Tissue selectivity of interferon-stimulated gene expression in mice infected with Dam(+) versus Dam(-) Salmonella enterica serovar Typhimurium strains.

The host interferon (IFN) system plays an important role in protection against microbial infections. Salmonella enterica serovar Typhimurium is highly virulent in the mouse model, whereas mutants that lack DNA adenine methylase (Dam(-)) are highly attenuated and elicit fully protective immune responses against murine typhoid fever. We examined the expression of IFN-responsive genes in several mouse tissues following infection with Dam(+) or Dam(-) Salmonella. Infection of mice with Dam(+) Salmonella resulted in the induction of host genes known to be indicators of IFN bioactivity and regulated by either IFN-alpha/beta (Mx1) or IFN-gamma (class II transactivator protein [CIITA] and inducible nitric oxide synthase [iNOS]) or by both IFN-alpha/beta and IFN-gamma (RNA-specific adenosine deaminase [ADAR1] and RNA-dependent protein kinase [PKR]) in a tissue-specific manner compared to uninfected animals. Since the Mx1 promoter is IFN-alpha/beta specific and the Mx1 gene is not inducible directly by IFN-gamma, these data suggest a role of IFN-alpha/beta in the host response to Salmonella infection. Mice infected with Dam(-) Salmonella showed reduced expression of the same set of IFN-stimulated genes (ISGs) as that observed after infection with wild-type Salmonella. The reduced capacity to induce ISGs persisted in Dam(-)-vaccinated mice after challenge with the virulent (Dam(+)) strain. Finally, although no Dam(-) organisms were recovered from the liver or spleen after oral infection of mice, ADAR, PKR, Mx, and CIITA expression levels were elevated in these tissues relative to those in uninfected mice, suggestive of the distant action of a signaling molecule(s) in the activation of ISG expression.