CLONING OF SYRIAN-HAMSTER (MESOCRICETUS-AURATUS) CYTOKINE CDNAS AND ANALYSIS OF CYTOKINE MESSENGER-RNA EXPRESSION IN EXPERIMENTAL VISCERAL LEISHMANIASIS

The Syrian golden hamster (Mesocricetus auratus) is uniquely susceptib le to a variety of intracellular pathogens and is an excellent model f or a number of human infectious diseases, The molecular basis for this high level of susceptibility is unknown, and immunological studies re lated to this model have been limited by the lack of available reagent s, In this report we describe the cloning and sequence analysis of por tions of the Syrian hamster interleukin 2 (IL-2), IL-4, gamma interfer on (IFN-gamma), tumor necrosis factor alpha, IL-10, IL-12p40, and tran sforming growth factor beta cDNAs, In addition, we examined the cytoki ne response to infection with the intracellular protozoan Leishmania d onovani in this animal model, Sequence analysis of the hamster cytokin es revealed 69 to 93% homology with the corresponding mouse, rat, and human nucleotide sequences and 48 to 100% homology with the deduced am ino acid sequences, The hamster IFN-gamma, compared with the mouse and rat homologs, had an additional 17 amino acids at the C terminus that could decrease the biological activity of this molecule and thus cont ribute to the extreme susceptibility of this animal to intracellular p athogens. The splenic expression of these genes in response to infecti on with L. donovani, the cause of visceral leishmaniasis (VL), was det ermined by Northern blotting. VL in the hamster is a progressive, leth al disease which very closely mimics active human disease, In this mod el there was pronounced expression of the Th1 cytokine mRNAs, with tra nscripts being detected as early as 1 week postinfection, Basal expres sion of IL-4 in uninfected hamsters was prominent but did not increase in response to infection with L. donovani, IL-12 transcript expressio n was detected at low levels in infected animals and paralleled the ex pression of IFN-gamma, Expression of IL-10, a potent macrophage deacti vator, increased throughout the course of infection and could contribu te to the progressive nature of this infection. These initial studies are the first to examine the molecular immunopathogenesis of a hamster model of VL infection and indicate that progressive disease in this m odel of VL is not associated with early polarization of the splenic ce llular immune response toward a Th2 phenotype and away from a Th1 phen otype.