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PubMed2001

Innate immunity and inflammation: a transcriptional paradigm.

The innate immune response and the process of inflammation are interwoven. Excessive and continuing cytokine production in response to bacterial lipopolysacharides (LPS) or superantigens is a hallmark of the systemic inflammatory response (IR), which can be life-threatening. Dissemination of these bacterial products induces waves of proinflammatory cytokines that cause vascular injury and multiple organ dysfunction. Both LPS and superantigens induce signaling to the nucleus in mononuclear phagocytes and T cells, respectively. These signaling pathways are mediated by NF-kappaB and other stress-responsive transcription factors (SRTFs), which play a critical role in reprogramming gene expression. The nuclear import of NF-kappaB allows transcriptional activation of over 100 genes that encode mediators of inflammatory and immune responses. We have developed a novel method to block nuclear import of NF-kappaB through cell-permeable peptide transduction in monocytes, macrophages, T lymphocytes, and endothelial cells. Strikingly, a cell-permeable peptide that antagonizes nuclear import of NF-kappaB and other SRTFs, suppressed the systemic production of proinflammatory cytokines (TNFalpha and interferon gamma) in mice challenged with a lethal dose of LPS, and increased their survival by at least 90%. Thus, systemic inflammatory responses are critically dependent on the transcriptional activation ofcytokine genes that are controlled by NF-kappaB and other SRTFs.

Active Transport, Cell Nucleus↗

PubMed2005

Constitutive innate immunity is a component of the pace-of-life syndrome in tropical birds.

We studied the relationship between one component of immune function and basal metabolic rate (BMR), an indicator of the 'pace-of-life syndrome', among 12 tropical bird species and among individuals of the tropical house wren (Troglodytes aedon), to gain insights into functional connections between life history and physiology. To assess constitutive innate immunity we introduced a new technique in the field of ecological and evolutionary immunology that quantifies the bactericidal activity of whole blood. This in vitro assay utilises a single blood sample to provide a functional, integrated measure of constitutive innate immunity. We found that the bactericidal activity of whole blood varied considerably among species and among individuals within a species. This variation was not correlated with body mass or whole-organism BMR. However, among species, bacteria killing activity was negatively correlated with mass-adjusted BMR, suggesting that species with a slower pace-of-life have evolved a more robust constitutive innate immune capability. Among individuals of a single species, the house wren, bacteria killing activity was positively correlated with mass-adjusted BMR, pointing to physiological differences in individual quality on which natural selection potentially could act.

Animals↗

PubMed2001

LBP, CD14, TLR4 and the murine innate immune response to a peritoneal Salmonella infection.

In mice, defense against an intraperitoneal Salmonella infection depends on a vigorous innate immune response. Mutations which lead to an inadequate early response to the pathogen thus identify genes involved in innate immunity. The best studied host resistance factor, NRAMP-1, is an endosomal membrane protein whose loss leads to an inability of the animals to hold the infection in check. However, innate defense against Salmonella is not restricted to mechanisms which directly attack the pathogen within macrophages. Here we have examined the contribution of the LBP, CD14 and TLR4 gene products to innate defense against Salmonella. To this end, we have generated mice which carry a wild-type allele of NRAMP-1, but which are deficient for the LBP, CD14 or TLR4 genes. Loss of any of these genes leads to a susceptibility to Salmonella as dramatic as that seen in animals lacking functional NRAMP-1 protein. This indicates that LBP, CD14 and TLR4 are all critical elements required in the proper induction of this innate defense system.

Acute-Phase Proteins↗

PubMed2006

Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men.

BACKGROUND: Increasing intakes of long-chain n-3 polyunsaturated fatty acids (PUFAs) can decrease markers of immunity. However, dose- and age-related responses have not been identified. OBJECTIVE: The objective was to determine the effects of different amounts of eicosapentaenoic acid (EPA) on innate immune outcomes in young and older males. DESIGN: In a controlled, double-blind study, healthy young and older men consumed 1 of 4 supplements provided as capsules: placebo (corn oil) or different amounts of an oil providing 1.35, 2.7, or 4.05 g EPA/d for 12 wk. Blood samples were collected at baseline and after 12 wk. RESULTS: EPA was incorporated in a linear dose-response fashion into plasma and mononuclear cell (MNC) phospholipids; incorporation was greater in the older men. EPA treatment did not alter neutrophil or monocyte phagocytosis, monocyte respiratory burst, or the production of inflammatory cytokines by MNCs in the young or older men. EPA treatment caused a dose-dependent decrease in neutrophil respiratory burst only in the older men. Increased incorporation of EPA into plasma or MNC phospholipids was associated with decreased production of prostaglandin E2 by MNCs from both young and older men. CONCLUSIONS: Older subjects incorporate EPA into plasma and MNC phospholipids more readily than do younger subjects. Other than prostaglandin E2 production, innate immune responses in young subjects are not affected by an EPA intake of < or =4.05 g/d. Older subjects are more sensitive to the immunologic effects of EPA, and the neutrophil respiratory burst is lower at higher EPA intakes.

Adolescent↗

PubMed2006

[Innate immunity restoration in patients with HIV/AIDS infection associated with antiretroviral therapy].

BACKGROUND: Highly active antiretroviral therapy (HAART) in HIV/AIDS infection induces an important reduction of the viral load (VL) and an immune system reconstitution. CD4+ T lymphocyte count is the immunological measurement commonly used for the follow up of HIV/AIDS patients. AIM: To study prospectively the restoration of the innate immune system in patients with HIV/AIDS infection during their first year on HAART. PATIENTS AND METHODS: 25 naive HIV/AIDS patients, from San José Hospital and University of Chile Clinical Hospital, Santiago, Chile, were studied between years 2002-2003. Every 4 months after HAART initiation, CD3+, CD4+, CD8+ T lymphocytes and CD16/56+ natural killer (NK) cells were quantified by flow cytometry. NK cell cytotoxicity was measured using radioactive chrome liberation (Cr51). Tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) were measured in peripheral blood mononuclear cells and viral load was determined using Amplicor HIV-1 from Roche Diagnostics Systems. RESULTS: Thirteen of the 25 patients continued in the study. They were all males, average age 35 years old (23-50). At baseline average CD4+ count was 146 cells/microL (31-362) and average viral load was 82.000 copies/mL (4.000-290.000). A raise in CD3+, CD4+, CD8+, and CD16/56 cells was noted at months 9-12 of therapy. Viral load became undetectable in the same period. NK cell function was decreased at the beginning of the therapy (1-4 months), reaching its highest values at months 9-12. There was no significant change in IL-10. TNF-alpha increased in six patients during the study. CONCLUSIONS: In this group of patients, innate immunity was restored during HAART. These results should be confirmed in studies with a longer follow up period and also measuring cytokines such as MIP-1a, MIP-1ss and RANTES.

Acquired Immunodeficiency Syndrome↗

PubMed2025

Perinatal dysfunction of innate immunity in cystic fibrosis.

In patients with cystic fibrosis (CF), repeated cycles of infection and inflammation eventually lead to fatal lung damage. Although diminished mucus clearance can be restored by highly effective CFTR modulator therapy, inflammation and infection often persist. To elucidate the role of the innate immune system in CF etiology, we investigated a CF pig model and compared these results with those for preschool children with CF. In newborn CF pigs, we observed changes in lung immune cell composition before the onset of infection that were dominated by increased monocyte infiltration, whereas neutrophil numbers remained constant. Flow cytometric and transcriptomic profiling revealed that the infiltrating myeloid cells displayed a more immature status. Cells with comparably immature transcriptomic profiles were enriched in the blood of CF pigs at birth as well as in preschool children with CF. This pattern coincided with decreased CD16 expression in the myeloid cells of both pigs and humans, which translated into lower phagocytic activity and reduced production of reactive oxygen species in both species. These results were indicative of a congenital, translationally conserved, and functionally relevant aberration of the immune system in CF. In newborn wild-type pigs, CFTR transcription in immune cells, including lung-derived and circulating monocytes, isolated from the bone marrow, thymus, spleen, and blood was below the detection limits of highly sensitive assays, suggesting an indirect etiology of the observed effects. Our findings highlight the need for additional immunological treatments to target innate immune deficits in patients with CF.

Cystic Fibrosis↗

PubMed2003

Innate immune collectins bind nucleic acids and enhance DNA clearance in vitro.

Collectins are a class of innate immune proteins that opsonize microbes and other ligands via their carbohydrate-recognition domains and enhance their clearance by phagocytes. We hypothesized that collectins, such as pulmonary surfactant protein (SP-) A and D and mannose-binding lectin (MBL), could bind nucleic acid, which is a pentameric sugar-based anionic polymer. We have shown that SP-D and MBL bind to both DNA and RNA effectively and also that SP-D enhances the uptake of DNA by human monocytic cells. Therefore, our results suggest that nucleic acids may be a novel class of ligands for collectins. This class of innate immune proteins could enhance the clearance of DNA that is released by necrotic cells or microbial cells. Our findings may have important biological implications, such as the alleviation of DNA-mediated tissue inflammation.

Binding Sites↗

PubMed2006

Rapid virus dissemination in infant macaques after oral simian immunodeficiency virus exposure in the presence of local innate immune responses.

A vaccine to protect human immunodeficiency virus (HIV)-exposed infants is an important goal in the global fight against the HIV pandemic. Two major challenges in pediatric HIV vaccine design are the competence of the neonatal/infant immune system in comparison to the adult immune system and the frequent exposure to HIV via breast-feeding. Based on the hypothesis that an effective vaccine needs to elicit antiviral immune responses directly at the site of virus entry, the pattern of virus dissemination in relation to host immune responses was determined in mucosal and lymphoid tissues of infant macaques at 1 week after multiple oral exposures to simian immunodeficiency virus (SIV). The results show that SIV disseminates systemically by 1 week. Infant macaques can respond rapidly to virus challenge and mount strong innate immune responses. However, despite systemic infection, these responses are most pronounced in tissues close to the viral entry site, with the tonsil being the primary site of virus replication and induction of immune responses. Thus, distinct anatomic compartments are characterized by unique cytokine gene expression patterns. Importantly, the early response at mucosal entry sites is dominated by the induction of proinflammatory cytokines, while cytokines with direct antiviral activity, alpha/beta interferons, are only minimally induced. In contrast, both antiviral and proinflammatory cytokines are induced in lymphoid tissues. Thus, although infant macaques can respond quickly to oral viral challenge, the locally elicited immune responses at mucosal entry sites are likely to favor immune activation and thereby virus replication and are insufficient to limit virus replication and dissemination.

AIDS Vaccines↗

PubMed2006

Innate immune defense through RNA interference.

RNA interference (RNAi, also known as RNA silencing) has recently emerged as a fundamental and widespread regulator of gene expression. New developments in this field implicate RNAi in the innate immune response to infection in plants and animals. Evidence from plants, tissue culture cells, and Caenorhabditis elegans-based systems previously suggested that RNAi plays a role in the defense against viral infection, but definitive evidence using viruses and whole animals has been lacking. Two recent reports now show that both Drosophila embryos and adult flies mount a substantial innate immune response to insect viruses that requires the RNAi machinery. This innate response is distinct from known bacterial and fungal defense systems provided by the Toll and immune deficiency (Imd) pathways, thus defining a previously unrecognized strategy to fight viral infection. Whether RNAi, aside from its function in counteracting viruses, is also used to fight bacterial infection remained enigmatic. New evidence, however, now shows that in Arabidopsis, the bacterial component, flagellin, induces the expression of a specific microRNA, which in turn leads to the down-regulation of the signaling pathways that are implicated in disease susceptibility. This down-regulation then increases the plant's resistance to infection. Whether RNAi mechanisms also exist for combating bacterial diseases in animals remains an intriguing question for future studies.

Animals↗

PubMed2006

Recognition of cytosolic DNA activates an IRF3-dependent innate immune response.

Nucleic acid recognition upon viral infection triggers type I interferon production. Viral RNA is detected by both endosomal, TLR-dependent and cytosolic, RIG-I/MDA5-dependent pathways. TLR9 is the only known sensor of foreign DNA; it is unknown whether innate immune recognition of DNA exists in the cytosol. Here we present evidence that cytosolic DNA activates a potent type I interferon response to the invasive bacterium Listeria monocytogenes. The noninvasive Legionella pneumophila triggers an identical response through its type IV secretion system. Activation of type I interferons by cytosolic DNA is TLR independent and requires IRF3 but occurs without detectable activation of NF-kappaB and MAP kinases. Microarray analyses reveal a unique but overlapping gene-expression program activated by cytosolic DNA compared to TLR9- and RIG-I/MDA5-dependent responses. These findings define an innate immune response to DNA linked to type I interferon production.

Animals↗

PubMed2004

Innate immune functions of the keratinocytes. A review.

Human keratinocytes are known to kill living microbes. They express different pattern recognition receptors (PRRs) such as the Toll-like receptor 2 (TLR2), TLR4, the CD1d molecule and a keratinocyte mannose-binding receptor (KcMR). In response to challenge with microbes or microbial-derived substances the activation and nuclear translocation of NF-kappaB, the production of nitric oxide (NO) and inflammatory cytokines occur in keratinocytes, in a TLR-dependent manner. Blocking of NF-kappaB activation or NO production inhibit the Candida albicans-killing activity of keratinocytes. This Candida killing activity could be inhibited by blocking of KcMR. Recognition of invading pathogens in the epidermis triggers cytokine production in keratinocytes leading to elimination of pathogens and the activation of the adaptive immune system. These findings stress the importance of the role of keratinocytes in innate immunity.

Humans↗

PubMed2004

The host resistance locus sst1 controls innate immunity to Listeria monocytogenes infection in immunodeficient mice.

Epidemiological, clinical, and experimental approaches have convincingly demonstrated that host resistance to infection with intracellular pathogens is significantly influenced by genetic polymorphisms. Using a mouse model of infection with virulent Mycobacterium tuberculosis (MTB), we have previously identified the sst1 locus as a genetic determinant of host resistance to tuberculosis. In this study we demonstrate that susceptibility to another intracellular pathogen, Listeria monocytogenes, is also influenced by the sst1 locus. The contribution of sst1 to anti-listerial immunity is much greater in immunodeficient scid mice, indicating that this locus controls innate immunity and becomes particularly important when adaptive immunity is significantly depressed. Similar to our previous observations using infection with MTB, the resistant allele of sst1 prevents formation of necrotic infectious lesions in vivo. We have shown that macrophages obtained from sst1-resistant congenic mice possess superior ability to kill L. monocytogenes in vitro. The bactericidal effect of sst1 is dependent on IFN-gamma activation and reactive oxygen radical production by activated macrophages after infection, but is independent of NO production. It is possible that there is a single gene that controls common IFN-dependent macrophage function, which is important in the pathogenesis of infections caused by both MTB and L. monocytogenes. However, host resistance to the two pathogens may be controlled by two different polymorphic genes encoded within the sst1 locus. The polymorphic gene(s) encoded within the sst1 locus that controls macrophage interactions with the two intracellular pathogens remains to be elucidated.

Animals↗

PubMed2002

Streptococcal inhibitor of complement inhibits two additional components of the mucosal innate immune system: secretory leukocyte proteinase inhibitor and lysozyme.

Streptococcal inhibitor of complement (SIC) is a 31-kDa extracellular protein of a few, very virulent, strains of Streptococcus pyogenes (particularly M1 strains). It is secreted in large quantities (about 5 mg/liter) and inhibits complement lysis by blocking the membrane insertion site on C5b67. We describe investigations into the interaction of SIC with three further major components of the innate immune system found in airway surface liquid, namely, secretory leukocyte proteinase inhibitor (SLPI), lysozyme, and lactoferrin. Enzyme-linked immunosorbent assays showed that SIC binds to SLPI and to both human and hen egg lysozyme (HEL) but not to lactoferrin. Studies using (125)I-labeled proteins showed that SIC binds approximately two molecules of SLPI and four molecules of lysozyme. SLPI binding shows little temperature dependence and a small positive enthalpy, suggesting that the binding is largely hydrophobic. By contrast, lysozyme binding shows strong temperature dependence and a substantial negative enthalpy, suggesting that the binding is largely ionic. Lysozyme is precipitated from solution by SIC. Further studies examined the ability of SIC to block the biological activities of SLPI and lysozyme. An M1 strain of group A streptococci was killed by SLPI, and the antibacterial activity of this protein was inhibited by SIC. SIC did not inhibit the antiproteinase activity of SLPI, implying that there is specific inhibition of the antibacterial domain. The antibacterial and enzymatic activities of lysozyme were also inhibited by SIC. SIC is the first biological inhibitor of the antibacterial action of SLPI to be described and may prove to be an important tool for investigating this activity in vivo. Inhibition of the antibacterial actions of SLPI and lysozyme would be advantageous to S. pyogenes in establishing colonization on mucosal surfaces, and we propose that this is the principal function of SIC.

Animals↗

PubMed2006

Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses.

Viral and microbial constituents contain specific motifs or pathogen-associated molecular patterns (PAMPs) that are recognized by cell surface- and endosome-associated Toll-like receptors (TLRs). In addition, intracellular viral double-stranded RNA is detected by two recently characterized DExD/H box RNA helicases, RIG-I and Mda-5. Both TLR-dependent and -independent pathways engage the IkappaB kinase (IKK) complex and related kinases TBK-1 and IKKvarepsilon. Activation of the nuclear factor kappaB (NF-kappaB) and interferon regulatory factor (IRF) transcription factor pathways are essential immediate early steps of immune activation; as a result, both pathways represent prime candidates for viral interference. Many viruses have developed strategies to manipulate NF-kappaB signaling through the use of multifunctional viral proteins that target the host innate immune response pathways. This review discusses three rapidly evolving areas of research on viral pathogenesis: the recognition and signaling in response to virus infection through TLR-dependent and -independent mechanisms, the involvement of NF-kappaB in the host innate immune response and the multitude of strategies used by different viruses to short circuit the NF-kappaB pathway.

Animals↗

PubMed2006

Adaptive response of Yersinia pestis to extracellular effectors of innate immunity during bubonic plague.

Yersinia pestis causes bubonic plague, characterized by an enlarged, painful lymph node, termed a bubo, that develops after bacterial dissemination from a fleabite site. In susceptible animals, the bacteria rapidly escape containment in the lymph node, spread systemically through the blood, and produce fatal sepsis. The fulminant progression of disease has been largely ascribed to the ability of Y. pestis to avoid phagocytosis and exposure to antimicrobial effectors of innate immunity. In vivo microarray analysis of Y. pestis gene expression, however, revealed an adaptive response to nitric oxide (NO)-derived reactive nitrogen species and to iron limitation in the extracellular environment of the bubo. Polymorphonuclear neutrophils recruited to the infected lymph node expressed abundant inducible NO synthase, and several Y. pestis homologs of genes involved in the protective response to reactive nitrogen species were up-regulated in the bubo. Mutation of one of these genes, which encodes the Hmp flavohemoglobin that detoxifies NO, attenuated virulence. Thus, the ability of Y. pestis to destroy immune cells and remain extracellular in the bubo appears to limit exposure to some but not all innate immune effectors. High NO levels induced during plague may also influence the developing adaptive immune response and contribute to septic shock.

Adaptation, Biological↗

PubMed2006

WFDC2 (HE4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung.

BACKGROUND: The Whey Acidic Protein domain is an evolutionarily conserved motif found in a number of proteins, the best studied of which are antiproteinases involved in the innate immune defence of multiple epithelia. We recently characterised the WFDC2 gene which encodes a two WAP domain-containing protein, initially suggested as a marker for epididymis, and showed that it is highly expressed in the lung and salivary gland. The precise location of WFDC2 protein in these sites has not been described. METHODS: We used immunohistochemistry to localise WFDC2 in normal tissues of the respiratory tract, naso- and oropharynx, as well as in chronically inflamed lung from Cystic Fibrosis and a range of pulmonary carcinomas. We have complemented these studies with molecular analysis of WFDC2 gene expression in primary human lung cell cultures. RESULTS: WFDC2 is expressed in some epithelial cells of the upper airways as well as in mucous cells and ducts of submucosal glands. No staining was seen in peripheral lung. Intense staining is found in major salivary glands and in minor glands of the nose, sinuses, posterior tongue and tonsil. Studies with the related protein Secretory Leukocyte Protease Inhibitor (SLPI) show that although both proteins are expressed in similar tissues, the precise cellular localisation differs. Significant increases in expression and localisation of WFDC2 are seen in patients with Cystic Fibrosis. SLPI expression was greatly reduced in the same samples. In cultures of tracheobronchial epithelial cells, expression of WFDC2 and SLPI are differentially regulated during differentiation yet WFDC2 is not induced by pro-inflammatory mediators. The majority of adenocarcinomas stain with WFDC2 whilst a significant minority of squamous, small cell and large cell carcinomas exhibit focal staining. There is no clear association with tumour grade. CONCLUSION: We believe that these studies support the hypothesis that WFDC2 may be a component of the innate immune defences of the lung, nasal and oral cavities and suggest that WFDC2 functions in concert with related WAP domain containing proteins in epithelial host defence. We also suggest that WFDC2 re-expression in lung carcinomas may prove to be associated with tumour type and should be studied in further detail.

Adenocarcinoma↗

PubMed2002

Molecular biology and immunology for clinicians 21: The innate immune system: an introduction.

The human (mammalian) immune response includes two interrelated but separable components: the innate immune system and an adaptive immune response. The former constitutes the sole immune defense strategy of invertebrates. It is only with vertebrate evolution that an adaptive immune response, first cellular, then later humoral, develops. Recent studies and a reconsideration of the innate system allow a fuller appreciation of its complexities, unique qualities, and irreplaceable value. In the early days of an infection, long before an effective adaptive immune response can be mounted, the innate system puts up an effective defense. Innate systems provide the costimulatory signal needed to unleash the adaptive immune response. Future contributions to this series will provide details about some of the specific innate immune systems. This article serves as an introduction to this underappreciated (until recently) aspect of human immune defenses.

Journal Article↗

PubMed2002

Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response.

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein. Unlike their Hck(-/-) "loss-of-function" counterparts, Hck(F/F) "gain-of-function" mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck(F/F) mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), Hck(F/F) mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)alpha. Similarly, Hck(F/F) mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from Hck(F/F) mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFalpha production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in Hck(F/F) mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.

Amino Acid Substitution↗