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Influence of macrophage resistance gene Lsh/Ity/Bcg (candidate Nramp) on Toxoplasma gondii infection in mice

Blackwell, J M and Roberts, C W and Roach, T I and Alexander, J (1994) Influence of macrophage resistance gene Lsh/Ity/Bcg (candidate Nramp) on Toxoplasma gondii infection in mice. Clinical and Experimental Immunology, 97 (1). pp. 107-112. ISSN 0009-9104

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Abstract

Functional studies have shown that the murine macrophage resistance gene Lsh/Ity/Bcg (candidate Nramp) regulates macrophage priming/activation for antimicrobial activity via the tumour necrosis factor-alpha (TNF-alpha)-dependent production of reactive nitrogen intermediates. Since Toxoplasma gondii also parasitizes macrophages, is a stimulator of endogenous TNF-alpha release, and is sensitive to nitric oxide-mediated killing in activated macrophages, studies were carried out using chromosome 1 congenic mouse strains to determine whether Lsh influences T. gondii infection. Two interesting observations were made: (i) contrary to expectation, mice carrying the Lsh-resistant allele died earlier over the acute phase of infection than Lsh-susceptible mice; and (ii) Lsh-resistant mice which survived this acute phase of infection showed lower brain cyst numbers than the Lsh-susceptible mice. Whilst the latter occurred independently of route of inoculation (oral, intraperitoneal, or subcutaneous), the former was influenced both by the route of inoculation and the genetic background on which the Lsh-resistant allele had been isolated. Hence, following oral administration of 20 brain cysts of the RRA strain of T. gondii, mice carrying the Lsh-resistant allele on a B10 genetic background showed a significantly enhanced rate of mortality over the acute (first 8-12 days) phase of infection than BIO Lsh-susceptible mice. Although this acute phase of infection in B10 background mice was accompanied by an increase in serum TNF-alpha levels in both Lsh-resistant and -susceptible mouse strains, early mortality preceded the TNF-alpha peak, and administration of neutralizing rabbit anti-TNF-alpha did not significantly enhance survival. Hence, inflammatory mediators other than TNF-alpha appear to be responsible for the increased rate of acute mortality observed in resistant mice. Infection intraper itoneally led to delayed mortality in B10 mice, with the mean time to 50% mortality now being significantly longer in Lsh-resistant than in Lsh-susceptible mice. On a BALB genetic background, it was the i.p. route of infection which led to acute mortality and more rapid death in the Lsh-resistant strain. When a less virulent inoculum was used and mortality delayed, Lsh-susceptible mice died more rapidly, and i.p. administration of rabbit anti-TNF-alpha led to 100% mortality between days 8 and 10 of infection in both susceptible and resistant mouse strains, consistent with a crucial protective role for TNF-alpha during this phase of infection. Overall these results show that the Lsh gene plays different modulating roles over the course of T. gondii infection depending on the potency of the parasite inoculum, the route and kinetics of infection, and the genetic background of the congenic mouse strains upon which the resistant allele has been isolated. These results probably reflect pleiotropic effects of macrophage products stimulated by differential priming/activation rather than the direct effect of macrophage toxoplasmacidal activity.

Item type: Article
ID code: 31747
Keywords: animals, antibodies, Female, macrophage activation, male, mice, mice, inbred BALB C, mice, inbred C57BL, neutralization tests, species specificity, toxoplasmosis, animal, tumor necrosis factor-alpha, Pharmacy and materia medica, Therapeutics. Pharmacology, Pharmacology, Toxicology and Pharmaceutics(all)
Subjects: Medicine > Pharmacy and materia medica
Medicine > Therapeutics. Pharmacology
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Related URLs:
    Depositing user: Pure Administrator
    Date Deposited: 13 Jul 2011 09:57
    Last modified: 12 Jun 2014 12:32
    URI: http://strathprints.strath.ac.uk/id/eprint/31747

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