Interleukin-17 in host defence against bacterial,mycobacterial and fungal pathogens

The mammalian immune system is intricately regulated, allowing for potent pathogen-specific immunity to be rapidly activated in response to infection with a broad and diverse array of potential pathogens. As a result of their ability to differentiate into distinct effector lineages, CD4 T cells significantly contribute to pathogen-specific adaptive immune responses. Through the production of effector cytokines, CD4 T helper (Th) cells orchestrate the precise mobilization of specific immune cells to eradicate infection. The protective effects of the newly identified lineage of Th17 cells against pathogens like Klebsiella pneumoniae, Citrobacter rodentium and Candida albicans indicate the capacity of Th17 cells to confer protection against extracellular bacterial and fungal pathogens, filling a critical void in host immunity not covered by the classically described Th1 lineage that activates immunity to intracellular pathogens or the Th2 lineage that is important in protection against mucosal parasitic pathogens. Host defence by Th17 cells extends beyond protection against extracellular bacterial and fungal pathogens, as demonstrated in infections against intracellular bacteria like Listeria monocytogenes and Salmonella enterica, as well as Mycobacterium tuberculosis. Herein, we summarize both experimental data from mouse infection models and epidemiological studies in humans that demonstrate the protective effects of interleukin-17 and Th17 CD4 T cells in immunity to bacterial, mycobacterial and fungal pathogens.     

自然杀伤T细胞在抗感染免疫中的作用研究进展

Natural killer T cell(NKT) are a unique T cell lineage expressing T cell receptor(TCR)and natural killer cell(NK) lineage receptors, and can recognize glycolipids presented by CD1d molecules expressed on antigen presenting cell through cell recognition pathway. After activated, NKT cells can release large amounts of cytokines, such as IL-4 and IFN-γ, and play a regulatory role in both innate and adaptive immune response. NKT cells can also act as direct effector cells via cytolysis or granulysin. NKT cells play an important role in infectious diseases, autoimmune disease,and cancer.     

自然杀伤T细胞在抗感染免疫中的作用研究进展

Natural killer T cell(NKT) are a unique T cell lineage expressing T cell receptor(TCR)and natural killer cell(NK) lineage receptors, and can recognize glycolipids presented by CD1d molecules expressed on antigen presenting cell through cell recognition pathway. After activated, NKT cells can release large amounts of cytokines, such as IL-4 and IFN-γ, and play a regulatory role in both innate and adaptive immune response. NKT cells can also act as direct effector cells via cytolysis or granulysin. NKT cells play an important role in infectious diseases, autoimmune disease,and cancer.     

自然杀伤T细胞在抗感染免疫中的作用研究进展

自然杀伤T细胞（NKT）是一类同时表达T细胞受体（TCR）dB和NK细胞表面标志的T细胞亚群,能识别由抗原提呈细胞（APC）表面CD1d分子提呈的脂类抗原。NKT细胞经抗原刺激后能迅速分泌大量的细胞因子（如IFN-1和IL-4）,调节固有免疫和适应性免疫,还能直接杀伤靶细胞,具有效应细胞的功能,在机体抗感染、肿瘤和自身免疫病方面发挥重要作用。     

Role of secretory antibodies in the defence against infections

Adaptive immunity mediated by secretory antibodies is important in the defence against mucosal infections. Specific secretory immunoglobulin A (SIgA) can inhibit initial pathogen colonization by performing immune exclusion both on the mucosal surface and within virus-infected secretory epithelial cells without causing tissue damage. Resistance against toxin-producing bacteria such as Vibrio cholerae appears to be particularly dependent on SIgA antibodies. Like natural infections, live topical vaccines or adequate combinations of inactivated vaccines and mucosal adjuvants give rise not only to SIgA antibodies, but also to long-standing serum IgG and IgA responses. The intranasal route of vaccine application could be particularly attractive to achieve this result, but only if successful stimulation is obtained without the use of toxic adjuvants. The degree of protection after vaccination may range from complete inhibition of reinfection to reduction of symptoms. In this scenario it is generally difficult to determine unequivocally the relative importance of SIgA versus serum antibodies. However, infection models in knockout mice strongly support the notion that SIgA exerts a decisive role in protection and cross-protection against a variety of infectious agents.     

Novel roles of osteopontin and CXC chemokine ligand 7 in the defence against mycobacterial infection

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced human monocyte-derived macrophage (GM-Mphi) or macrophage CSF (M-CSF)-induced human monocyte-derived Mphi (M-Mphi) are distinct in terms of the resistance to Mycobacterium tuberculosis. To elucidate the role of molecules involved in the functional differences between these Mphis, we investigated the gene expression profiles using microarray. After culture of CD14+ monocytes with CSFs, Mphis were cultured with or without bacillus Calmette-Guérin (BCG) (GM-Mphi-BCG and M-Mphi-BCG). The gene expression profiles from these cells were compared. Chemokines highly expressed in M-Mphis were selected and evaluated for anti-mycobacterial activity and superoxide production. FN1 and FCGR2B were the most up-regulated genes in GM-Mphi and M-Mphi, respectively. After stimulation with BCG, three chemokine genes (Osteopontin (SPP1), CXC chemokine ligand 7 (CXCL7) and CC chemokine ligand 11 (CCL11)) were highly expressed in M-Mphi-BCG when compared to those in GM-Mphi-BCG. A significantly increased resistance to M. tuberculosis H37Ra was observed after the stimulation of GM-Mphi with SPP1 or CXCL7. Superoxide production levels of SPP1- or CXCL7-stimulated GM-Mphis were higher than those of GM-Mphis without stimulation. These results indicate that both SPP1 and CXCL7 might have a role in the resistance against mycobacteria, at least in part, through augmenting reactive oxygen intermediate production in Mphis.     

Detrimental role of endogenous nitric oxide in host defence against Sporothrix schenckii

Dendritic cells (DCs) play a key role in the type and course of an immune response. The manipulation of human DCs to produce therapeutic agents by transduction with viral vectors is a growing area of research. We present an investigation into the effects of adenoviral vector infection on human DCs and other cell types, and on their subsequent ability to induce T-cell proliferation. We show that infection with replication-deficient adenovirus results in impaired proliferation of T cells in a mixed lymphocyte reaction (MLR). We show this to be an active suppression rather than a defect in the DCs as T cells also fail to proliferate in response to phytohaemagglutinin in the presence of adenoviral vector-infected DCs. This suppression is not attributable to phenotypic changes, death or inability of the DCs to produce cytokines on stimulation. By separation of DCs from T cells, and addition of conditioned supernatants, we show that suppression is mediated by a soluble factor. Blocking of interleukin (IL)-10 but not transforming growth factor (TGF)-beta could overcome the suppressive effect in some donors, and the source of the suppressive IL-10 was lymphocytes exposed to conditioned supernatant. Together our data suggest that infection of DCs by adenoviral vectors leads to suppression of the resulting immune response.     

Impaired host defence against Mycobacterium avium in mice with chronic granulomatous disease

Patients with chronic granulomatous disease (CGD), an inherited disorder of phagocytic cells, often contract recurrent life‐threatening bacterial and fungal infections. CGD is considered to arise from a functional defect of the O₂‐generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in phagocytes. To determine whether or not NADPH oxidase is crucial to the host defence against Mycobacterium avium, we investigated the response against M. avium using CGD model mice (gp91‐phox^‐) of C57BL/6 strain. A tracheal injection of 1 × 10⁷ colony‐forming units (CFU)/head of M. avium strain FN into the CGD mice resulted in a pulmonary infection, while also increasing the mortality rate. In contrast, normal C57BL/6 mice injected with same dose of the organisms did not develop severe pulmonary infection and were able to survive through 2 months of observation. The macrophages obtained from the CGD mice were observed to have a higher burden of the bacterial growth than macrophages from normal C57BL/6 mice. These results suggest that the defect of the NADPH oxidase function impairs the host defence against M. avium infection.     

Cell adhesion molecules in the pathogenesis of and host defence against microbial infection.

Eukaryotic cell adhesion molecules (CAMs) are used by various cells and extracellular molecules in host defence against infection. They are involved in many processes including recognition by circulating phagocytes of a site of inflammation, transmigration through the endothelial barrier, diapedesis through basement membrane and extracellular matrix, and release of effector mechanisms at the infected site. CAMs involved in leucocyte-endothelial cell interaction include the selectins, integrins, and members of the immunoglobulin superfamily. However, CAMs are also used by various microorganisms (protozoa, fungi, bacteria, and viruses) during their pathogenesis. For example, bacteria that utilise CAMs include Mycobacterium tuberculosis, Listeria monocytogenes, Yersinia spp, enteropathogenic Escherichia coli, Shigella spp, Neisseria spp, Bordetella spp, and Borrelia burgdorferi. In addition, CAMs are involved in the pathogenetic effects of the RTX toxins of Pasteurella haemolytica, Actinobacillus actinomycetemcomitans, and the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes. A recurrent and topical theme of potential importance within the bacterial group is the intimate relation between CAMs, bacterial protein receptors, and type III secretion systems. For example, the IpaBCD protein complex is secreted by the type III system of Shigella flexneri and interacts with alpha 5 beta 1 integrin on the eukaryotic cell surface, followed by Rho mediated internalisation; this illustrates the relevance of cellular microbiology. CAMs might prove to be novel therapeutic targets. Comparative genomics has provided the knowledge of shared virulence determinants among diverse bacterial genera, and will continue to deepen our understanding of microbial pathogenesis, particularly in the context of the interaction of prokaryotic and eukaryotic molecules.     

Cell adhesion molecules in the pathogenesis of and host defence against microbial infection.

Eukaryotic cell adhesion molecules (CAMs) are used by various cells and extracellular molecules in host defence against infection. They are involved in many processes including recognition by circulating phagocytes of a site of inflammation, transmigration through the endothelial barrier, diapedesis through basement membrane and extracellular matrix, and release of effector mechanisms at the infected site. CAMs involved in leucocyte-endothelial cell interaction include the selectins, integrins, and members of the immunoglobulin superfamily. However, CAMs are also used by various microorganisms (protozoa, fungi, bacteria, and viruses) during their pathogenesis. For example, bacteria that utilise CAMs include Mycobacterium tuberculosis, Listeria monocytogenes, Yersinia spp, enteropathogenic Escherichia coli, Shigella spp, Neisseria spp, Bordetella spp, and Borrelia burgdorferi. In addition, CAMs are involved in the pathogenetic effects of the RTX toxins of Pasteurella haemolytica, Actinobacillus actinomycetemcomitans, and the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes. A recurrent and topical theme of potential importance within the bacterial group is the intimate relation between CAMs, bacterial protein receptors, and type III secretion systems. For example, the IpaBCD protein complex is secreted by the type III system of Shigella flexneri and interacts with alpha 5 beta 1 integrin on the eukaryotic cell surface, followed by Rho mediated internalisation; this illustrates the relevance of cellular microbiology. CAMs might prove to be novel therapeutic targets. Comparative genomics has provided the knowledge of shared virulence determinants among diverse bacterial genera, and will continue to deepen our understanding of microbial pathogenesis, particularly in the context of the interaction of prokaryotic and eukaryotic molecules.     

Macrophage apoptosis in mycobacterial infections

Mycobacterial diseases are a major public health concern. In the case of tuberculosis, the problem has been acerbated due to the emergence of drug-resistant strains of Mycobacterium tuberculosis, and Mycobacterium avium is the major opportunistic pathogen in HIV-1 infection in the United States. M. tuberculosis and M. avium replicate in human macrophages and induce apoptosis. Incubation of freshly added uninfected autologous macrophages with apoptotic M. avium-infected macrophages results in 90% inhibition of bacterial growth. Apoptosis also prevents the release of intracellular components and the spread of mycobacterial infection by sequestering the pathogens within apoptotic bodies. Consistent with the model that host cell apoptosis is a defense mechanism against mycobacteria is the finding that the virulent M. tuberculosis strain H37Rv induces substantially less macrophage apoptosis than the attenuated strain H37Ra. Evasion of apoptosis by this pathogen is achieved by enhanced release of sTNFR2 by H37Rv-infected macrophages and subsequent formation of inactive TNF-alpha-TNFR2 complexes. These observations contribute to the hypothesis that apoptosis of the host macrophage is an important defense mechanism in mycobacterial infections, which prevents the spread of the infection.