Purpose Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses, and activation and recruitment of NK and T cells, in association with increased survival of mice bearing hepatic metastases. The Lm ΔactA/ΔinlB strain, engineered to express human mesothelin (CRS-207), a tumor-associated antigen expressed by a variety of tumors, induces mesothelin-specific T cell responses against mesothelin-expressing murine tumors. These two Phase 1 studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively. Experimental Design A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1×106, 3×107, or 3×108 colony forming units [cfu]. CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic or ovarian cancers. 17 subjects received up to 4 doses of 1×108, 3×108, 1×109, or 1×1010 cfu. Results A single infusion of ANZ-100 was well tolerated to the maximum planned dose. Adverse events included transient laboratory abnormalities and symptoms associated with cytokine release. Multiple infusions of CRS-207 were well tolerated up to 1×109 cfu, the determined maximum tolerated dose. Immune activation was observed for both ANZ-100 and CRS-207 as measured by serum cytokine/chemokine levels and NK cell activation. In the CRS-207 study, Listeriolysin O and mesothelin-specific T cell responses were detected and 37% of subjects lived ≥ 15 months. Conclusions ANZ-100 and CRS-207 administration was safe and resulted in immune activation.

The DNA uptake competence (Com) system of the intracellular bacterial pathogen Listeria monocytogenes is considered nonfunctional. There are no known conditions for DNA transformation, and the Com master activator gene, comK, is interrupted by a temperate prophage. Here, we show that the L. monocytogenes Com system is required during infection to promote bacterial escape from macrophage phagosomes in a manner that is independent of DNA uptake. Further, we find that regulation of the Com system relies on the formation of a functional comK gene via prophage excision. Prophage excision is specifically induced during intracellular growth, primarily within phagosomes, yet, in contrast to classic prophage induction, progeny virions are not produced. This study presents the characterization of an active prophage that serves as a genetic switch to modulate the virulence of its bacterial host in the course of infection.

Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory.

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A patient with a trauma-related left tibial infection associated with extensively drug-resistant Acinetobacter baumannii and multidrug-resistant Klebsiella pneumoniae was treated with bacteriophages and antibiotics. There was rapid tissue healing and positive culture eradication. As a result, the patient’s leg did not have to be amputated and he is undergoing rehabilitation.

Recurrent group G Steptococcus bacteremia, associated with lymphatic disorders and possibly emm stG 840.0, is described.

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Dermatophytes are common pathogens of skin but rarely cause invasive disease. We present a case of deep infection by Trichophyton rubrum in an immunocompromised patient. T. rubrum was identified by morphological characteristics and confirmed by PCR. Invasiveness was apparent by histopathology and immunohistochemistry. The patient was treated successfully with itraconazole. CASE REPORTA 56-year-old male was admitted for evaluation of elevated erythrocyte sedimentation rate (ESR), anemia, and multiple subcutaneous nodules on both legs. The patient was under close medical supervision due to an autoimmune disease with liver, cardiac, and lung involvement.His medical history included pericarditis (27 years before admission), and a profound jaundice after a respiratory infection treated with cefuroxime (3 years before admission). Serology was negative for hepatitis viruses and positive for antiparietal, antinuclear, and antineutrophil cytoplasmic antibodies. Liver biopsy revealed a profound destruction of liver architecture, fibrosis, active inflammation, and cholestasis. Treatment with steroids was followed by a good clinical response and normalization of liver enzymes. Attempts to wean the patient from steroids including administration of azathioprine and cyclosporine failed, and during the 2 years prior to admission he received both prednisone and cyclosporine. Several weeks before admission, he was evaluated for a chronic cough. He had undergone a transbronchial biopsy that disclosed chronic inflammation and thickening of the basement membrane, without any specific diagnosis, but responded to an increase of the dose of steroids. A few weeks later, while trying to taper the steroids, he developed multiple, hard cutaneous nodules, distributed mainly on the lower limbs. Some later softened and discharged caseous material spontaneously.Other underlying conditions included glucose-6-phosphate dehydrogenase deficiency, nephrolithiasis, benign prostate hypertrophy, bilateral inguinal hernia repair, and osteoporosis.On admission, medications included prednisone (10 mg once a day [QD]), cyclosporine (100 mg QD), ursodeoxycholic acid (300 mg twice a day), alendronate (10 mg QD), omeprazole (20 mg QD), and calcium (600 mg) and vitamin D (0.25 g) once daily. On physical examination, rhonchi were heard over both lungs. A few hard, mobile subcutaneous nodules were present on both lower limbs, mainly around the knees and thighs (Fig. 1a), and the sacral area. Some of these nodules were purplish and soft. Onychomycosis was present on the feet and both hands (Fig. 1b and c).Laboratory test results were as follows: ESR, 80; hemoglobin level, 10.8 g/dl; leukocyte count, 7,900/l (42% granulocytes); albumin level, 34 g/liter; total protein level, 83 g/liter; liver enzyme levels, normal.Two of the patient's nodules were excised. A granulomatous inflammatory reaction was present in the dermis and hypodermis. It was composed of monocytes, macrophages, multinucleated giant cells, and rare neutrophils (Fig. 2). Septate hyphae were revealed...