Susceptibility to bacterial infections after a primary immune stimulation differs drastically depending on the presensitization of the innate immune system. To determine the conditions that either induce protection or enhanced susceptibility to infection with Salmonella enterica serovar Typhimurium, we pretreated mice either with tumor necrosis factor (TNF), whole killed bacteria, or sublethal cecal ligation and puncture (CLP) as a mouse model for septic peritonitis. Impaired production of the cytokines TNF, interleukin-6 (IL-6), and IL-10 was induced by these pretreatment schedules, with TNF-signaling not being essential for this effect. Injection of TNF or killed bacteria enhanced survival of mice infected subsequently with serovar Typhimurium. In contrast, sepsis such as that induced by CLP only protected from shock induced by D-galactosamine and lipopolysaccharide or by a high dose of bacteria but sensitized to a secondary bacterial infection. Such sepsis-induced enhanced susceptibility to infection was critically dependent on TNF function.

Nosocomial infections in immune-suppressed patients are a widespread problem in intensive care medicine. Such patients are highly susceptible to infections because their immune defenses are impaired and, therefore, unable to adequately combat invading microorganisms. To investigate the problem of sepsis-induced immune suppression, we used a model in which mice developed sublethal peritonitis induced by cecal ligation and puncture (CLP). Two days after CLP mice were in an immune-suppressed state, as measured by impaired capacity to produce tumor necrosis factor (TNF) and enhanced susceptibility to bacterial infections. Since macrophage migration inhibitory factor (MIF) is a critical mediator of septic shock by modulation of innate immune responses, the role of MIF in sepsis-induced immune suppression was analyzed. Neutralization of endogenous MIF further enhanced susceptibility to bacterial superinfection after CLP. Conversely, treatment with recombinant human MIF before the bacterial superinfection protected the animals. MIF treatment reconstituted the impaired capacity to produce proinflammatory cytokines, such as TNF and interleukin-6. This study indicates that MIF might be able to ameliorate the sepsis-induced immune suppression by reenabling the organism to react adequately to a secondary bacterial challenge.