Genetically determined susceptibility to Leishmania tropica infection is expressed by haematopoietic donor cells in mouse radiation chimaeras

Abstract

Models of the different disease patterns of cutaneous leishmaniasis can be established by infecting various inbred strains of mice with Leishmania tropica. The BALB/c strain is exceptionally susceptible in that the infection is dosage independent and inexorably progressive, terminating in cutaneous and fatal visceral metastasis^1–3. This is largely determined by a single autosomal non-H–2-linked gene³, seemingly not identical to the well-characterized Lsh gene which determines innate susceptibility to systemic Leishmania donovani infection^4,5. Although H–2-linked genetic influences are also detectable in the immune stage of both leishmanial infections^3,6, they are relatively minor in the case of L. tropica. Thus, although progression of disease induced by lower infecting doses is slower in congeneic B ALB/K (H–2^k) than in BALB/c or BALB/B (H–2^b) mice, the eventual outcome is similar in all three³. This inability to control L. tropica infection seems to involve profound impairment of potentially curative cell-mediated immunity by the generation of a specific suppressor T-cell population⁷. With two other pathogens which infect mononuclear phagocytes, Listeria monocytogenes and Mycobacterium iepraemurium, differences in mouse strain susceptibility have been attributed to extrinsic factors regulating macrophage activity rather than to intrinsic gene expression within the cells themselves^8,9. The relative strain susceptibility of mice to myxoviruses (determined by the dominant allele Mx) is also a genetic characteristic of their macrophages in vitro¹⁰. Nevertheless, radiation chimaeras exhibit the myxovirus resistance profile of the host despite near-total haematopoietic cell replacement, including donor macrophages which can still express their original susceptibility in vitro¹¹. In contrast, the experiments described here indicate unequivocally that susceptibility to L. tropica in radiation chimaeras compatible at the major histocompatibility (H–2) locus is determined by the descendants of donor haematopoietic cells and not by host environmental factors.