Gamma interferon and interleukin-10 gene expression in innately susceptible and resistant mice during the early phase of Salmonella typhimurium infection

Abstract

Previous studies have shown that gamma interferon (IFN-␥) plays a major role in natural resistance to Salmonella typhimurium during the early phase of infection. To assess whether the level of natural resistance in mice is related to the level of IFN-␥ gene expression, we compared IFN-␥ mRNA levels by means of reverse transcriptase-PCR in the spleens of genetically susceptible Ity s (C57BL/6 and BALB/c) and resistant Ity r (CBA and DBA/2) mice during the first 5 days of infection. The mRNA expression of interleukin-10 (IL-10), a cytokine which antagonizes IFN-␥ effects, was also investigated. Mice were infected with 10 3 CFU of the virulent strain S. typhimurium C5, a dose which is lethal within a week for susceptible mice only. IFN-␥ mRNA increased to similar levels in both susceptible and resistant mice, suggesting that susceptibility to S. typhimurium infection is not related to defective IFN-␥ gene expression. In contrast, IL-10 mRNA reached much higher levels in susceptible than in resistant mice. Similar results were found in Ity congenic mice, confirming a link between the presence of the Ity s allele and a high level of IL-10 gene expression during infection. High levels of IL-10 mRNA in susceptible mice correlated with high IL-10 serum levels (on day 5), whereas IL-10 was not detectable in the sera of resistant mice. However, administration of neutralizing anti-IL-10 monoclonal antibodies did not modify the course of infection. To evaluate the influence of bacterial multiplication on IL-10 mRNA expression, susceptible mice were infected with an attenuated strain of S. typhimurium. This strain induced a low level of IL-10 mRNA expression. When susceptible mice were immunized with an attenuated strain and challenged with the virulent strain, they inhibited the growth of the challenge bacteria and exhibited a low level of IL-10 mRNA. In contrast, when resistant mice were infected with a high (lethal) dose of the virulent strain, they exhibited a high level of IL-10 mRNA. Taken together, these results indicate that the level of IL-10 gene expression correlates with the level of bacterial multiplication in the organs and that the high level of IL-10 mRNA in Ity s mice is a consequence rather than the cause of their susceptibility to S. typhimurium infection. Salmonella typhimurium is a facultative intracellular bacterium which can enter and multiply within macrophages and also nonphagocytic cells (18). During experimental infection in mice, the bacteria replicate mainly in the spleen and liver and induce a disease similar to human typhoid fever. Following intravenous challenge, acquired immunity to mouse salmonellosis is mainly T cell mediated, with the participation of both CD4 ϩ and CD8 ϩ subpopulations (21, 28). The antibody response also contributes to acquired immunity (11, 20). The survival of animals before the development of specific acquired immunity depends on natural resistance. Natural resistance to S. typhimurium infection in mice is regulated by several genes (30), in particular Ity, which contr...

Induction of cvtokines and expression of surface receptors in Mono Mac 6 cells after infection with different Legionella species

“…Genetically susceptible mice produced high levels of IL-10, associated with bacterial multiplication, after infection with Salmonella typhimurium, whereas in genetically resistant mice, IL-10 and bacterial multiplication were not detectable. Furthermore, an attenuated strain of Salmonella typhimurium generated only low levels of IL-10 in susceptible mice (46). Listeria monocytogenes and Mycobacterium bovis induced high levels of IL-I0 after infection of mouse splenocytes and may use the induction of this cytokine as an evasion mechanism from the protective immune response of the host (23)(24)(25).…”

Immune response to infection with Salmonella typhimurium in mice

“…Other T cell-derived cytokines that have been analyzed in Salmonella infection are IL-4 and IL-10 [52,65]. IL-10, which is produced by a variety of cells including T cells, is able to counter-regulate both the production of other cytokines and macrophage activation.…”

“…However, neutralizing anti-IL-10 antibodies did not modify the course of infection. It was therefore suggested that IL-10 is not involved in protection but rather reflects severity of disease [65].…”

Salmonella typhimurium Persists within Macrophages in the Mesenteric Lymph Nodes of Chronically Infected Nramp1+/+ Mice and Can Be Reactivated by IFNγ Neutralization

“…IFN␥ has been shown to be important for the maintenance of the latent state in the M. tuberculosis mouse model of infection as well as the latent state of Chlamydia trachomatis in cell culture (43,56). Previous studies of the role of IFN␥ in the acute Salmonella mouse infection have shown that IFN␥ plays a role in controlling the early phase of Salmonella replication, but is not necessary for bacterial clearance (57)(58)(59). We tested the role of IFN␥ in the persistent S. typhimurium infection in mice by neutralizing this cytokine in chronically infected mice.…”