Protection against lethal sepsis following immunization with Candida species varies by isolate and inversely correlates with bone marrow tissue damage

INTRODUCTIONIntra-abdominal infections (IAI) can occur as a result of bowel perforations, laparotomy surgery, intestinal hernias, and insertion of medical devices, such as peritoneal catheters (1, 2). If these infections are left untreated or misdiagnosed, microorganisms can migrate into the bloodstream, causing sepsis and leading to significant morbidity and mortality (3 5). IAIs are often polymicrobial and infections involving both fungal and bacterial pathogens result in significantly higher mortality rates compared with infections involving bacterial species alone (6 12). Along with gram-negative enteric bacteria, gram-positive species including Staphylococcus aureus (Sa) are also co-isolated pathogens, particularly with nosocomial infections (13 18). This polymicrobial pairing can be enhanced based on a predilection of Sa for Candida albicans (Ca) hyphae, which are observed co-associated within peritoneal tissue lesions (19). The pathogenesis of this lethal polymicrobial IAI is becoming better understood, with inflammatory responses leading to sepsis considered a key hallmark factor in mortality (20, 21).Our laboratory has been studying Ca/Sa polymicrobial IAI using an experimental mouse model that results in 80–90% mortality by 48 to 72 h post-inoculation (22 24). Characterization of host responses during Ca/Sa polymicrobial IAI revealed that mortality is associated with robust inflammation, with elevated levels of hallmark sepsis proinflammatory cytokines (IL-6, TNF-α, and IL-1β), both locally and systemically, as early as 4 h and continuing through 24 to 48 h post-inoculation. On the other hand, at similar time points there were equivalent microbial burdens in non-lethal monomicrobial and lethal polymicrobial infections, both locally in the

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