery of antigens to specific intracellular compartments inside APCs for efficient processing and presentation. In these studies, we have designed an approach for targeted antigen delivery by decorating the surface of polyanhydride nanoparticles with specific carbohydrates to provide pathogen-like properties. Two conserved carbohydrate structures often found on the surface of respiratory pathogens, galactose and di-mannose, were used to functionalize the surface of polyanhydride nanoparticles and target CLRs on alveolar macrophages (AM?), a principle respiratory tract APC. Co-culture of functionalized nanoparticles with AM? significantly increased cell surface expression of MHC I and II, CD86, CD40 and the CLR CIRE over non-functionalized nanoparticles. Di-mannose and galactose functionalization also enhanced the expression of the macrophage mannose receptor (MMR) and the macrophage galactose lectin, respectively. This enhanced AM? activation phenotype was found to be dependent upon nanoparticle internalization. Functionalization also promoted increased AM? production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. Additional studies demonstrated the requirement of the MMR for the enhanced cellular uptake and activation provided by the di-mannose functionalized nanoparticles. Together, these data indicate that targeted engagement of MMR and other CLRs is a viable strategy for enhancing the intrinsic adjuvant properties of nanovaccine adjuvants and promoting robust pulmonary immunity.     

TRAIL-R as a negative regulator of innate immune cell responses

TRAIL receptor (TRAIL-R) signaling has been implicated in inducing apoptosis in tumor cells, but little is understood about its physiological function. Here, we report the generation and characterization of TRAIL-R(-/-) mice, which develop normal lymphocyte populations but possess enhanced innate immune responses. TRAIL-R(-/-) mice exhibited increased clearance of murine cytomegalovirus that correlated with increased levels of IL-12, IFN-alpha, and IFN-gamma. Stimulation of macrophages with Mycobacterium and Toll-like receptor (TLR)-2, -3, and -4, but not TLR9, ligands resulted in high levels of TRAIL upregulation and enhanced cytokine production in TRAIL-R(-/-) cells. The immediate-early TLR signaling events in TRAIL-R(-/-) macrophages and dendritic cells are normal, but I kappa B-alpha homeostatic regulation and NF-kappa B activity at later time points is perturbed. These data suggest that TRAIL-R negatively regulates innate immune responses.     

Bioaerosols and innate immune responses in airway diseases

PURPOSE OF REVIEW: We review the role of bioaerosols in the pathogenesis of inflammatory airway disease. The focus is on recent discoveries in innate immune responses induced by common components of bioaerosols. RECENT FINDINGS: Common components of bioaerosols include endotoxin, peptidoglycan and beta-glucan; all of which have been associated with inflammatory airway disease. Endotoxin signaling through toll-like receptor 4 is well characterized and updated. Peptidoglycan is now known to signal through three types of molecules: toll-like receptor 2; peptidoglycan recognition proteins; and nucleotide-binding oligomerization domain molecules. Beta-glucan, a common fungal cell wall component, signals through the newly discovered receptor, dectin-1. Emerging data indicate that genetic polymorphisms influence the response to bioaerosols. SUMMARY: Activation of the innate immune system by bioaerosols is becoming better understood. This knowledge provides an opportunity to better prevent and treat airway diseases that result from environmental exposure.     

Adaptive and innate immune responses in celiac disease

Celiac disease (CD) is a complex small intestinal disorder due to a dysregulated immune response to wheat gliadin and related proteins which leads to a small intestinal enteropathy. It is generally accepted that CD is a T-cell mediated disease, in which, gliadin derived peptides, either in native form or deamidated by tissue transglutaminase, activate lamina propria infiltrating T lymphocytes which release proinflammatory cytokines. Recent studies indicate that gliadin contains also peptides able to activate an innate immune response. In particular, they induce a selective expansion of IEL, particularly TCRgamma/delta+ and CD8+TCR alpha/beta+ lymphocytes bearing the CD94 NK receptor, as well as a strong epithelial expression of MICA molecules which interact with NKG2D receptor expressed on TCRgamma/delta+ and NK cells. Most of the events of innate immune activation events are inhibited by antibodies neutralizing IL-15, thus confirming the key role of this cytokine as a mediator of intestinal mucosa damage induced by ingestion of gliadin. It remains to be established to what extent the ability of gliadin peptides to activate innate immunity relates to other biological properties exerted not only on celiac cells and tissues; the specificity of celiac patients is probably related to their genetic make up.     

Novel adjuvants and delivery systems for enhancing immune responses induced by immunogens

Vaccines are the most important preventive measure against infectious diseases. In developing an effective vaccine, besides the primary challenge of identifying the most relevant immunogen and efficient regime of immunization, selection of a potent adjuvant and delivery method is equally critical. The formulation of immunogens with different adjuvants may affect the affinity maturation of antibody responses differently, suggesting that the structure of specific epitopes within the immunogen may be influenced by different adjuvants. Thus, developing adjuvants that can efficiently activate both the innate and adaptive arms of the immune system is a major challenge for vaccine researchers. The use of novel adjuvants in combination with novel immunogen design holds great promise towards the goal of enhancing the potency, breadth and durability of vaccines. This article summarizes the different immunopotentiator (and immunomodulators) as well as the delivery systems that are available for vaccine generation and the types of immune responses that each of them induces. Also discussed are adjuvants that have a combination of both immunomodualtory and delivery properties.     

Chemokine gene adjuvants can modulate immune responses induced by DNA vaccines.

Nucleic acid immunization has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. Moreover, immune responses induced by DNA immunization can be enhanced by the use of molecular adjuvants. For example, coadministration of costimulatory molecules (CD80 and CD86), proinflammatory cytokines (interleukin-1alpha [IL-1alpha], tumor necrosis factor-alpha [TNF-alpha, and TNF-beta), Th1 cytokines (interleukin-2 [IL-2], IL-12, IL-15, and IL-18), Th2 cytokines (IL-4, IL-5, and IL-10), and granulocytes-macrophage colony-stimulating factor (GM-CSF) with DNA vaccine constructs leads to modulation of the magnitude and direction (humoral or cellular) of the immune responses. To further engineer the immune response in vivo, we compared the induction and regulation of immune responses from the codelivery of chemokine (IL-8, interferon-gamma-inducible protein-10 [gammaIP-10], macrophage inhibitory protein-1alpha [MIP-1alpha], and RANTES) genes with codelivery of cytokine genes. We found that as in cytokine gene codelivery, coimmunization with chemokine genes along with DNA immunogen constructs can modulate the direction and magnitude of induced immune responses. We observed that coimmunization with IL-8, gammaIP-10, and MIP-1alpha genes increased the antibody response. We also found that coinjection with IL-8, gammaIP-10, and RANTES resulted in a dramatic enhancement of T helper (Th) proliferation response. Furthermore, among all coinjection combinations, we found that RANTES coinjection caused a high level of cytotoxic lymphocyte (CTL) enhancement. This enhancement of CTL responses observed from the coinjection with RANTES was CD8+ T cell dependent. Together with earlier reports on the utility of coimmunizing immunologically important molecules with DNA immunogens, we demonstrate the potential of this strategy as an important tool for the development of more rationally designed vaccines.     

DAMPs activating innate and adaptive immune responses in COPD

Chronic obstructive pulmonary disease (COPD), a progressive lung disease characterized by sustained neutrophilic airway inflammation, is caused by chronic exposure to noxious stimuli, e.g., cigarette smoke. This chronic exposure can induce immunogenic cell death of structural airway cells, inducing the release of damage-associated molecular patterns (DAMPs). Levels of several DAMPs, including S100 proteins, defensins, and high-mobility group box-1 (HMGB1), are increased in extracellular lung fluids of COPD patients. As DAMPs can attract and activate immune cells upon binding to pattern recognition receptors, we propose that their release may contribute to neutrophilic airway inflammation. In this review, we discuss the novel role of DAMPs in COPD pathogenesis. Relevant DAMPs are categorized based on their subcellular origin, i.e. cytoplasm, endoplasmic reticulum, nucleus, and mitochondria. Furthermore, their potential role in the pathophysiology of COPD will be discussed.