Caenorhabditis elegans DAF-16 regulates lifespan and immune responses to Cryptococcus neoformans and Cryptococcus gattii infections

Abstract

Background Cryptococcosis is a life-threatening infection is primarily caused by two sibling species Cryptococcus neoformans and Cryptococcus gattii. Several virulence-related factors of these cryptococci have been widely investigated in Caenorhabditis elegans, representing a facile in vivo model of host–pathogen interaction. While recent studies elucidated cryptococcal virulence factors, intrinsic host factors that affect susceptibility to infections by cryptococci remain unclear and poorly investigated. Results Here, we showed that defects in C. elegans insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway influenced animal lifespan and mechanisms of host resistance in cryptococcal infections, which required the activation of aging regulator DAF-16/Forkhead box O transcription factor. Moreover, accumulation of lipofuscin, DAF-16 nuclear localization, and expression of superoxide dismutase (SOD-3) were elevated in C. elegans due to host defenses during cryptococcal infections. Conclusion The present study demonstrated the relationship between longevity and immunity, which may provide a possibility for novel therapeutic intervention to improve host resistance against cryptococcal infections.

Infections of Cryptococcus species induce degeneration of dopaminergic neurons and accumulation of α-Synuclein in Caenorhabditis elegans

“…Thus, we employed this transgenic C. elegans strain (BZ555) to visualize the DA neurons in a living animal. We previously reported that C. neoformans and C. gattii can accumulate and kill the wildtype (N2) C. elegans ( Kitisin et al., 2022 ). In the present study, we found that accumulation of C. neoformans and C. gattii yeast cells in the distended gastrointestinal tract was anatomically close to 6 DA neurons ( Figures 1A, B ) ( Harrington et al., 2010 ).…”

“…Therefore, we employed this transgenic C. elegans strain (NL5901) to visualize the accumulation of human α-synuclein in a living animal. We have previously reported that infections of C. neoformans and C. gattii can accelerate the aging process and reduce the lifespan of C. elegans involving with IIS/DAF-16 pathway ( Kitisin et al., 2022 ). A recent study has also reported that accumulation of aggregated human α-synuclein inclusions was strongly associated with the activation of DAF-16 suggesting the relationship between the IIS pathway and PD ( Haque et al., 2020 ).…”

“…C. elegans transgenic BZ555 [egIs1 [dat-1p::GFP]] and NL5901 [pkIs2386 [unc-54p::α-synuclein:YFP + unc-119(+)]] strains were obtained from the Caenorhabditis Genetics Center (CGC, USA) of the University of Minnesota. C. elegans were maintained as described previously ( Kitisin et al., 2022 ). Escherichia coli OP50 was obtained from the CGC and used as a food source for C. elegans .…”

“…Accumulation of a-synuclein was observed in NL5901 worms after infection with C. neoformans and C. gattii as described previously with some modifications (Chalorak et al, 2018;Kitisin et al, 2022). Briefly, age-synchronized L4 NL5901 worms were transferred onto yeast-containing BHI/FUdR plates and incubated at 25°C for 72 h. Worms cultured on E. coli OP50 were used as a control.…”

“…Several alternative cryptococcosis invertebrate models have been introduced including Caenorhabditis elegans ( Mylonakis et al., 2002 ; Mylonakis et al., 2004 ), Drosophila melanogaster ( Apidianakis et al., 2004 ), and Galleria mellonella ( Mylonakis et al., 2005 ). In a previous study, our laboratory showed that both C. neoformans ATCC#32045 and C. gattii ATCC#56992 can reduce the lifespan of C. elegans by regulating the insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway and DAF-16 has been shown to play a central role during cryptococcal infections ( Kitisin et al., 2022 ). Although C. elegans has been extensively used as a model to screen targeted drugs for anti-Parkinson effects ( Chalorak et al., 2018 ; Malaiwong et al., 2019 ), however, the study of C. elegans neurodegeneration caused by pathogenic fungal infections has been limited.…”