muramidase and Cryptococcosis

Lysozymes are antimicrobial enzymes that perform a critical role in resisting infection in a wide-range of eukaryotes. However, using the nematode Caenorhabditis elegans as a model host we now demonstrate that deletion of the protist type lysozyme LYS-7 renders animals susceptible to killing by the fatal fungal human pathogen Cryptococcus neoformans, but, remarkably, enhances tolerance to the enteric bacteria Salmonella Typhimurium. This trade-off in immunological susceptibility in C. elegans is further mediated by the reciprocal activity of lys-7 and the tyrosine kinase abl-1. Together this implies a greater complexity in C. elegans innate immune function than previously thought.

Topics: Adaptation, Physiological; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cryptococcosis; Cryptococcus neoformans; Dosage Compensation, Genetic; Genes, Helminth; Humans; Muramidase; Mutation; Phenotype; Proto-Oncogene Proteins c-abl; Salmonella Infections, Animal; Salmonella typhimurium; Suppression, Genetic

Rats and mice are considered resistant and susceptible hosts, respectively, for experimental cryptococcosis. For both species, alveolar macrophages (AM) are central components of the host response to pulmonary Cryptococcus neoformans infection. We explored the role of AM in three strains of mice and three strains of rats during cryptococcal infection by comparing the outcome of infection after macrophage depletion using liposomal clodronate. AM depletion was associated with enhancement and amelioration of disease in rats and mice, respectively, as measured by lung fungal burden. The apparent protective role for AM in rats correlated with enhanced anti-cryptococcal activity as measured by phagocytic activity, oxidative burst, lysozyme secretion, and ability to limit intracellular growth of C. neoformans. Furthermore, rat AM were more resistant to lysis in association with intracellular infection. In summary, differences in AM function in rats and mice suggest an explanation for the species differences in susceptibility to C. neoformans based on the inherent efficacy of a central effector cell of the innate immune system.

Topics: Animals; Cryptococcosis; Cryptococcus neoformans; Cytokines; Disease Susceptibility; Female; Immunity, Innate; Lung Diseases, Fungal; Macrophages, Alveolar; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Muramidase; Nitric Oxide; Pneumonia; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Sprague-Dawley; Respiratory Burst; Species Specificity

TGF-beta1 (TGF) has been implicated in the pathogenesis of several chronic infections and is thought to promote microbial persistence by interfering with macrophage function. In rats with experimental pulmonary cryptococcosis, increased lung levels of TGF were present at 12 mo of infection. Within the lung, expression of TGF localized to epithelioid cells and foamy macrophages in areas of inflammation. Increased TGF expression was also observed in the lungs of experimentally infected mice and a patient with pulmonary cryptococcosis. TGF reduced Ab and serum-mediated phagocytosis of Cryptococcus neoformans by rat alveolar macrophages (AM) and peripheral blood monocytes, and this was associated with decreased chemokine production and oxidative burst. Interestingly, TGF-treated rat AM limited both intracellular and extracellular growth of C. neoformans. Control of C. neoformans growth by TGF-treated rat AM was due to increased secretion of lysozyme, a protein with potent antifungal activity. The effects of TGF on the course of infection were dependent on the timing of TGF administration relative to the time of infection. TGF treatment of chronically infected rats resulted in reduced lung fungal burden, while treatment early in the course of infection resulted in increased fungal burden. In summary, our studies suggest a dual role for TGF in persistent fungal pneumonia whereby it contributes to the local control of infection by enhancing macrophage antifungal efficacy through increased lysozyme secretion, while limiting inflammation by inhibiting macrophage/monocyte phagocytosis and reducing associated chemokine production and oxidative burst.

Topics: Animals; Cell Line; Chemokines; Child; Cryptococcosis; Cryptococcus neoformans; Female; Humans; Immunohistochemistry; Lung Diseases, Fungal; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Muramidase; Phagocytosis; Rats; Rats, Inbred F344; Recombinant Proteins; Respiratory Burst; Transforming Growth Factor beta; Transforming Growth Factor beta1

The significance of the measurement of lactate, lysozyme and PHI in CSF for differential diagnosis of meningitis was examined in 58 cases of viral, 36 of bacterial and 5 of tuberculous etiology. In the early phase of the illness CSF lactate was found to be the most sensitive parameter for distinction of viral from bacterial or tuberculous meningitis respectively. Except for one case CSF lactate exceeded 3.8 mmol/l in all cases of bacterial etiology, whereas this value was never reached in any case of viral meningitis. While lactate concentration was maximal on the day of admission and declined continuously thereafter, PHI activity reached its maximum on the third day after beginning of the therapy. At this time all patients with a bacterial or tuberculous meningitis had PHI activities about 50 U/l. This value wasn't exceeded in any case of viral meningitis. In a few cases some days after onset of therapy a distinction of bacterial meningitis from viral forms was still possible by PHI determination but not by lactate measurement. Determination of lysozyme also could be helpful in the later phase of the disease.

Topics: Bacterial Infections; Cryptococcosis; Diagnosis, Differential; Glucose-6-Phosphate Isomerase; Humans; Lactates; Lactic Acid; Meningitis; Meningitis, Viral; Muramidase; Mycoplasma Infections; Tuberculosis, Meningeal

Topics: Amides; Animals; Antibodies; Bilirubin; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cryptococcosis; Ethanol; Hexachlorocyclohexane; Hyperbilirubinemia; Iron; Liver; Liver Diseases; Male; Muramidase; Naphthalenes; Necrosis; Nitrosamines; Protein Deficiency; Rats; Sulfhydryl Compounds; Thiocyanates

Topics: Animals; Cryptococcosis; Cryptococcus; Culture Media; Deoxyribonucleases; Dogs; Guinea Pigs; Histones; In Vitro Techniques; Kidney; Liver; Mice; Muramidase; Peptides; Proteins; Rabbits; Rats; RNA; Spleen; Tissue Extracts

Topics: Animals; Antibody Formation; Blood Proteins; Cryptococcosis; Cryptococcus; Deoxyribonucleases; Guinea Pigs; Hemagglutination Tests; Histones; In Vitro Techniques; Liver; Mice; Muramidase; Pancreas; Phagocytosis; Proteins; Rabbits; Rats; RNA; Spleen; Tissue Extracts