Cryptococcus Neoformans Infection and Immune Cell Regulation in Human Monocytes

Abstract

Background/Aims: Cryptococcus neoformans infections are becoming increasingly prevalent and remain a life-threatening clinical issue in immune-compromised hosts. The microorganism evades a variety of endogenous anti-fungal mechanims of host immune cells. The signaling pathways in human immune cells that become activated in response to Cryptococcus neoformans infection have yet to be fully characterized. Methods: Human monocytes were incubated with Cryptococcus neoformans, and the whole transcriptome of monocytes was sequenced before and after exposure to Cryptococcus neoformans using mass parallel sequencing techniques. Based on the genes that demonstrated altered expression patterns, we performed GO and KEGG enrichment analysis to further characterize the pathways involved in monocyte activation by Cryptococcus neoformans. Results: We found that immune and inflammatory responses, as well as chemotaxis, were the most heavily activated cellular events. Specifically, the toll-like receptor, tumor necrosis factor, NF-kB and Jak-STAT pathways were the most active pathways in response to Cryptococcus neoformans infection. The sequencing data of selected genes from the transcriptome analysis were further validated by real-time polymerase chain reactions. Conclusion: Taken together, our study is the first characterization of the transcriptome alterations in human immune cells upon C. neoformans infection, providing additional information that may be helpful in discovering novel anti-fungal targets.

Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection

“…The scope of reprogramming was broad, and included pathways that control the metabolism, signaling and cytoskeletal architecture of host cells. These findings extend previous studies where the global analysis of the transcriptional response to Cn infection demonstrated reprogramming of host transcriptional circuitry (Chen et al, 2015; Liu et al, 2014). …”

Fulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: Case report and review of fungal pericarditis

“…Although our patient had active chronic myelomonocytic leukaemia, a low‐risk leukaemia for fungal infections, he had several risk factors, such cytopenia and importantly prior treatment with ruxolitinib, a JAK ½ inhibitor implicated in severe opportunistic infections such as mycobacterial, Pneumocystis jirovecii , VZV, PML infections and a case of C. neoformans pneumonia . In fact, Chen et al have shown that the JAK‐STAT pathway is activated in human monocytes in response to C. neoformans . Ruxolitinib impairs dendritic cell and T‐cell function and reduces pro‐inflammatory cytokines, which could predispose this patient to increased risk for reactivation of a fulminant cryptococcosis .…”

IntracellularCryptococcus neoformansdisrupts the transcriptome profile of M1- and M2-polarized host macrophages

“…The effect of intracellular Cn on the host macrophage transcriptome has been investigated in a small number of earlier studies [18, 20]. While the overlap between the gene expression changes detected in these studies and ours were limited, possibly due to the use of differing cell models and older microarray technology [20], certain consistencies are evident.…”

“…As M2 cells typically present a less hostile environment for the intracellular growth and replication of microbes, a variety of pathogens have evolved mechanisms to interfere with host cell polarization as a survival strategy (reviewed in [17]). While previous studies have suggested that Cn minimally affects the expression of Nos2 and Argl, the principle markers of the M1 and M2 states [13], the impact on the broader transcriptome associated with these states remains unclear and is not captured in earlier microarray or RNA sequencing-based analyses of Cn -infected macrophages where polarization state is not explicitly considered [18–20].…”