Genomic Deletion Marking an Emerging Subclone of \u3ci\u3eFrancisella tularensis\u3c/i\u3e subsp. \u3ci\u3eholarctica\u3c/i\u3e in France and the Iberian Peninsula

Francisella tularensis subsp. holarctica is widely disseminated in North America and the boreal and temperate regions of the Eurasian continent. Comparative genomic analyses identified a 1.59-kb genomic deletion specific to F. tularensis subsp. holarctica isolates from Spain and France. Phylogenetic analysis of strains carrying this deletion by multiple-locus variable-number tandem repeat analysis showed that the strains comprise a highly related set of genotypes, implying that these strains were recently introduced or recently emerged by clonal expansion in France and the Iberian Peninsula

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Histoplasmosis in Solid Organ Transplant Recipients at a Large Midwestern University Transplant Center

Histoplasma capsulatum sporadically causes severe infections in solid organ transplant (SOT) patients in the Midwest, but it has been an unusual infection among those patients followed at the University of Nebraska Medical Center (UNMC), located at the western edge of the ‘histo belt.’ Nine SOT patients with histoplasmosis are described (6 renal or renal-pancreas and 3 liver recipients) who developed severe histoplasmosis over a recent 2.5-year period at UNMC. Symptoms started a median of 11 months (range, 1.2–90 months) after organ transplant and consisted primarily of fever, cough, shortness of breath, and malaise or fatigue present for approximately 30 days prior to medical evaluation. All patients had an abnormal chest radiograph and/or computed tomographic scan. Tacrolimus was the main immunosuppressant in all 9 patients, along with prednisone or mycophenolate. Dacluzimab or thymoglobulin had been given around the time of transplant in 6 of 9. None was treated for an episode of acute rejection within 2 months before onset of histoplasmosis, although 2 were on high-dose immunosuppression after recent transplants. Diagnosis was made by culture in 8 of the 9 patients, with positive serum and urine histoplasma antigen tests in all 9 cases. From 1997 to 2001, during a period of relative quiescence of the disease in the general population, the rate of clinical histoplasmosis among SOT patients at UNMC was estimated at 0.11%, whereas during 2002 through the first half of 2004, the rate rose 17-fold to 1.9%. Histoplasmosis can present as a prolonged febrile illness with subacute pulmonary symptoms in a cohort of SOT patients, despite the absence of a regional outbreak

Identification and First Report of Inonotus (Phellinus) tropicalis as an Etiologic Agent in a Patient with Chronic Granulomatous Disease

Although isolates of filamentous basidiomycetes can usually be recognized in a clinical laboratory setting, identification is problematic, as they seldom exhibit diagnostic morphological features formed in nature. This paper is the first report of Inonotus (Phellinus) tropicalis inciting human disease and describes the methods used to support the identification