Interleukin-4 Causes Susceptibility to Invasive Pulmonary Aspergillosis through Suppression of Protective Type I Responses

Aspergillus fumigatus, an opportunistic fungal pathogen, causes multiple allergic and non-allergic airway diseases. Invasive pulmonary aspergillosis (IPA) is a nonallergic, life-threatening disease of immunocompromised patients. In a murine model of IPA, interleukin (IL)—4-deficient (IL-4−/−) BALB/c mice were used to examine the role of IL-4 in lung pathology and immune responses. IL-4−/− mice were more resistant than wild-type mice to infection caused by multiple intranasal injections of viable A. fumigatus conidia. Resistance was associated with decreased lung inflammatory pathology, impaired T helper (Th)—2 responses (including lung eosinophilia), and an IL-12—dependent Th1 response. In contrast, development of host-detrimental antifungal Th2 cells occurred in IL-12−/− and interferon-γ−/− mice and in IL-4−/− mice when subjected to IL-12 neutralization. These results demonstrate that IL-4 renders mice susceptible to infection with A. fumigatus by inhibition of protective Th1 responses. IL-4 appears to have a distinct role in the pathogenesis of allergic and nonallergic lung diseases caused by the fungu

Neutralization of chemokines RANTES and MIG increases virus antigen expression and spinal cord pathology during Theiler's virus infection.

The role of chemokines during some viral infections is unpredictable because the inflammatory response regulated by these molecules can have two, contrasting effects-viral immunity and immunopathologic injury to host tissues. Using Theiler's virus infection of SJL mice as a model of this type of disease, we have investigated the roles of two chemokines-regulated on activation, normal T cell-expressed and secreted (RANTES) chemokine and monokine induced by IFN-gamma (MIG)-by treating mice with antisera that block lymphocyte migration. Control, infected mice showed virus persistence, mild inflammation and a small degree of demyelination in the white matter of the spinal cord at 6 weeks post-infection. Treatment of mice with RANTES antiserum starting at 2 weeks post-infection increased both viral antigen expression and the severity of inflammatory demyelination at 6 weeks post-infection. MIG antiserum increased the spread of virus and the proportion of spinal cord white matter with demyelination. Overall, viral antigen levels correlated strongly with the extent of pathology. At the RNA level, high virus expression was associated with low IL-2 and high IL-10 levels, and RANTES antiserum decreased the IL-2/IL-10 ratio. Our results suggest that RANTES and MIG participate in an immune response that attempts to restrict viral expression while limiting immunopathology and that anti-chemokine treatment poses the risk of exacerbating both conditions in the long term

Immunological significance of genetic variation in structural proteins and the genetic determinants for cross protection of Porcine Reproductive and Respiratory Syndrome (PRRS) virus

The enormous genetic and antigenic diversity of PRRSV has become a diagnostic concern as it interferes with the accuracy of diagnostic tests and hampers the development of effective vaccines and the eradication of the disease. This study was conducted to assess the effects of genetic variation on serologic diagnosis and cross protection by antibody among different PRRS viruses and to identify the genetic elements critically associated with cross protection. Identification of the important genetic elements for cross protection would be useful not only to classify the viruses according to their immunologic relatedness but also to develop better disease-control methods including vaccines.;Three independent studies were designed to accomplish the stated objectives. The first study was conducted to determine if serologic data and the performance of serologic assays could be influenced by genotypic and/or biotypic differences of PRRS viruses and, if so, to assess the degree of effect. In the study, a comparative serologic study was conducted on five field and two cell-attenuated viruses to determine if serologic responses to PRRS virus infection could be influenced by biotypic and/or genotypic differences of the viruses. The isolates used for the study varied in their virulence to pigs and in genomic sequences. Ten pigs were inoculated with each isolate (1 x 103 TCID50) via the intranasal route. All inoculated animals became viremic during the study period. Some animals inoculated with the attenuated viruses remained seronegative until the end of the study (42 days PI), but all of the animals inoculated with field viruses developed ELISA- and IFA-detectable antibodies, regardless of the virus strain used in the IFA assay. In contrast, a great degree of variation in the onset and level of serum virus neutralization (SVN) antibody was observed by individual pigs and by each virus. The reactivity of SVN antibody was highly specific for homologous viruses. Therefore, it was concluded that the biotypic differences among PRRS viruses may affect the kinetics of humoral immune response in infected pigs. In addition, the IFA test may be used as a confirmatory test when a false-positive ELISA result is suspected or vise-a-versa at least among North American strains (PRRS virus type 2), but SVN antibody titers are highly affected by antigenic variability.;The second study was to identify genetic determinants associated with cross protection in ORF5 that encodes the major envelop protein (GP5) since GP5 has been postulated to be the most important protein to induce SVN antibody. The genetic elements within ORF5 which affect cross-neutralization were determined by genetically comparing field isolates which were classified according to their relative susceptibility to SVN antibody raised against VR2332 strain (North American prototype PRRS virus). In addition, the mutants in which the amino acid sequences were substituted with those found in the viruses resistant to SVN antibody at specific sites in ORF5 were generated using a VR2332-backboned infectious cDNA clone and site mutagenesis to confirm the role of those identified sites. Five common sites/domains (I to V) were identified in ORF5 from the sequence comparison after sixty-nine field isolated were classified based on the result of in vitro SVN test and/or animal challenge after passive immunization of SVN antibody. This suggests that the changes in amino acid sequences at three sites (32-34, 38-39, and 57-59) located in the N-terminal ectodomain of ORF5 significantly affected the susceptibility of the viruses to SVN antibody.;Finally, the third study was performed to assess the role of other structural proteins besides GP5 in cross protection among PRRS viruses and to define the corresponding genetic elements in each protein. In this study, chimeric mutants were generated by replacing ORF5 of an infectious clone constructed based on VR-2332 sequences with that of JA142, SDSU73, PRRS124, or 2M11715 to assess the role of ORF5 in cross neutralization. These viruses were genetically and antigenically distinct from VR-2332. In addition, chimeric mutants were constructed by substituting single or multiple structural genes of the VR-2332-infectious clone with the corresponding gene(s) of JA142. Virus neutralization test was performed on all mutants to determine the affect of substitutions on the susceptibility or resistance of viruses to the neutralizing activity of antisera generated against VR-2332, JA142, SDSU73 and PRRS124. All ORF5-replaced mutants showed the level of susceptibility or resistance close to that of the donor strains against homologous or heterologouos antisera but failed to achieve a complete reversion of cross neutralization. In contrast, substitution of ORFs 3-6 completely reversed the susceptibility of viruses to the neutralizing activity of anti-VR-2332 or JA142 antiserum. ORFs 3, 5, and 6 were additively responsible for such reversion between VR-2332 and JA142. These results indicate that the genetic similarity of ORFs 3 and 6 besides ORF5 should be taken into consideration to achieve the full-capacity of virus neutralization between two different PRRS viruses.;In conclusion, genetic variation of PRRSV negatively impacts cross neutralization among PRRS viruses. The similarity of specific amino acid determinants in GP3, GP5 and M proteins may significantly contribute to the level of cross protection between two viruses

Enhanced release of elastase is not concomitant with increased secretion of granulocyte-activating cytokines in whole blood from patients with sepsis

Die Diskussion am Ende des Artikels wurde gelöscht (§137l UrhG).Background The proteolytic enzyme elastase released by granulocytes (polymorphonuclear leukocytes [PMN]) in high concentrations during sepsis causes degradation of essential plasma proteins, endothelial damage, and tissue edema. This may result in organ dysfunction and organ failure during sepsis, since increased elastase plasma levels correlate with the mortality rate of patients with sepsis. In vitro studies demonstrated a regulatory role of inflammatory cytokines (tumor necrosis factor-{alpha} [TNF-{alpha}], interleukin 1β [IL-1β], IL-8]) upregulatingprotease release by PMN. In this light, the interactions between cytokine release by macrophages and altered elastase secretion during sepsis remain to be determined. Methods An ex vivo model consisting of lipopolysaccharide stimulation of human whole blood as a relevant physiological milieu was used. Heparinized blood was obtained from 20 patients with sepsis syndrome (APACHE II [Acute Physiology and Chronic Health Evaluation II] score 28.5±1.2 points [mean±SD]) on days 0 through 3, 5, 7, and 10 after sepsis diagnosis and from 20 control patients without infection. Blood was incubated with lipopolysaccharide (1 mg/L) for 8 hours. Plasma levels of elastase, TNF-{alpha}, IL-1β, and IL-8 were determined using enzyme-linked immunosorbent assay or bioassay (TNF-{alpha}), respectively. Results Elastase plasma levels in whole blood from patients with sepsis were increased up to 188% (P<.01) above normal, while the release of TNF-{alpha} (-87%), IL-1 β (-91%), and IL-8 (-51%) was markedly (P<.01) decreased compared with control patients. Neutralization of TNF-{alpha} or IL-1β did not attenuate the increased release of elastase. Conclusions These data indicate an increased release of elastase by PMN despite a reduced secretion of PMNactivating cytokines. Although priming effects of TNF-{alpha}, IL-1β, and IL-8 on protease secretion in vivo cannot be excluded completely, other mediators or mechanisms may be involved in the upregulation of detrimental protease release during sepsis

Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism.

BALB/c mice infected with Leishmania major develop fatal, progressive disease, despite an immune response characterized by expansion of CD4+ T cells in the draining lymph nodes. The immune response has been further characterized by a lack of IFN-gamma mRNA, but increased IL-4 mRNA in lymphoid tissues, and striking elevation of serum IgE. Treatment of infected BALB/c mice with rIFN-gamma at doses shown to be beneficial in other protozoan infections was insufficient to ameliorate L. major infection. In contrast, neutralization of IL-4 by six weekly injections of mAb 11B11 led to attenuation of disease in 100% of animals, and complete cure in 85%. Resolution of disease required the presence of T cells, and recovered mice remained resistant to reinfection at 12 wk. This immunity was adoptively transferable and was dependent on both CD4+ and CD8+ cells. Although administration of anti-IL-4 was associated with fourfold increase in IFN-gamma mRNA in lymph node cells draining the lesion, the coadministration of neutralizing R4 6A2 anti-IFN-gamma mAb had no effect on resistance to disease. This was in marked contrast to resolution of disease in both resistant C57BL/6- and GK1.5-pretreated BALB/c mice that was abrogated by in vivo treatment with anti-IFN-gamma. These data suggest a novel mechanism of cellular immunity established by interference with the development of Th2 cells during infection

Causes of bearing corrosion

Thesis (M.A.)--Boston University, 1941. This item was digitized by the Internet Archive

Type I interferon-driven susceptibility to Mycobacterium tuberculosis is mediated by IL-1Ra.

The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis and is responsible for more human mortality than any other single pathogen1. Progression to active disease occurs in only a fraction of infected individuals and is predicted by an elevated type I interferon (IFN) response2-7. Whether or how IFNs mediate susceptibility to Mtb has been difficult to study due to a lack of suitable mouse models6-11. Here, we examined B6.Sst1S congenic mice that carry the 'susceptible' allele of the Sst1 locus that results in exacerbated Mtb disease12-14. We found that enhanced production of type I IFNs was responsible for the susceptibility of B6.Sst1S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections6,7,15-18. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, Il1rn, which encodes interleukin-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb in B6.Sst1S mice. In addition, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6.Sst1S mice. Our results illustrate the value of the B6.Sst1S mouse to model IFN-driven susceptibility to Mtb, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo

IL-17A/F-Signaling Does Not Contribute to the Initial Phase of Mucosal Inflammation Triggered by S. Typhimurium

Salmonella enterica subspecies 1 serovar Typhimurium (S. Typhimurium) causes diarrhea and acute inflammation of the intestinal mucosa. The pro-inflammatory cytokines IL-17A and IL-17F are strongly induced in the infected mucosa but their contribution in driving the tissue inflammation is not understood. We have used the streptomycin mouse model to analyze the role of IL-17A and IL-17F and their cognate receptor IL-17RA in S. Typhimurium enterocolitis. Neutralization of IL-17A and IL-17F did not affect mucosal inflammation triggered by infection or spread of S. Typhimurium to systemic sites by 48 h p.i. Similarly, Il17ra−/− mice did not display any reduction in infection or inflammation by 12 h p.i. The same results were obtained using S. Typhimurium variants infecting via the TTSS1 type III secretion system, the TTSS1 effector SipA or the TTSS1 effector SopE. Moreover, the expression pattern of 45 genes encoding chemokines/cytokines (including CXCL1, CXCL2, IL-17A, IL-17F, IL-1α, IL-1β, IFNγ, CXCL-10, CXCL-9, IL-6, CCL3, CCL4) and antibacterial molecules was not affected by Il17ra deficiency by 12 h p.i. Thus, in spite of the strong increase in Il17a/Il17f mRNA in the infected mucosa, IL-17RA signaling seems to be dispensable for eliciting the acute disease. Future work will have to address whether this is attributable to redundancy in the cytokine signaling network