Francisella tularensis aortitis.

Francisella tularensis, the agent of tularemia, is a Gram-negative coccobacillus primarily pathogen for animals and occasionally for humans. The clinical manifestations of tularemia include pneumonia, ulceroglandular, oropharyngeal, or typhoidal disease. Rare manifestations are also described, but to our knowledge, we describe here the first case of F. tularensis aortitis in a human. Diagnosis was confirmed by the presence of F. tularensis in blood culture, by the presence of F. tularensis DNA in the aortic biopsy and by specific IgG and IgM responses against the bacteria. The outcome was favorable after surgery and specific antimicrobial therapy.

Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice.

The transforming growth factor beta 1 (TGF beta 1) signalling pathway is important in embryogenesis and has been implicated in hereditary haemorrhagic telangiectasia (HHT), atherosclerosis, tumorigenesis and immunomodulation. Therefore, identification of factors which modulate TGF beta 1 bioactivity in vivo is important. On a mixed genetic background, approximately 50% Tgfb1-/- conceptuses die midgestation from defective yolk sac vasculogenesis. The other half are developmentally normal but die three weeks postpartum. Intriguingly, the vascular defects of Tgfb1-/- mice share histological similarities to lesions seen in HHT patients. It has been suggested that dichotomy in Tgfb1-/- lethal phenotypes is due to maternal TGF beta 1 rescue of some, but not all, Tgfb1-/- embryos12. Here we show that the Tgfb1-/- phenotype depends on the genetic background of the conceptus. In NIH/Ola, C57BL/6J/Ola and F1 conceptuses, Tgfb1-/- lethality can be categorized into three developmental classes. A major codominant modifier gene of embryo lethality was mapped to proximal mouse chromosome 5, using a genome scan for non-mendelian distribution of alleles in Tgfb1-/- neonatal animals which survive prenatal lethality. This gene accounts for around three quarters of the genetic effect between mouse strains and can, in part, explain the distribution of the three lethal phenotypes. This approach, using neonatal DNA samples, is generally applicable to identification of loci that influence the effect of early embryonic lethal mutations, thus furthering knowledge of genetic interactions that occur during early mammalian development in vivo.

Changing profile of encephalitis: Results of a 4-year study in France.

CONTEXT: In 2007, we performed a nationwide prospective study to assess the epidemiology of encephalitis in France. We aimed to evaluate epidemiological changes 10years later. METHODS: We performed a 4-year prospective cohort study in France (ENCEIF) from 2016 to 2019. Medical history, comorbidities, as well as clinical, biological, imaging, and demographic data were collected. For the comparison analysis, we selected similar data from adult patients enrolled in the 2007 study. We used Stata statistical software, version 15 (Stata Corp). Indicative variable distributions were compared using Pearson's Chi2 test, and means were compared using Student's t-test for continuous variables. RESULTS: We analyzed 494 cases from 62 hospitals. A causative agent was identified in 65.7% of cases. Viruses represented 81.8% of causative agents, Herpesviridae being the most frequent (63.6%). Arboviruses accounted for 10.8%. Bacteria and parasites were responsible for respectively 14.8% and 1.2% of documented cases. Zoonotic infections represented 21% of cases. When comparing ENCEIF with the 2007 cohort (222 adults patients from 59 hospitals), a higher proportion of etiologies were obtained in 2016-2019 (66% vs. 53%). Between 2007 and 2016-2019, the proportions of Herpes simplex virus and Listeria encephalitis cases remained similar, but the proportion of tuberculosis cases decreased (P=0.0001), while tick-borne encephalitis virus (P=0.01) and VZV cases (P=0.03) increased. In the 2016-2019 study, 32 causative agents were identified, whereas only 17 were identified in the 2007 study. CONCLUSION: Our results emphasize the need to regularly perform such studies to monitor the evolution of infectious encephalitis and to adapt guidelines.

Cyclosporin A inhibition of interleukin 2 gene expression, but not natural killer cell proliferation, after interferon induction in vivo.

The IFN inducer, poly(I:C), elicits acute NK cell blastogenesis and proliferation in vivo. The role of IL-2 in mediating this proliferation was investigated in the studies presented here. Blast NK cells were isolated from poly(I:C)-treated, T cell-deficient athymic mice. Dividing cells, incorporating [3H]thymidine, were enriched in the J11d- low density populations isolated from poly(I:C)-treated mice, and were characterized as NK by the following criteria: (a) they were eliminated by treatment with anti-AGM1 in vivo; and (b) they directly mediated lysis of NK-sensitive target cells in a single cell cytotoxicity assay with autoradiography. These poly(I:C)-induced blast NK cells were responsive to IL-2, but, when compared with in vivo activated T cells, responsiveness required 1,000-fold higher concentrations of the factor. The technique of in situ hybridization was used to evaluate induction of IL-2 gene expression after poly(I:C) treatment in vivo. Treatment of euthymic, athymic, and severe combined immunodeficient mice with poly(I:C) activated IL-2 gene expression in a small percentage of spleen leukocytes. The transcription-positive cells were enriched in low density cell populations. These findings demonstrate that IL-2 transcription occurs after IFN induction in vivo, and suggest that an endogenous source of IL-2 exists other than the mature T cell. To assess the IL-2 dependence of in vivo NK cell expansion, poly(I:C)-treated athymic mice were given cyclosporin A (CsA), an agent that regulates IL-2 production at the level of gene transcription. The drug resulted in an 85-100% reduction in the percentages of cells transcribing IL-2. In contrast, CsA administration did not block IFN-enhanced NK cell cytolytic activity, expansion of large granular lymphocyte numbers, or NK cell proliferation. These findings demonstrate that although the proliferation of blast NK cells can be supported by IL-2, IL-2 is not an important mediator of IFN-induced NK cell expansion. Moreover, they establish that the acute proliferation of NK cells in response to IFNs is CsA insensitive.

Interleukin 2-induced proliferation of murine natural killer cells in vivo.

The growth factor, IL-2, was administered to mice to evaluate the in vivo responsiveness of NK cells to this factor. The immediate effects of this factor on NK cells were determined by examining cytotoxic activity at 18-24 h after a single treatment with rIL-2. Although moderate doses of rIL-2 (3 x 10(4) U) could be shown to activate existing cytotoxic cells on a per cell basis, higher doses (10(6) U) were required to elicit blast size killer cells. The elicited killer cells were characterized as NK cells by the following criteria: (a) they were readily induced in athymic mice; (b) they mediated killing of NK-sensitive YAC-1 target cells but not NK-resistant P815 target cells; and (c) they expressed the NK cell determinants asialo ganglio-n-tetraosylceramide and NK1.1, but not the T cell determinants CD3, L3T4, or Lyt-2. High-dose IL-2 treatment induced not only the appearance of blast size NK cells, but also the expansion of this population. After treatments, the number of large granular lymphocytes and the number of NK1.1+ cells were increased at least twofold. Analysis of DNA content within the NK1.1+ cell subset demonstrated that IL-2 preferentially drove NK1.1+ cells into S and G2/M phases of the cell cycle. The in vivo elicited blast lymphocytes were examined by Northern blot analysis and in situ hybridization for expression of the IL-2-R p55 alpha chain gene. As previous work from this laboratory has demonstrated that NK cells proliferate in response to IFNs and IFN inducers in vivo, blast lymphocytes were also prepared after IFN treatments. The NK cells were not induced to express detectable levels of the alpha chain gene under any of the conditions examined. Blast T lymphocytes, isolated at times during viral infections when IL-2 production can be demonstrated in vitro, were induced to transcribe the alpha chain gene. Treatments of euthymic mice with high-dose IL-2 also induced transcription of the alpha chain gene in 41% of the non-B blast lymphocytes, but only background percentages of the NK1.1+ cells expressed the alpha chain gene. Transcription of the alpha chain gene was not induced in the NK cell-abundant athymic mice after IL-2 treatment. All of the in vivo elicited blast lymphocytes were induced to express IFN-gamma. Taken together, these data definitively demonstrate that IL-2 can induce NK cell proliferation and expansion in vivo. They also show that exposure to IL-2 in vivo, either by administration or endogenous production of the factor, induces transcription of the IL-2-R alpha chain gene in populations of cells containing T cell subsets. The results suggest, however, that murine NK cells are not induced to express high levels of the alpha chain gene in response to IL-2 in vivo.

Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration.

The presence of natural killer (NK) cells contributes to early defense against murine cytomegalovirus (MCMV) infection. Although NK cells can mediate in vivo protection against MCMV, the mechanism by which they do so has not been defined. The studies presented here evaluate cytokine production by NK cells activated during MCMV infection and the role of NK cell-produced cytokines in early in vivo antiviral defenses. Experiments with normal C57BL/6, T cell-deficient C57BL/6 nude, and severe combined immunodeficient mice lacking T and B cells demonstrated that both interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) production were induced at early times after infection with MCMV. Conditioned media samples prepared with cells from these mice, on day 2 after infection, produced 11-43 pg/million cells of IFN-gamma and 12-19 pg/million cells of TNF as evaluated by specific protein enzyme-linked immunosorbent assays. Studies in the NK- and T cell-deficient mouse line, E26, in mice that had been depleted in vivo of NK cells by treatment with antibodies eliminating NK cells, anti-asialo ganglio-N-tetraosylceramide or anti-NK1.1, and with populations of cells that had been depleted of NK cells by complement treatment with the anti-NK cell antibody, SW3A4, demonstrated that NK cells were solely responsible for the IFN-gamma but were not required for TNF production. The in vivo absence of NK cells was accompanied by increased viral hepatitis and viral replication in both immunocompetent and immunodeficient mice, as well as decreased survival time of immunodeficient mice. In vivo treatments with antibodies neutralizing IFN-gamma demonstrated that this factor contributed to the NK cell-mediated antiviral defense and reduced the measured parameters of viral defense to levels indistinguishable from those observed in NK cell-deficient mice. These effects appeared to be independent of cytolytic activity, as NK cells isolated from anti-IFN-gamma-treated mice mediated killing at levels comparable to those observed in control-treated mice. The consequences of interleukin 12 (IL-12) administration, a known potent inducer of IFN-gamma production by NK cells, were evaluated in MCMV-infected mice. Low IL-12 doses, i.e., 1 ng/d, increased NK cell cytotoxicity and IFN-gamma production up to twofold and resulted in improved antiviral status; virus-induced hepatitis was decreased as much as fivefold, and viral burdens were decreased to levels below detection.(ABSTRACT TRUNCATED AT 400 WORDS)

Early murine cytomegalovirus (MCMV) infection induces liver natural killer (NK) cell inflammation and protection through macrophage inflammatory protein 1alpha (MIP-1alpha)-dependent pathways.

Natural killer (NK) cells mediate defense against early murine cytomegalovirus (MCMV) infections in liver. The chemokine, macrophage inflammatory protein 1alpha (MIP-1alpha), can promote inflammatory responses. Our studies evaluated contributions of NK cells to early MCMV-induced liver inflammation and MIP-1alpha requirements for inflammation and delivery of antiviral defenses. NK cells were shown to be responsible for focal inflammation, and to be induced to migrate at high levels, in MCMV-infected livers. MIP-1alpha gene expression was elevated at coinciding times, and mice deficient in MIP-1alpha function were dramatically inhibited in both inflammatory and protective liver responses. The results precisely define MIP-1alpha-dependent steps required to achieve NK cell inflammation during, and mechanisms promoting defense against, viral infections in tissues.

Characterization of early cytokine responses and an interleukin (IL)-6-dependent pathway of endogenous glucocorticoid induction during murine cytomegalovirus infection.

Early infection with murine cytomegalovirus (MCMV) induces circulating levels of interleukin (IL)-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Studies presented here further characterize these responses by defining kinetics and extending evaluation to include IL-1, IL-6, and glucocorticoids. IL-12 p40, IFN-gamma, TNF, IL-1alpha, and IL-6 were shown to be increased, but IL-1beta was undetectable, in serum of MCMV-infected mice. The IL-12 p40, IFN-gamma, TNF, and IL-6 responses were dramatic with peak levels reaching >150-10,000 pg/ml at 32-40 h after infection and rapidly declining thereafter. Glucocorticoid induction, peaking at 36 h and reaching 30-fold increases above control values, accompanied the cytokine responses. Mice with cytokine deficiencies or neutralized cytokine function demonstrated that IL-6 was the pivotal mediator of the glucocorticoid response, with IL-1 contributing to IL-6 production. The IL-6 requirement appeared to be specific for virus-type stimuli as the synthetic analogue of viral nucleic acid, polyinosinic-polycytidylic acid, also induced IL-6-dependent glucocorticoid release, but treatments with the bacterial product lipopolysaccharide and a non-immune physical restraint stressor elicited IL-6-independent responses. Collectively, the results identify IL-6 as a primary mediator of glucocorticoid induction, and elucidate specific pathways of interactions between immune and neuroendocrine systems during viral infection.

Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells.

Diabetes-prone BioBreeding/Worcester (BB/Wor) rats received thrice weekly injections of mAb against antigens expressed on the surface of all T cells (OX19), cytotoxic/suppressor, and NK cells (OX8), helper/inducer cells (W3/25, OX35, OX38), and Ia+ cells (OX6, 3JP, OX17). Treatment with OX8 or OX19 achieved stable reductions of splenic and peripheral blood NK cells and helper/inducer T lymphocytes, respectively, and protected against diabetes. OX19 injections also prevented lymphocytic insulitis, thyroiditis, and the synthesis of autoantibodies to thyroid colloid and smooth muscle antigens. OX8 injections reduced splenic NK-mediated YAC-1 cell lysis, but did not prevent insulitis, thyroiditis, or autoantibody synthesis. Injections of mAb specific for antigens on the surface of helper/inducer cells, and for cells expressing IaE antigens provided marginal protection against diabetes without reductions of phenotypic subsets. These findings suggest that pancreatic beta cell destruction in the spontaneously diabetic BB/Wor rat is mediated by the combined action of NK and helper/inducer cells.

Two roads diverged: interferon alpha/beta- and interleukin 12-mediated pathways in promoting T cell interferon gamma responses during viral infection.

Viral infections induce CD8 T cell expansion and interferon (IFN)-gamma production for defense, but the innate cytokines shaping these responses have not been identified. Although interleukin (IL)-12 has the potential to contribute, IL-12-dependent T cell IFN-gamma has not been detected during viral infections. Moreover, certain viruses fail to induce IL-12, and elicit high levels of IFN-alpha/beta to negatively regulate it. The endogenous factors promoting virus-induced T cell IFN-gamma production were defined in studies evaluating CD8 T cell responses during lymphocytic choriomeningitis virus infections of mice. Two divergent supporting pathways were characterized. Under normal conditions of infections, the CD8 T cell IFN-gamma response was dependent on endogenous IFN-alpha/beta effects, but was IL-12 independent. In contrast, in the absence of IFN-alpha/beta functions, an IL-12 response was revealed and substituted an alternative pathway to IFN-gamma. IFN-alpha/beta-mediated effects resulted in enhanced, but the alternative pathway also promoted, resistance to infection. These observations define uniquely important IFN-alpha/beta-controlled pathways shaping T cell responses during viral infections, and demonstrate plasticity of immune responses in accessing divergent innate mechanisms to achieve similar ultimate goals.

Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids.

Interleukin 12 (IL-12) doses in excess of 100 ng/d have been shown to induce profound immunotoxicities in mice infected with lymphocytic choriomeningitis virus (LCMV). These immunotoxicities are characterized by almost complete inhibition of virus-induced CD8+ T cell expansion and CTL activation, and up to 2 log increases in viral replication. They are accompanied by induction of serum tumor necrosis factor (TNF). The studies presented here were undertaken to characterize mechanisms for the IL-12-induced toxicities and to examine expression and function of TNF in this context. Several physiological changes were induced in IL-12-treated uninfected and dramatically elevated in IL-12-treated virus-infected mice. IL-12 induced (a) decreases in body weights, > 10% in uninfected and > 20% in LCMV-infected mice; (b) elevation of circulating glucocorticoid levels to > 10 micrograms/dl in uninfected and > 20 micrograms/dl in infected mice; and (c) decreases in thymic mass, > 30% in uninfected and up to 95% in infected mice. These changes are known to be associated with circulating TNF. Northern blot and in situ hybridization analyses demonstrated that IL-12 induced TNF-alpha expression and that LCMV infection synergized with IL-12 for induction of this factor. Antibodies neutralizing TNF reversed all of the IL-12-induced toxicities in LCMV-infected mice including the immunotoxicities against CD8+ T cells and anti-viral defenses. The TNF-mediated immunotoxicities appeared to result from an induced cellular sensitivity to the factor, as splenic leukocytes and CD8+ T cell subsets isolated from LCMV-infected mice were more sensitive to TNF-mediated cytotoxicity in culture than were equivalent populations prepared from uninfected mice. Experiments with the glucocorticoid type II receptor antagonist, RU486, demonstrated that endogenous glucocorticoids were secondary intermediaries in IL-12-induced thymic atrophy. Studies in IL-2-deficient mice showed that the synergism was dependent upon endogenous IL-2. The results delineate a unique mechanism of TNF-mediated toxicity. In addition, they have significant implications concerning potential detrimental consequences of in vivo TNF induction and of IL-12 administration for protective anti-viral responses.

Community-acquired bacterial meningitis in adults: in-hospital prognosis, long-term disability and determinants of outcome in a multicentre prospective cohort.

OBJECTIVES: To identify factors associated with unfavourable in-hospital outcome (death or disability) in adults with community-acquired bacterial meningitis (CABM). METHODS: In a prospective multicentre cohort study (COMBAT; February 2013 to July 2015), all consecutive cases of CABM in the 69 participating centres in France were enrolled and followed up for 12 months. Factors associated with unfavourable outcome were identified by logistic regression and long-term disability was analysed. RESULTS: Among the 533 individuals enrolled, (Streptococcus pneumoniae 53.8% (280/520 isolates identified), Neisseria meningitidis 21.3% (111/520), others 24.9% (129/520)), case fatality rate was 16.9% (90/533) and unfavourable outcome occurred in 45.0% (225/500). Factors independently associated with unfavourable outcome were: age >70 years (adjusted odds ratio (aOR) 4.64; 95% CI 1.93-11.15), male gender (aOR 2.11; 95% CI 1.25-3.57), chronic renal failure (aOR 6.65; 95% CI 1.57-28.12), purpura fulminans (aOR 4.37; 95% CI 1.38-13.81), localized neurological signs (aOR 3.72; 95% CI 2.29-6.05), disseminated intravascular coagulation (aOR 3.19; 95% CI 1.16-8.79), cerebrospinal fluid (CSF) white-cell count <1500 cells/µL (aOR 2.40; 95% CI 1.42-4.03), CSF glucose concentration (0.1-2.5 g/L: aOR 1.92; 95% CI 1.01-3.67; <0.1 g/L: aOR 2.24; 95% CI 1.01-4.97), elevated CSF protein concentration (aOR 1.09; 95% CI 1.03-1.17), time interval between hospitalization and lumbar puncture >1 day (aOR 2.94; 95% CI 1.32-6.54), and S. pneumoniae meningitis (aOR 4.99; 95% CI 1.98-12.56), or meningitis other than N. meningitidis (aOR 4.54; 95% CI 1.68-12.27). At 12 months, 26.7% (74/277) had hearing loss, 32.8% (87/265) depressive symptoms, 31.0% (86/277) persistent headache, and 53.4% had a physical health-related quality of life (142/266) <25th centile of the distribution of the score in the general French population (p < 0.0001). CONCLUSIONS: The burden of CABM (death, disability, depression, impaired quality of life and hearing loss) is high. Identification of cases from the first symptoms may improve prognosis. CLINICALTRIAL: Gov identification number: NCT01730690.

Acceptance of pregnant women's vaccination against pertussis among French women and health professionals: PREVACOQ-1 and -2 studies.

OBJECTIVES: Protection of French young infants against pertussis only relies on their relatives' vaccination. The alternative is vaccination of pregnant women against pertussis (cocooning strategy), but this strategy is not yet recommended in France. We assessed the acceptance of this strategy among French postpartum women and health professionals. PATIENTS AND METHODS: We performed a multicenter survey in 2016 among postpartum women and health professionals (family physicians, obstetricians-gynecologists, midwives, and medical students) to determine the acceptance of anti-pertussis vaccination. We evaluated knowledge, perception, and attitude towards vaccination to identify factors associated with acceptance. RESULTS: Questionnaires were completed by 52% (1208/2337) of women and 40% (694/1754) of health professionals. Seventy-seven per cent of women (95% CI: 74-79) and 93% of health professionals (95% CI: 91-95) were favorable to anti-pertussis vaccination of pregnant women. Thirty-three per cent (227/687) of health professionals believed that pertussis induced life-long immunity and 20% (136/687) of them were not aware of the cocooning strategy. In multivariate analysis, factors associated with acceptance among women were younger age, higher knowledge, having received advice during pregnancy, being vaccinated against influenza, and having never refused any vaccine; among health professionals, factors associated with acceptance were belief that inactivated vaccines are obstetrically safe, regular practice of influenza vaccination in pregnant women, pertussis cocooning strategy, and never prescribing preventive homeopathy for influenza. CONCLUSION: Vaccination of pregnant women against pertussis should be well-accepted by informed mothers and health professionals. If this strategy were to be implemented in France, efforts should be made towards adequate information.

A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense.

Macrophage inflammatory protein 1alpha (MIP-1alpha) promotes natural killer (NK) cell inflammation in livers during murine cytomegalovirus (MCMV) infections, and NK cell-produced interferon gamma (IFN-gamma) contributes to defense against MCMV infections. A specific role for local NK cell IFN-gamma production, however, has not been established. The importance of MIP-1alpha and NK cell-produced IFN-gamma in shaping endogenous immune responses and defense in different compartments was examined. MIP-1alpha deficiency profoundly decreased resistance to MCMV and was associated with dramatically reduced NK cell accumulation and IFN-gamma production in liver. MIP-1alpha-independent IFN-gamma responses were observed in serum and spleen, and infection-induced elevations in blood NK cell populations occurred in absence of the factor, but peak liver expression of another chemokine, the monokine induced by IFN-gamma (Mig), depended upon presence of MIP-1alpha, NK cells, and IFN-gamma. The Mig response was also important for viral resistance. Thus, serum cytokine responses are insufficient; MIP-1alpha is critical for NK cell migration and IFN-gamma delivery to mediate protection; and Mig induction in tissues is a downstream protective response resulting from the process. These results define a critical chemokine-to-cytokine-to-chemokine cascade required for defense during a viral infection establishing itself in tissues.

Activation and function of natural killer cell responses during viral infections.

Although the role of natural killer (NK) cells in defense against certain viral infections has been appreciated for a number of years, characterization of the virus-induced endogenous mechanisms regulating NK cell responses and functions has been limited to interferon (IFN)-alpha/beta-mediated activation of NK cell cytotoxicity. Studies of experimental infections have demonstrated that virus-induced NK cells undergo blastogenesis and can be activated to produce IFN-gamma. Recent work has shown that some, but not all, viral infections induce IL-12, the expression of which results in NK cell IFN-gamma production, and that NK cell IFN-gamma production contributes to an antiviral state. IL-12 expression can be regulated by IFN-alpha/beta, and endogenous IFN-alpha/beta is responsible for the lack of IL-12 during viral infections that fail to elicit detectable production of this factor. Once T cell responses are activated, additional mechanisms are in place to turn off NK cell functions. These studies demonstrate that viral infections elicit unique mechanisms for regulating NK cell responses, and suggest that the host requires tight control of NK cells under these conditions.

Cytokines in the generation of immune responses to, and resolution of, virus infection.

A number of immune system components contribute to defense against viral infections. Although some of these overlap in part with those contributing to resistance against non-viral agents, the major anti-viral players comprise a unique subset. In particular, natural killer cells and CD8+ cytotoxic T cells are prominent in defense against viruses. With the exception of interferon-alpha/beta, cytokine responses during viral infections have not been thoroughly characterized and are poorly understood with regard to in vivo expression and function. The availability of recombinant cytokines, assays to measure induced cytokine expression, and cytokine and cytokine receptor negative mice has made it possible to begin to characterize other factors contributing to defense and immune regulation during viral infections. Advances have been made in characterizing the expression and functions of interferon-gamma, IL-2, IL-4, IL-10, transforming growth factor-beta, and IL-12. The results thus far suggest that there are at least three different stages of immune responses to viral infections and that unique cytokine profiles are associated with each of these stages.

NK cells and NKT cells in innate defense against viral infections.

NK cells contribute to innate defense during certain viral infections, but the mechanisms for their regulation and delivery of antiviral effects are incompletely understood. A second NK cell population, from within T cell populations--NKT cells--has a unique potential to initiate cellular effector mechanisms, including those delivered by NK cells, provided that the antigen for their restricted TCR is induced during infection. If elicited, particular innate cytokine responses promote activation of NK cell cytotoxicity or IFN-gamma production. These responses can contribute to defense by mediating antiviral and/or immunoregulatory effects. Roles of positive or negative receptors for target cells in protection against viruses are less clear. Exciting new data indicate that, in at least one system, NK cell receptors that positively signal for activation participate in the recruitment of these cells into antiviral defense mechanisms. Other recent evidence suggests that NKT cells may be important for protection during one viral infection and may be artificially activated by delivery of antigen to promote antiviral defense. Taken together, these recent advances in the characterization of the NK and NKT cell responses are filling in the details of the complex and critical events taking place, at the earliest times after challenge, to promote resistance to viruses.

Effects of IL-12 on immune responses to microbial infections: a key mediator in regulating disease outcome.

Recent studies have documented that the immunoregulatory functions of IL-12 may play a role in promoting endogenous protective responses during infections and/or contribute to pathology resulting from unregulated cytokine expression. Pathogen induction of IL-12 elicits interferon-gamma production by natural killer cells, which contributes to early defense during certain bacterial, parasitic, and viral infections. IL-12 also facilitates the development of T helper type 1 (Th1) lymphocytes required for late protection against bacteria, parasites, and fungi. During viral infections, however, there appear to be mechanisms independent of IL-12 for inducing protective T-cell responses. In contrast, negative regulation of IL-12 during acute infections can be a key event in the establishment of chronic infection and protection against harmful excessive cellular immune response. Under appropriate conditions, IL-12 has therapeutic efficacy for promoting defense against a variety of pathogens, and for use as a vaccine adjuvant to enhance beneficial Th1 over detrimental Th2 lymphocyte responses. This information extends knowledge about the regulation of immune responses to infectious agents, and provides new insights for the development of treatment and adjuvant strategies to potentiate beneficial or inhibit detrimental endogenous immune responses.