Experimental model of intracerebral infection with Cryptococcus neoformans: roles of phagocytes and opsonization

Abstract

A murine model of intracerebral (i.c.) infection with Cryptococcus neoformans in which naive mice receiving an i.c. fungal inoculation developed a severe disease has been established. The effect was strictly dependent on the number of microorganisms injected and evolved as lethal meningoencephalitis. Murine susceptibility to i.c. infection with C. neoformans was enhanced by treatment with chloroquine and colchicine, agents known to greatly affect the host phagocytic compartment. Furthermore, the life spans of both naive and drug-treated mice were significantly augmented when opsonized fungi were injected. Therefore, phagocyte-mediated mechanisms are likely involved in local resistance to i.c. infection with C. neoformans. Further support for this conclusion was supplied by in vitro data showing that microglial cells were proficient anticryptococcal effectors, provided opsonized microorganisms were used.

The human immunodeficiency virus (HIV) protease inhibitor indinavir directly affects the opportunistic fungal pathogenCryptococcus neoformans

“…Since it is proposed that C. neoformans produces proteases, as biochemical devise(s) for nutritional recruitment [16,19], we suggest that such a pathway is critically disturbed upon exposure to the PI indinavir. By a murine model of experimental meningoencephalitis, it has been demonstrated that the brain phagocytic compartment is an important defence barrier against C. neoformans [27,[30][31][32]. Accordingly, in vitro studies reveal that microglial cells are endowed with direct antifungal activity and their efficacy may further increase, under appropriate conditions [27,28,33].…”

Differential microbial clearance and immunoresponse of Balb/c (Nramp1 susceptible) and DBA2 (Nramp1 resistant) mice intracerebrally infected with Mycobacterium bovis BCG (BCG)

“…i.c. inoculations were performed on anesthetized mice, as previously described [11]. Brie£y, mice received the inoculum (30 Wl) into the brain, 1 mm lateral and posterior to the bregma, at a depth of 2 mm with a 0.1-ml microsyringe and a 27-gauge disposable needle.…”

The ABC transporter-encoding geneAFR1affects the resistance ofCryptococcus neoformansto microglia-mediated antifungal activity by delaying phagosomal maturation

“…Microglia may either allow C. neoformans intracellular survival and replication (Lee et al, 1995) or exert anticryptococcal activity, whose levels are enhanced upon exposure to IFN-g or chloroquine (Blasi et al, 1995b;Mazzolla et al, 1997;Saleppico et al, 1999). Furthermore, C. neoformans resistance to microglia is partially reduced by yeast cell preopsonization with fresh serum or by pretreatment with protease inhibitors (Blasi et al, 1992(Blasi et al, , 1995aLipovsky et al, 1997). Thus, both the early yeast-to-microglia recognition step(s) and the postphagocytosis intracellular events seem to be relevant in the outcome of such pathogen-host cell interplay.…”