1. Achtman, A.H., S. Pilat, C.W. Law, D.J. Lynn, L. Janot, M. Mayer, S. Ma, J. Kindrachuk, B.B. Finlay, F.S.L. Brinkman, G.K. Smyth, R.E.W. Hancock and L. Schofield. 2012. Effective adjunctive therapy by an innate defense regulatory peptide in a pre-clinical model of severe malaria. Science Transl. Med. 4:135ra64.
Severe malaria is a blood borne parasitic disease that afflicts more than 200 million individuals annually. Even in the best clinical settings case fatality rates remain high since anti-malarial drugs are directed against the parasite but do not reduce life-threatening (brain) inflammation. Innate defense regulator (IDR) peptides, developed in our lab as selective modulators of innate immunity, were assessed as an adjunctive therapy for alleviating severe malaria in a Plasmodium berghei model of experimental cerebral malaria (ECM). Co-administration of IDR-1018 with standard first-line anti-malarials significantly increased survival of infected mice while down-regulating key inflammatory networks associated with fatality. This provides a new strategy host-directed adjunctive therapy for severe disease in combination with anti-malarial treatment.
2. Nijnik, A., S. Clare, C. Hale, C. Raisen, R.E. McIntyre, K. Yusa, A.R. Everitt, L. Mottram, C. Podrini, M. Lucas, J. Estabel, D. Goulding, N. Adams, R. Ramirez-Solis, J.K. White, D.J. Adams, R.E.W. Hancock, and G. Dougan. 2012. The critical role of histone H2A-deubiquitinase Mysm1 in haematopoiesis and lymphocyte differentiation. Blood 119:1370-1379.
The differentiation of stem cells and specification of cell lineages depend on coordinated gene expression networks, but our knowledge of the chromatin modifying factors regulating these events remains incomplete. Histone H2A ubiquitination is associated with gene silencing, and controlled in part by enzymes. We developed a targeted mouse line with homozygous mutations in the Mysm1 gene encoding a H2A-deubiquitinating enzyme. Defects were demonstrated in bone marrow haematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. In particular, the development of lymphocytes was impaired at the earliest stages of their differentiation; and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. This was due to a cell-intrinsic requirement for Mysm1 in the bone marrow and was associated with elevated levels of reactive oxygen species, a DNA damage marker γH2AX, and the p53 tumor suppressor protein in the haematopoietic progenitors. Thus Mysm1 is involved in the maintenance bone marrow stem cell function, in the control of oxidative stress and genetic stability in haematopoietic progenitors, and in the development of lymphoid and erythroid lineages.