Increased susceptibility of TNF-alpha lymphotoxin-alpha double knockout mice to systemic candidiasis through impaired recruitment of neutrophils and phagocytosis of Candida albicans

TNF-alpha and lymphotoxin-alpha (LT) are members of the TNF family, and the se cytokines play crucial roles in the defense against infection with Candi da albicans, The aim of the present study was to investigate the role of en dogenous TNF and LT during disseminated candidiasis in TNF-/-LT-/- knockout mice. The TNF- and LT-deficient animals had a significantly increased mort ality following C, albicans infection compared with control mice, and this was due to a 10- to 1000-fold increased outgrowth of the yeast in their org ans. No differences between TNF-/-LT-/- mice and TNF+/+LT+/+ were observed when mice were rendered neutropenic, suggesting that activation of neutroph ils mediates the beneficial effects of endogenous TNF and LT. Histopatholog y of the organs, combined with neutrophil recruitment experiments, showed a dramatic delay in the neutrophil recruitment at the sites of Candida infec tion in the TNF-/-LT-/- mice. Moreover, the neutrophils of deficient animal s were less potent to phagocytize Candida blastospores than control neutrop hils, In contrast, the killing of Candida and the oxygen radical production did not differ between neutrophils of TNF-/-LT-/- and TNF+/+LT+/+ mice. Pe ak circulating IL-6 was significantly higher in TNF-/-LT-/- mice during inf ection. Peritoneal macrophages of TNF-/-LT-/- mice did not produce TNF, and synthesized significantly lower amounts of IL-1 alpha, IL-1 beta, IL-6, an d macrophage-inflammatory proteln-1 alpha than macrophages of TNF+/+LT+/+ a nimals did. In conclusion, endogenous TNF and/or LT contribute to host resi stance to disseminated candidiasis, and their absence in TNF-/-LT-/- mice r enders the animals susceptible through impaired recruitment of neutrophils and impaired phagocytosis of C, albicans.