Cytokine Profiles of AIDS Patients Are Similar to Those of Mice with DisseminatedCryptococcus neoformansInfection

Abstract

Cryptococcosis is an hematogenously disseminated meningoencephalitis during which the relationship between the disease severity and the immune response remains unclear. We thus analyzed, by enzyme-linked immunosorbent assay, proinflammatory (tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) and anti-inflammatory (IL-10) cytokine levels in plasma at the time of diagnosis in 51 AIDS patients with culture-proven cryptococcosis. We used a murine model to determine the correlation between cytokine levels and fungal burden in blood and tissues and the kinetics of the immune response and of the formation of cerebral lesions. In AIDS patients, plasma TNF-α and IL-10, but not IL-6, levels were significantly higher in the case of fungemia or disseminated infection than in their absence, whereas the presence of meningitis had no influence on these levels. In mice, none of these cytokines were detected within the first day after inoculation. Later on, TNF-α and IL-10, but not IL-6, levels in plasma correlated significantly with the fungal burden in the blood and spleen but not the brain. In the brain, cytokine levels were low compared to those in other compartments, and tissue lesions and a degree of infection similar to those observed in humans were seen, further suggesting the relevance of this experimental model. Thus, AIDS patients with cryptococcosis produce an immune response that reflects the dissemination but not the meningeal involvement. This murine model of disseminated cryptococcosis can be used to investigate the pathophysiology of cryptococcosis and new therapeutic approaches.

Influence of gender and age on course of infection and cytokine responses in mice with disseminated Cryptococcus neoformans infection

“…Once again, these results emphasize the need to also assess other components of the immune response. Nevertheless, the higher plasma TNF-a, IFN-g and IL-10, but not IL-6, levels found in young mice are in agreement with previous data obtained in this model showing a higher production of the above cytokines in the more severely infected animals [28].…”

“…Here, the more pronounced cytokine responses were found in the spleen and blood of female mice in two independent experiments, markedly contrasting with the similar fungal load observed in these compartments. Of note, the similar cytokine profiles observed in the brains of male and female mice, compared to the differences observed in the other compartments, further confirm the uniqueness of the brain in this model of disseminated cryptococcosis [28,31]. The higher levels of TNF-a and IFN-g in females compared to males, at least in blood and spleen, are in accordance with the influence of 17b-estradiol and progesterone, but not testosterone, on TNF-a release by male rat peritoneal macrophages [15], the increased transcriptions of IFN-g and TNF-a mRNA in the liver after estrogen treatment in lipopolysaccharide-challenged rats [9], and the enhanced TNF-a synthesis by the alveolar macrophages of endotoxin-injected female rats compared to male rats [10].…”

Cas1p is a membrane protein necessary for the O‐acetylation of the Cryptococcus neoformans capsular polysaccharide

“…This result represents the first demonstration that the capsule structure can influence the pathophysiology of cryptococcosis. However, it must be kept in mind that, even though this murine model of cryptococcosis which mimics disseminated infection in humans has been previously validated (Lortholary et al, 1999a;1999b), it does not mean that it is relevant for other clinical situations. For example, this model does not take into account the most common route of infestation, i.e.…”

HIV and co‐infections

“…Inoculation of Cryptococcus spp. into mice showed a rise in plasma TNF-a and IL-10, which was correlated to fungal burden in the blood and spleen but not in brain (90). The degree and kinetics of anti-inflammatory and pro-inflammatory responses are likely also to differ at different sites, in human cryptococcosis.…”