Varney et al. report that that deletion of the TRAF-interacting protein TIFAB contributes to an MDS-like phenotype in mice by up-regulating TRAF6 and contributing to hematopoietic dysfunction.

IntroductionMyelodysplastic syndrome (MDS) is a hematologic malignancy defined by blood cytopenias due to ineffective hematopoiesis, a predisposition to acute myeloid leukemia (AML), and genomic instability. 1,2 Molecular-targeted therapies do not exist for MDS and the mechanisms of current therapies are largely unknown. More recently, bortezomib (Velcade), which is widely used for the treatment of multiple myeloma (MM) and lymphomas, is being evaluated as a single agent or in combination with chemotherapy in certain MDS and AML patients. [3][4][5] Bortezomib is a selective and reversible inhibitor of the 26S proteasome, and mechanistic studies have revealed that inhibition of the proteasome complex leads to accumulation of lysine (K)-48 ubiquitin-linked proteins and consequently to cytotoxic effects in malignant cells. 6 Proapoptotic and cell-cycle inhibitor proteins are stabilized after proteasome inhibition and thought to contribute to the anticancer effect by inducing apoptosis and inhibiting the cell cycle, respectively. 6 Nevertheless, the molecular and cellular mechanisms of bortezomib-induced cytotoxicity remain unknown, particularly in MDS/AML. Whereas the role of bortezomib in regulating cell-cycle entry and survival have been characterized partially in MDS/AML, 7-9 recent evidence has pointed to a more general cellular effect: bortezomib treatment results in the accumulation of nondegraded proteins, leading to endoplasmic reticulum stress and autophagy in cancer. [10][11][12] Under normal cellular stresses, autophagy, a catabolic pathway, degrades long-lived proteins and defective and superfluous organelles. 13 However, under conditions of extreme cellular stress, autophagy is used by the cell to undergo death. 14 Human miR-146a, a candidate gene in del(5q) MDS/AML, is reduced significantly in del(5q) and normal karyotype MDS/AML patients. [15][16][17] TRAF6 is a key target of miR-146a 15,18,19 and, as expected, miR-146a-knockout mice have a dramatic increase in TRAF6 protein within the hematopoietic compartment. 20,21 Retroviral overexpression of TRAF6 in mouse hematopoietic stem/ progenitor cells results in MDS-like hematopoietic defects and progression to AML. 15 Bortezomib has been shown previously to be effective for an MDS patient with del(5q) and was also reported to reduce directly TRAF6 mRNA and protein in osteoclast precursors from MM patients. 22,23 Because TRAF6 is implicated in MDS/AML and bortezomib has been shown to be effective in del(5q) MDS and to inhibit TRAF6 in MM, we hypothesized that one mechanism of bortezomib action is through inhibition of TRAF6. The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org FromIn the present study, we identified TRAF6 as a relevant target of bortezomib-induced...

is the primary causative agent of pertussis (whooping cough), which is a respiratory infection that leads to a violent cough and can be fatal in infants. There is a need to develop more effective vaccines because of the resurgence of cases of pertussis in the United States since the switch from the whole-cell pertussis vaccines (wP) to the acellular pertussis vaccines (aP; diphtheria-tetanus-acellular-pertussis vaccine/tetanus-diphtheria-pertussis vaccine). Adenylate cyclase toxin (ACT) is a major virulence factor of that is (i) required for establishment of infection, (ii) an effective immunogen, and (iii) a protective antigen. The C-terminal repeats-in-toxin domain (RTX) of ACT is sufficient to induce production of toxin-neutralizing antibodies. In this study, we characterized the effectiveness of vaccines containing the RTX antigen against experimental murine infection with RTX was not protective as a single-antigen vaccine against challenge, and adding RTX to 1/5 human dose of aP did not enhance protection. Since the doses of aP used in murine studies are not proportionate to mouse/human body masses, we titrated the aP from 1/20 to 1/160 of the human dose. Mice receiving 1/80 human aP dose had bacterial burden comparable to those of naive controls. Adding RTX antigen to the 1/80 aP base resulted in enhanced bacterial clearance. Inclusion of RTX induced production of antibodies recognizing RTX, enhanced production of anti-pertussis toxin, decreased secretion of proinflammatory cytokines, such as interleukin-6, and decreased recruitment of total macrophages in the lung. This study shows that adding RTX antigen to an appropriate dose of aP can enhance protection against challenge in mice.

No abstract

Current acellular pertussis vaccines fall short of optimal protection against the human respiratory pathogen Bordetella pertussis resulting in increased incidence of a previously controlled vaccine- preventable disease. Natural infection is known to induce a protective mucosal immunity. Therefore, in this study, we aimed to use acellular pertussis vaccines to recapitulate these mucosal immune responses. We utilized a murine immunization and challenge model to characterize the efficacy of intranasal immunization (IN) with DTaP vaccine or DTaP vaccine supplemented with curdlan, a known Th1/Th17 promoting adjuvant. Protection from IN delivered DTaP was compared to protection mediated by intraperitoneal injection of DTaP and whole-cell pertussis vaccines. We tracked fluorescently labeled DTaP after immunization and detected that DTaP localized preferentially in the lungs while DTaP with curdlan was predominantly in the nasal turbinates. IN immunization with DTaP, with or without curdlan adjuvant, resulted in anti-B. pertussis and anti-pertussis toxin IgG titers at the same level as intraperitoneally administered DTaP. IN immunization was able to protect against B. pertussis challenge and we observed decreased pulmonary pro-inflammatory cytokines, neutrophil infiltrates in the lung, and bacterial burden in the upper and lower respiratory tract at day 3 post challenge. Furthermore, IN immunization with DTaP triggered mucosal immune responses such as production of B. pertussis-specific IgA, and increased IL-17A. Together, the induction of a mucosal immune response and humoral antibody-mediated protection associated with an IN administered DTaP and curdlan adjuvant warrant further exploration as a pertussis vaccine candidate formulation.