Distinct innate immune responses between sublethal and lethal models of disseminated candidiasis in newborn BALB/c...

Invasive candidiasis is associated with a high incidence and mortality rates in infants, especially in preterm newborns. The immunopathogenesis of the mycosis during the neonatal period is poorly understood. Although several in vivo models exist to study invasive candidiasis, the majority of studies employ distinct routes of infection and use 2 to 6 day-old mice that could be less comparable in studying candidiasis in preterm infants. In this study, by using 0-days-old mice we developed a new neonatal murine model of intravenous Candida albicans infection. Using different inoculums of Candida albicans we evaluated survival, dissemination of the fungus, frequency of CD45⁺ cells, and cytokine production in the liver, brain, and kidneys of newborn and adult BALB/c mice. Unexpectedly, the newborn mice infected with a low inoculum (1×10⁵ cfu per mouse) of Candida albicans survive to the infection. Compared to adult mice, the liver and brain of newborn animals had the greatest fungal burden, fungal invasion and leukocyte infiltrate. A moderate production of TNFα, IL-1β, IL-6 and IFNγ was detected in tissues of newborn mice infected with a non-lethal inoculum of Candida albicans. In contrast, overproduction of TNFα, IL-1β, IL-6 and IL-10 was determined when injecting with a lethal inoculum. In agreement, flow cytometry of brain and liver showed an inoculum-dependent CD45⁺ leukocyte infiltration in newborn mice infected with Candida albicans. Overall, our data shows that Candida albicans infection in newborn mice affects mainly the brain and liver and a 2-fold increase of the inoculum rapidly becomes lethal probably due to massive fungal invasion and exacerbated CD45⁺ leukocyte infiltrate and cytokine production. This study is the first analysis of innate immune responses in different tissues during early neonatal disseminated candidiasis.