Biology subjects

Ruberto, A. A.

Publications and source records attributed to Ruberto, A. A..

5 recordsLinked to original sources

bioRxiv2025

Memory Regulatory T Cells Reprogram into Protective Tfh-like Effectors in Recurrent Malaria

Although people living in malaria-endemic areas experience repeated infections with Plasmodium, the role of regulatory T cells (Tregs) in recurrent malaria remains poorly understood. During a primary infection with Plasmodium, Tregs suppress protective immunity by inhibiting germinal center (GC) reactions, thereby impeding the control of parasitemia. In contrast, we demonstrate here that memory Tregs (mTregs) remaining after the clearance of initial Plasmodium infection acquire protective functions upon recall. Relying on longitudinal studies in humans and mice, we show that mTregs undergo antigen-driven expansion and inflammation-induced epigenetic reprogramming during reinfection to transition from Foxp3+ immunosuppressive cells to Bcl6+ follicular T helper (Tfh)-like effectors. These mTreg-derived Tfh-like cells enhance GC responses and the generation of Plasmodium-specific antibodies, ultimately facilitating Plasmodium control. Precluding such mTreg-to-Tfh differentiation abolished protection. Our findings reveal a previously unrecognized adaptive plasticity in canonical mTregs that enables a context-dependent functional switch from immunoregulatory to protective effectors during recurrent infections.

immunology↗

bioRxiv2024

The Toxoplasma gondii homolog of ATPase inhibitory factor 1 is critical for mitochondrial cristae maintenance and stress response

The production of energy in the form of ATP by the mitochondrial ATP synthase must be tightly controlled. One well-conserved form of regulation is mediated via ATPase inhibitory factor 1 (IF1), which governs ATP synthase activity and gene expression patterns through a cytoprotective process known as mitohormesis. In apicomplexans, the processes regulating ATP synthase activity are not fully elucidated. Using the model apicomplexan Toxoplasma gondii, we found that knockout and overexpression of TgIF1, the structural homolog of IF1, significantly affected gene expression. Additionally, TgIF1 overexpression resulted in the formation of a stable TgIF1 oligomer that increased the presence of higher order ATP synthase oligomers. We also show that parasites lacking TgIF1 exhibit reduced mitochondrial cristae density, and that while TgIF1 levels do not affect growth in conventional culture conditions, they are crucial for parasite survival under hypoxia. Interestingly, TgIF1 overexpression enhances recovery from oxidative stress, suggesting a mitohormetic function. In summary, while TgIF1 does not appear to play a role in metabolic regulation under conventional growth conditions, our work highlights its importance for adapting to stressors faced by T. gondii and other apicomplexans throughout their intricate life cycles. SIGNIFICANCE STATEMENTO_LIToxoplasma gondii is a member of the Apicomplexa, a phylum consisting of parasites responsible for significant global morbidity and mortality. An intact mitochondrial ATP synthase is critical T. gondii survival, but how this enzyme is regulated is not completely understood. C_LIO_LIOur work demonstrates that the T. gondii homolog of ATPase inhibitory factor 1 (TgIF1) does not impact metabolism under standard culture conditions, but plays a role in mitochondrial cristae density and stress responses. C_LIO_LIThis study reveals the role of TgIF1 in regulating ATP synthase activity under stressful conditions and increases our understanding of this divergent enzyme in T. gondii. C_LI

molecular biology↗

bioRxiv2022

Single-cell RNA profiling of Plasmodium vivax liver stages reveals parasite- and host- specific transcriptomic signatures and drug targets

The resilience of Plasmodium vivax, the most widely distributed malaria-causing parasite in humans, is attributed to its ability to produce dormant liver forms known as hypnozoites, which can activate weeks, months, or even years after an initial mosquito bite. The factors underlying hypnozoite formation and activation are poorly understood, as is the parasites influence on the host hepatocyte. Here, we shed light on transcriptome-wide signatures of both the parasite and the infected host cell by sequencing over 1,000 P. vivax-infected hepatocytes at single-cell resolution. We distinguish between replicating schizonts and hypnozoites at the transcriptional level, identifying key differences in transcripts encoding for RNA-binding proteins associated with cell fate. In infected hepatocytes, we show that genes associated with energy metabolism and antioxidant stress response were upregulated, and those involved in the host immune response downregulated, suggesting both schizonts and hypnozoites alter the host intracellular environment. The transcriptional markers in schizonts, hypnozoites, and infected hepatocytes revealed here pinpoint potential factors underlying dormancy and can inform therapeutic targets against P. vivax liver-stage infection.

microbiology↗

bioRxiv2021

Single-cell RNA sequencing of Plasmodium vivax sporozoites reveals stage- and species-specific transcriptomic signatures

Plasmodium vivax sporozoites reside in the salivary glands of a mosquito before infecting a human host. Previous transcriptome-wide studies in populations of these forms were limited in their ability to elucidate cell-to-cell variation, thereby masking cellular states potentially important in understanding transmission outcomes. In this study, we performed transcription profiling on 9,947 P. vivax sporozoites to assess the extent to which they differ at single-cell resolution. We show that sporozoites residing in the mosquitos salivary glands exist in distinct developmental states, as defined by their transcriptomic signatures. Additionally, relative to P. falciparum, P. vivax displays overlapping and unique gene usage patterns, highlighting conserved and species-specific gene programs. Notably, distinguishing P. vivax from P. falciparum were a subset of P. vivax sporozoites expressing genes associated with translational regulation and repression. Finally, our comparison of single-cell transcriptomic data from P. vivax sporozoite and erythrocytic forms reveals gene usage patterns unique to sporozoites. In defining the transcriptomic signatures of individual P. vivax sporozoites, our work provides new insights into the factors driving their developmental trajectory and lays the groundwork for a more comprehensive P. vivax cell atlas.

genomics↗

bioRxiv2020

KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism

The mammalian circadian timing system and metabolism are highly interconnected, and disruption of this coupling is associated with negative health outcomes. Kruppel-like factors (KLFs) are transcription factors that govern metabolic homeostasis in various organs. Many KLFs show a circadian expression in the liver. Here, we show that the loss of the clock-controlled KLF10 in hepatocytes results in extensive reprogramming of the mouse liver circadian transcriptome, which in turn, alters the temporal coordination of pathways associated with energy metabolism. We also show that glucose and fructose induce Klf10, which helps mitigate glucose intolerance and hepatic steatosis in mice challenged with a sugar beverage. Functional genomics further reveal that KLF10 target genes are primarily involved in central carbon metabolism. Together, these findings show that in the liver, KLF10 integrates circadian timing and sugar metabolism related signaling, and serves as a transcriptional brake that protects against the deleterious effects of increased sugar consumption.

cell biology↗