In vivo Neutralization of Pro-inflammatory Cytokines During Secondary Streptococcus pneumoniae Infection Post Influenza A Virus Infection

An overt pro-inflammatory immune response is a key factor contributing to lethal pneumococcal infection in an influenza pre-infected host and represents a potential target for therapeutic intervention. However, there is a paucity of knowledge about the level of contribution of individual cytokines. Based on the predictions of our previous mathematical modeling approach, the potential benefit of IFN-γ- and/or IL-6-specific antibody-mediated cytokine neutralization was explored in C57BL/6 mice infected with the influenza A/PR/8/34 strain, which were subsequently infected with the Streptococcus pneumoniae strain TIGR4 on day 7 post influenza. While single IL-6 neutralization had no effect on respiratory bacterial clearance, single IFN-γ neutralization enhanced local bacterial clearance in the lungs. Concomitant neutralization of IFN-γ and IL-6 significantly reduced the degree of pneumonia as well as bacteremia compared to the control group, indicating a positive effect for the host during secondary bacterial infection. The results of our model-driven experimental study reveal that the predicted therapeutic value of IFN-γ and IL-6 neutralization in secondary pneumococcal infection following influenza infection is tightly dependent on the experimental protocol while at the same time paving the way toward the development of effective immune therapies

Interaction Effect of Gender and Neutralization Techniques on Information Security Policy Compliance: An Ethical Perspective

The study examines the following research question - does gender impact the efficacy of moral beliefs, and security policy understandability on security policy compliance intentions differently for various neutralization techniques? The empirical analysis conducted with data gathered from students using hypothetical scenarios suggest that gender does play a role in security policy noncompliance, however its significance is dependent upon the underlying neutralization technique. The paper provides several novel and important contributions. First, the study is among the first to extend the ethical decision making theory by suggesting that moral intensity is a function of neutralization, and individual factors such as perceived weight, value and one’s gender. Second, and more importantly the study is among the first to emphasize on the interplay between the ethics, gender, and neutralization techniques, as different ethical perspectives appeal differently to females than to males. The study has several important managerial implications as well

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

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

J. Randvere’s “Ruth” (1909) as an Example of Literary Decadence and the Quintessence of Young Estonia’s (1905–1915) Modern Ideology

This article is based on the interpretation of a segment of the reception of J. Randvere’s provocative, short essay-novella “Ruth” (1909), which was written by Johannes Aavik, a well-known Young Estonian and one of the principal modernizers of the Estonian language. This segment of reception regards “Ruth” as the quintessence of Young Estonia’s ideology, but does not offer a full explanation of how this ideology in “Ruth” is associated, on the one hand, with Young Estonians’ ambitions in modernizing Estonian literature and, on the other, with the broader fin de siècle European culture. I shall ask through which discourses does this ideology, which is innovative in the context of Estonian culture at the beginning of the 20th century, express itself in “Ruth”? What imaginations, representations and associations appear in “Ruth” in relation to the Young Estonian program, which interweaves tradition and/ or Estonian national-mindedness on the one hand, and Europeannes and/or modern ideas on the other. Or who are these Europeans and Estonians with whom Young Estonians wish to identify? Although Young Estonian ideology in “Ruth” has mostly been associated with connotations of decadence like “a culture of individuality”, “artificiality” and “aestheticism”, I will argue that in “Ruth” counter-discourses also come to the forefront. In other words, “Ruth” becomes the quintessence of the Young Estonia ideology, because it serves as a metaphoric counterpart to the Young Estonians’ program: “let us be Estonians, but let us become Europeans”. Through the reproduction of decadent discourse, which is in this text in the dominant position, “Ruth” oscillates between the ambivalent valorizations of signs of health (norms) and disease or decadence (deviation from the norms), accompanied, on the one hand, and among other things by opposition to the national discourse and, on the other hand, to the signs of decadence, that is the neutralization of the symptoms of decadence

Mycobacterium tuberculosis multi-drug-resistant strain M induces IL-17+ IFNγ- CD4+ T cell expansion through an IL-23 and TGF-β-dependent mechanism in patients with MDR-TB tuberculosis

We have previously reported that T cells from patients with multidrug-resistant tuberculosis (MDR-TB) express high levels of IL-17 in response to the MDR strain M(Haarlem family) of Mycobacterium tuberculosis (M.tuberculosis). Herein, we explore the pathways involved in the induction of h17 cells in MDR-TB patients and healthy tuberculin reactors (PPD+HD) by the M strain and the laboratory strain H37Rv. Our results show that IL-1β and IL-6 are crucial for the H37Rv and M-induced expansion of IL-17+IFNγ¯ and IL-17+IFNγ+ in CD4+ T cells from MDR-TB and PPD+HD. IL-23 plays an ambiguous role in Th1 and Th17 profiles: alone, IL-23 is responsible for M.tuberculosis induced IL-17 and IFNγ expression in CD4+ T cells from PPD+HD whereas, together with TGF-β, it promotes IL-17+IFNγ¯ expansion in MDR-TB. In fact, spontaneous and M.tuberculosis-induced TGF-β secretion is increased in cells from MDR-TB being theM strain the highest inducer. Interestingly, TLR-2 signaling mediates the expansion of IL-17+IFNγ¯ cells and the enhancement of latency-associated protein (LAP) expression in CD14+ and CD4+ T cells from MDR-TB, which suggests that M strain promotes IL-17+IFNγ¯ T cells through a strong TLR-2-dependent TGF-β production by antigenpresenting cells and CD4+ T cells. Finally, CD4+ T cells from MDR-TB patients infected with MDR Haarlem strains show higher IL-17+IFNγ¯ and lower IL-17+IFNγ+ levels than LAM-infected patients. The present findings deepen our understanding on the role of IL-17 in MDR-TB and highlight the influence of the genetic background of the infecting M.tuberculosis strain on the ex vivo Th17 response.Fil: Basile, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Kviatcovsky, Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Romero, María Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Monteserin, Johana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: Ritacco, Gloria Viviana. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: López, Beatriz. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C. G. Malbrán”; ArgentinaFil: Sabio y García, Carmen Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: García, A.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Vescovo, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Gonzalez Montaner, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Palmero, Domingo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas “Dr. Francisco Javier Muñiz”; ArgentinaFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: de la Barrera, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Leishmania promastigotes evade interleukin 12 (IL-12) induction by macrophages and stimulate a broad range of cytokines from CD4+ T cells during initiation of infection.

Leishmania major are intramacrophage parasites whose eradication requires the induction of T helper 1 (Th1) effector cells capable of activating macrophages to a microbicidal state. Interleukin 12 (IL-12) has been recently identified as a macrophage-derived cytokine capable of mediating Th1 effector cell development, and of markedly enhancing interferon gamma (IFN-gamma) production by T cells and natural killer cells. Infection of macrophages in vitro by promastigotes of L. major caused no induction of IL-12 p40 transcripts, whereas stimulation using heat-killed Listeria or bacterial lipopolysaccharide induced readily detectable IL-12 mRNA. Using a competitor construct to quantitate a number of transcripts, a kinetic analysis of cytokine induction during the first few days of infection by L. major was performed. All strains of mice examined, including susceptible BALB/c and resistant C57BL/6, B10.D2, and C3H/HeN, had the appearance of a CD4+ population in the draining lymph nodes that contained transcripts for IL-2, IL-4, and IFN-gamma (and in some cases, IL-10) that peaked 4 d after infection. In resistant mice, the transcripts for IL-2, IL-4, and IL-10 were subsequently downregulated, whereas in susceptible BALB/c mice, these transcripts were only slightly decreased, and IL-4 continued to be reexpressed at high levels. IL-12 transcripts were first detected in vivo by 7 d after infection, consistent with induction by intracellular amastigotes. Challenge of macrophages in vitro confirmed that amastigotes, in contrast to promastigotes, induced IL-12 p40 mRNA. Reexamination of the cytokine mRNA at 4 d revealed expression of IL-13 in all strains analyzed, suggesting that IL-2 and IL-13 may mediate the IL-12-independent production of IFN-gamma during the first days after infection. Leishmania have evolved to avoid inducing IL-12 from host macrophages during transmission from the insect vector, and cause a striking induction of mRNAs for IL-2, IL-4, IL-10, and IL-13 in CD4+ T cells. Each of these activities may favor survival of the organism

Yin and yang of interleukin-17 in host immunity to infection [version 1; referees: 2 approved]

The interleukin-17 (IL-17) family cytokines, such as IL-17A and IL-17F, play important protective roles in host immune response to a variety of infections such as bacterial, fungal, parasitic, and viral. The IL-17R signaling and downstream pathways mediate induction of proinflammatory molecules which participate in control of these pathogens. However, the production of IL-17 can also mediate pathology and inflammation associated with infections. In this review, we will discuss the yin-and-yang roles of IL-17 in host immunity to pathogens