Role of phagocytosis in the virulence of Cryptococcus neoformans.
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Although the pathogenesis of cerebral cryptococcosis is poorly understood, local immune cells, such as microglia and astrocytes, likely play a critical role in containing infection. Chloroquine (CQ) is a weak base that accumulates within acidic vacuoles and increases their pH. Consequently, proteolytic activity of lysosomal enzymes and intracellular iron release/availability are impaired, resulting in decreased availability of nutrients crucial to microorganism survival and growth in the host. We found that CQ enhances BV2 microglial-cell-mediated anticryptococcal activity in vitro. The phenomenon is (i) evident when both unopsonized and opsonized microorganisms are used and (ii) mimicked by NH4Cl, another weak base, and by bafilomycin A1, an inhibitor of vacuolar-type H+-ATPases. In vivo, intracerebral administration of CQ before lethal local challenge with Cryptococcus neoformans results in a significant augmentation of median survival time and a marked reduction of yeast growth in the brain and is associated with the enhancement of local interleukin 1beta (IL-1beta) and IL-6 mRNA transcripts. Overall, these results provide the first evidence that CQ enhances anticryptococcal host defenses.
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A 39 year old white man, with advanced Virchowian hanseniasis died with signs of extensive meningeal involvement. His medical background showed repeated episodes of Erythema nodosum hansenicum (ENH) in the last three years of his life, besides ischemic gangrena with amputation of the left leg and cerebral vascular ischemic attacks. The autopsy revealed an advanced stage of arteriosclerosis affecting mainly the brain and the distal segment of the aorta and its ramifications. A propagating thrombus was found along the left femoral and iliac arteries and in the terminal portion of the aorta extending to the renal arteries. Thrombosis was also found along the left femoral vein, left iliac vein and distal segment of the inferior cava. The brain showed anemic infarction in organization and a generalized meningoencephalic involvement with granulomatous reaction caused by Cryptococcus neoformans. It was suggested a possible relationship between Erythema nodosum reactions and thrombosis phenomena. Torulosis was considered as a final occurrence and the proliferative vasculitis due to the granulomatous process in the sub-arachnoidal space has certainly aggravated the cerebral ischemia.
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Passive immunization with monoclonal antibodies (MAbs) to melanin prolonged the survival of and reduced the fungal burden in Cryptococcus neoformans-infected mice in comparison to controls. MAbs to melanin reduced the growth rate of in vitro-melanized C. neoformans cells, suggesting a new mechanism of antibody-mediated protection.
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With help of Guizotia creatinine agar (syn. bird seed agar) Cryptococcus (Cr.) neoformans var. neoformans was isolated from 71 (7.7%) of 925 investigated droppings of birds kept within human living area. Cr. neoformans was detected in droppings of 1.2% from 164 psittacines, in droppings of 1.7% from 118 budgerigars and in droppings of 18.4% from (carrier) pigeons. This yeast was not isolated from droppings of 13 small parrots, 10 eclectus parrots, 13 rosellas, 21 cockatiels, 6 Polytelidus sp., 32 Cacatua sp., 13 Carduelis sp., 5 waxbills, 5 starlings, 120 chicken, 9 turkeys, 2 geese, 2 Turdus sp., 1 duck and 1 gull.
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