Abstract
The lysosomal membrane transporter, Nramp1, plays a key role in innate immunity and resistance to infection with intracellular pathogens such as non-typhoidal Salmonella (NTS). NTS-susceptible C57BL/6 (B6) mice, which express the mutant Nramp1D169 allele, are unable to control acute infection with Salmonella enterica serovar Typhimurium following intraperitoneal or oral inoculation. Introducing functional Nramp1G169 into the B6 host background, either by constructing a congenic strain carrying Nramp1G169 from resistant A/J mice (Nramp-Cg) or overexpressing Nramp1G169 from a transgene (Nramp-Tg), conferred equivalent protection against acute Salmonella infection. In contrast, the contributions of Nramp1 for controlling chronic infection are more complex, involving temporal and anatomical differences in Nramp1-dependent host responses. Nramp-Cg, Nramp-Tg and NTS-resistant 129×1/SvJ mice survived oral Salmonella infection equally well for the first 2–3 weeks, providing evidence that Nramp1 contributes to the initial control of NTS bacteremia preceding establishment of chronic Salmonella infection. By day 30, increased host Nramp1 expression (Tg>Cg) provided greater protection as indicated by decreased splenic bacterial colonization (Tg<Cg). However, despite controlling bacterial growth within MLN as effectively as 129×1/SvJ mice, Nramp-Cg and Nramp-Tg mice eventually succumbed to infection. These data indicate: 1) discrete, anatomically localized host resistance is conferred by Nramp1 expression in NTS-susceptible mice, 2) restriction of systemic bacterial growth in the spleens of NTS-susceptible mice is enhanced by Nramp1 expression and dose-dependent, and 3) host genes other than Nramp1 also contribute to the ability of NTS-resistant 129×1/SvJ mice to control bacterial replication during chronic infection.
Highlights
Salmonella enterica serovars Typhi and Paratyphi are human pathogens that cause systemic typhoid fever in infected individuals
One inherited form of susceptibility to Salmonella infection is associated with a missense mutation in macrophage-encoded solute carrier family 11a member 1 (Slc11a1, hereafter referred to as natural resistance-associated macrophage protein, or Nramp1), which transports divalent cations out of bacteria-containing phagosomes, potentially inhibiting bacterial metallo-enzymes required for survival of many intracellular pathogens [2,3]
Relative RNA transcript levels were compared in bone marrow-derived macrophages cultured from C57BL/6, Nramp-Cg and Nramp-Tg mice
Summary
Salmonella enterica serovars Typhi and Paratyphi are human pathogens that cause systemic typhoid fever in infected individuals. NTS infection of susceptible (Nramp1G169D) mouse strains, such as C57BL/6 and BALB/c, leads to acute, systemic infection while resistant mice encoding the wild type Nramp allele (Nramp1G169), including strains 12961/SvJ, A/J, and C3H, develop long-term chronic colonization [4,5,6]. In both models, Salmonella cross the epithelial barrier and colonize the mesenteric lymph nodes (MLN) prior to systemic spread to the spleen and liver [4,7,8,9]. While Salmonella is progressively cleared from systemic tissues in 12961/SvJ mice, MLN colonization persists and can act as a reservoir for relapsing infections [4,10]
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