Cryptococcus neoformans Csn1201 Is Associated With Pulmonary Immune Responses and Disseminated Infection.

Cryptococcus neoformans is a major etiological agent of fungal meningoencephalitis. The outcome of cryptococcosis depends on the complex interactions between the pathogenic fungus and host immunity. The understanding of how C. neoformans manipulates the host immune response through its pathogenic factors remains incomplete. In this study, we defined the roles of a previously uncharacterized protein, Csn1201, in cryptococcal fitness and host immunity. Use of both inhalational and intravenous mouse models demonstrated that the CSN1201 deletion significantly blocked the pulmonary infection and extrapulmonary dissemination of C. neoformans. The in vivo hypovirulent phenotype of the csn1201Δ mutant was attributed to a combination of multiple factors, including preferential dendritic cell accumulation, enhanced Th1 and Th17 immune responses, decreased intracellular survival inside macrophages, and attenuated blood-brain barrier transcytosis rather than exclusively to pathogenic fitness. The csn1201Δ mutant exhibited decreased tolerance to various stressors in vitro, along with reduced capsule production and enhanced cell wall thickness under host-relevant conditions, indicating that the CSN1201 deletion might promote the exposure of cell wall components and thus induce a protective immune response. Taken together, our results strongly support the importance of cryptococcal Csn1201 in pulmonary immune responses and disseminated infection.

Complex Roles of Annexin A2 in Host Blood-Brain Barrier Invasion by Cryptococcus neoformans.

INTRODUCTION: Fungal transversal across the brain microvascular endothelial cells (BMECs) is the essential step for the development of cryptococcal meningoencephalitis. Annexin A2 (AnxA2) is an important signaling protein involved in several intracellular processes such as membrane trafficking, endocytosis, and exocytosis. AIM: To investigate the roles and mechanism of AnxA2 during cryptococcal transversal of BMECs. RESULTS: Cryptococcus neoformans infection initiated upregulation of AnxA2 in mouse BMECs. Blockade with anti-AnxA2 antibody led to a reduction in fungal transcytosis activity but no change in its adhesion efficiency. Intriguingly, AnxA2 depletion caused a significant increase in fungal association activity but had no effect on their transcytosis. AnxA2 suppression resulted in marked reduction in its partner protein S100A10, and S100A10 suppression in BMECs significantly reduced the cryptococcal transcytosis efficiency. Furthermore, AnxA2 dephosphorylation at Tyr23 and dephosphorylation of downstream cofilin were required for cryptococcal transversal of BMECs, both of which might be primarily involved in the association of C. neoformans with host cells. CONCLUSIONS: Our work indicated that AnxA2 played complex roles in traversal of C. neoformans across host BMECs, which might be dependent on downstream cofilin to inhibit fungal adhesion but rely on its partner S100A10 to promote cryptococcal transcytosis.

Cryptococcosis in kidney transplant recipients in a Chinese university hospital and a review of published cases.

BACKGROUND: Cryptococcosis is a severe fungal infection with a high mortality rate among solid-organ transplant recipients. Today, China is among the countries performing the most kidney transplants worldwide, however data on the association of cryptococcosis with kidney transplantation in mainland China remain scarce and fragmented. METHODS: We retrospectively analyzed cases of culture-confirmed cryptococcosis following kidney transplantation that have occurred at our hospital and reviewed the published cases in China over the last 30 years. RESULTS: Cryptococcosis in kidney transplant recipients was mainly caused by Cryptococcus neoformans var. grubii VNI strains and occurred most frequently in patients aged 41-50 years (37.9%, 11/29). The average time to infection after kidney transplantation was 5.16 ± 3.97 years. The clinical manifestations were found to be diverse, with slight to moderate headache and fever, meningeal irritation, and high cerebrospinal fluid pressure being relatively common. Physicians should be alert to these symptoms among kidney transplant recipients. CONCLUSIONS: Cryptococcosis is a serious infection among kidney transplant recipients in mainland China. It has unique characteristics, such as a relatively long time to onset after kidney transplantation, and diverse clinical manifestations. Treatment with intrathecal injection of amphotericin B is considered effective for central nervous system involvement. The findings of this study also highlight the urgent need for multicenter, prospective, and multidisciplinary clinical studies and education on cryptococcosis in kidney transplant recipients in China.

Invasive fungal infections secondary to acute-on-chronic liver failure: a retrospective study.

Although the consequences of invasive fungal infections (IFIs) secondary to chronic hepatitis B infections secondary IFIs are serious, the incidence and main pathogenic factors of IFIs in acute-on-chronic liver failure (ACLF) patients remain unclear. This study included 1200 hepatitis B patients who were treated in the Department of Infectious Diseases, Shanghai Changzheng Hospital from January 2006 to January 2009. Patients with ACLF were screened according to the diagnostic guidelines for liver failure. Patients with ACLF and secondary IFI were the disease group, and patients with ACLF without secondary IFI were the controls. The incidence of IFI, mortality, and possible IFI causes in two groups were evaluated retrospectively. Sixty patients with ACLF had secondary IFI, of which 14 were confirmed cases and 46 were suspected cases. The incidence of IFI was 47.62% for ACLF patients. Logistic regression analysis showed that the level of hepatitis B viral (HBV) DNA was an important risk factor for secondary IFI in ACLF patients. Receiver operating characteristic curve analysis suggested that when the number of HBV DNA copies was higher than 3.16 × 10(3) copies ml(-1) , the possibility of secondary IFI in ACLF patients increased significantly, while white blood cell levels showed protective effects for these patients. The incidence of IFI is high in ACLF patients and high hepatitis B virus DNA levels may be an independent risk factor of secondary IFI in these patients.