Natural resistance-associated macrophage protein 1 (Nramp1) plays an important role in restraining the growth of intracellular pathogens within macrophages. In this study, Nramp1 cDNA was cloned from Qinchuan cattle and its anti-bacterial activity was demonstrated as being able to significantly inhibit the growth of Salmonella abortusovis and Brucella abortus in macrophages. Calf fibroblasts stably transfected with pSP–NRAMP1–HA vector were used to reconstruct bovine embryos by somatic cell nuclear transfer (SCNT). Reconstructed embryos were maturated in vitro and the blastocyst formation rate (14.0%) was similar to that of control embryos (14.5%). Transgenic blastocysts were transplanted into 43 recipient cattle, of which 14 recipients became pregnant as evidenced by non-return estrus and by rectal palpation. One fetus was aborted after 6½ months of pregnancy and transgene integration was confirmed by semi-quantitative polymerase chain reaction. Together, this study showed that bovine Nramp1 retains biological function against the growth of intracellular bacteria and can be used to reconstruct embryos and produce Nramp1 transgenic cattle, which may benefit the animal and enhance their ability to prevent attack by intracellular pathogens.

Two important recent advances in Leishmania immunology are: (i) the demonstration of a dramatic dichotomy in T helper 1 versus T helper 2 subset expansion leading to protection versus disease exacerbation; and (ii) analysis of the macrophage activation pathways leading to enhanced intracellular killing of parasites, in particular the tumour necrosis factor α (TNFα)-dependent sustained induction of the inducible nitric oxide synthase gene (Nos2) leading to the generation of large amounts of nitric oxide (NO). Given the broad spectrum of disease phenotypes in human leishmaniasis, one might predict that a genetic defect at any key point in this macrophage activation pathway and/or in pathways leading to activation of different T cell subsets, and the latter may be a pleiotropic effect of the former, will contribute to disease susceptibility. By studying disease in genetically-defined inbred mouse strains, it has been possible to identify 5 regions of the murine genome carrying leishmanial susceptibility genes. The genes include: (i) Scl-2 (mouse chromosme 4/human chromosome 9p; candidate Janus tyrosine kinase 1) controlling a unique no lesion growth resistance phenotype to Leishmania mexicana; (ii) Scl-1 (distal mouse chromosome 11/human 17q; candidates Nos2, Sigje, MIP1α, MIP1β) controlling healing versus non-healing responses to L. major; (iii) the ‘T helper 2’ cytokine gene cluster (proximal murine chromosome 11/human 5p; candidates IL4,5,9) controlling later phases of L. major infection; (iv) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNFα/β genes); and (v) Nramp1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35). This review examines these 5 regions and the candidate genes within them, reflecting on their current status as candidates for human disease susceptibility genes.

Fe-deficiency anaemia is the most common cause of anaemia in developing countries. In these settings, many chronic infections, including tuberculosis (TB), are highly prevalent. Fe is an essential nutrient for both host and mycobacteria that play a pivotal role in host immunity and mycobacterial growth. A case–control study was performed in a TB-endemic region in Jakarta, Indonesia, among 378 pulmonary TB patients and 436 healthy controls from the same neighbourhood with the same socio-economic status. In a number of these subjects the Fe status could be explored. The distribution of three polymorphisms in the natural resistance-associated macrophage protein gene (NRAMP1) including INT4, D543N and 3′UTR was examined for a possible association with susceptibility to TB. Anaemia (corrected for sex) was present in 63·2 % of active TB compared with 6·8 % of controls, with female patients more often affected. Anaemia was more pronounced in advanced TB as diagnosed by chest radiography. Lower Hb concentrations in TB patients were accompanied by lower plasma Fe concentrations, lower Fe-binding capacity and higher plasma ferritin. After successful TB therapy, Fe parameters improved towards control values and Hb levels normalised, even without Fe supplementation. NRAMP1 gene polymorphisms were not associated with TB susceptibility, TB severity or anaemia. In conclusion, most active TB patients had anaemia, which was probably due to inflammation and not to Fe deficiency since TB treatment without Fe supplementation was sufficient to restore Hb concentration.