Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents.

The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the major component is glucuronoxylomannan (GXM), extensively accumulates in tissues and compromises host immune responses. C. neoformans travels from the lungs to the bloodstream and crosses to the brain via transcytosis, paracytosis, or inside of phagocytes using a "Trojan horse" mechanism. The fungus causes life-threatening meningoencephalitis with high mortality rates. Hence, we investigated the impact of intranasal exogenous GXM administration on C. neoformans infection in C57BL/6 mice. GXM enhances cryptococcal pulmonary infection and facilitates fungal systemic dissemination and brain invasion. Pre-challenge of GXM results in detection of the polysaccharide in lungs, serum, and surprisingly brain, the latter likely reached through the nasal cavity. GXM significantly alters endothelial cell tight junction protein expression in vivo, suggesting significant implications for the C. neoformans mechanisms of brain invasion. Using a microtiter transwell system, we showed that GXM disrupts the trans-endothelial electrical resistance, weakening human brain endothelial cell monolayers co-cultured with pericytes, supportive cells of blood vessels/capillaries found in the blood-brain barrier (BBB) to promote C. neoformans BBB penetration. Our findings should be considered in the development of therapeutics to combat the devastating complications of cryptococcosis that results in an estimated ~200,000 deaths worldwide each year.

Depletion of Alveolar Macrophages Increases Pulmonary Neutrophil Infiltration, Tissue Damage, and Sepsis in a Murine Model of Acinetobacter baumannii Pneumonia.

Acinetobacter baumannii has emerged as an important etiological agent of hospital-related infections, especially nosocomial pneumonia. The virulence factors of this bacterium and their interactions with the cells and molecules of the immune system just recently began to be extensively studied. Here, we investigated the impact of alveolar macrophages on A. baumannii pneumonia using a mouse model of infection and a flexible tissue culture system. We hypothesized that depletion of macrophages would enhance sepsis and severity of A. baumannii disease. We showed that macrophages are important for modulating the antibacterial function of neutrophils and play an important role in eradicating A. baumannii infection in vivo Our findings suggest that in the absence of macrophages in the lungs, A. baumannii replicates significantly, and host proinflammatory cytokines are considerably reduced. Neutrophils are abundantly recruited to pulmonary tissue, releasing high amounts of reactive oxygen species and causing extensive tissue damage. The ability of A. baumannii to form biofilms and resist oxidative stress in the respiratory tract facilitates systemic dissemination and ultimately death of infected C57BL/6 mice. These results provide novel information regarding A. baumannii pathogenesis and may be important for the development of therapies aimed at reducing morbidity and mortality associated with this emerging bacterial pathogen.