Biology subjects

Richter, F. C.

Publications and source records attributed to Richter, F. C..

9 recordsLinked to original sources

bioRxiv2026

Gut-derived ammonia modulates hypothalamic stress responses during viral infection

The gut-brain axis integrates microbial and host metabolism to regulate systemic physiology, yet its role during viral infection remains poorly defined. Viral infection induces behavioral changes and neuroendocrine stress responses accompanied by profound alterations in gut microbial metabolism. Here, we show that chronic viral infection in mice increases systemic levels of microbiota-derived ammonia in a CD8 T cell-dependent manner. Increased ammonia accumulates in the brain and selectively activates neurons within the paraventricular hypothalamus (PVH), driving corticosterone release into the circulation. Pharmacological inhibition of ammonia detoxification exacerbates these effects, leading to increased corticosterone levels, aggravated sickness behavior, and dampened antiviral responses. Together, these findings identify gut-derived ammonia as a previously unrecognized immunometabolic signal linking antiviral T cell responses to hypothalamic control of systemic stress during viral infection. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/736796v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1291dbcorg.highwire.dtl.DTLVardef@5f223corg.highwire.dtl.DTLVardef@1c0aafaorg.highwire.dtl.DTLVardef@190502_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

CD8+ T cells regulate the bioenergetic reprogramming of lymphoid organs and the heart during viral infection

The activation of the immune system is a bioenergetically-costly process1. Yet, essential bodily functions require a continuous energy supply, imposing energy constraints and trade-offs between competing processes2. Our understanding of the underlying bioenergetic adaptations reconciling rapid immune activation with other vital processes remains scarce. 3-6 Here, by using experimental models of viral infections, we identified an unexpected CD8+ T cell-driven redistribution of energy substrates between lymphoid organs and the heart. Viral infection promoted systemic hypoglycaemia and ketogenesis, together with systemic reallocation of energy substrates. Across organs analysed, secondary lymphoid organs and the heart showed the most dramatic changes. The former increased glucose uptake and oxidation while the heart showed the opposite, switching to preferential fatty acid utilization. These bioenergetic adaptations were absent in infected mice lacking CD8+ T cells or with T cells lacking the glucose transporter GLUT1. Pharmacological inhibition of fatty acid oxidation forced a systemic switch to glucose oxidation. This was associated with metabolic decompensation, reduced cardiac energetics, left ventricular stress, and mortality in otherwise nonlethal viral infections. Our results reveal how the energetic cost of immune cell activation imposes bioenergetic adaptations on non-lymphoid organs, posing a major challenge for the heart by completely relying on fatty acids.

immunology↗

bioRxiv2025

Crosstalk between CD8+ T cells and systemic bile acid metabolism controls LCMV-induced immunopathology

Antiviral immunity has a profound effect on host metabolism, which can, in turn, modulate immune responses and influences disease pathology. Among its many functions, the liver orchestrates systemic bile acid (BA) metabolism, a pathway disrupted in chronic liver diseases such as viral hepatitis. BAs have become increasingly recognized for their immunomodulatory properties, and multiple BA species are being explored as therapeutic agents in liver diseases. Understanding the interplay between immune responses and BA metabolism could unlock new therapeutic opportunities based on BA modulation. Using lymphocytic choriomeningitis virus (LCMV) as a model, we investigated the interplay between chronic hepatotropic virus infection, BA metabolism and immunity. Our findings reveal that chronic LCMV infection increases BA levels and shifts circulating and liver BA composition towards host-derived, conjugated BAs. At the same time, hepatic BA transport and synthesis genes are broadly downregulated, which is at least partially dependent on CD8+ T cells. Additionally, we found that sustained high BA levels impact CD8+ T cell responses to chronic LCMV infection. Mice with elevated circulating BAs due to the lack of BA transporters OATP1a and OATP1b, showed impaired T cell expansion and reduced liver immunopathology. These findings reveal a reciprocal interplay between CD8+ T cells and BA metabolism, expanding our understanding of adaptive immunity against viral hepatitis. Moreover, it highlights how immuno-metabolic changes in liver disease may affect the bodys ability to fight infections and cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/670599v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@7d4bcorg.highwire.dtl.DTLVardef@1f84b5org.highwire.dtl.DTLVardef@1419686org.highwire.dtl.DTLVardef@1014b8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Autophagy acts as a brake on obesity-related fibrosis by controlling purine nucleoside signalling

A hallmark of obesity is a pathological expansion of white adipose tissue (WAT), accompanied by marked tissue dysfunction and fibrosis. Autophagy promotes adipocyte differentiation and lipid homeostasis, but its role in obese adipocytes and adipose tissue dysfunction remains incompletely understood. Here, we demonstrate that autophagy is a key tissue-specific regulator of WAT remodelling in diet-induced obesity. Importantly, loss of adipocyte autophagy substantially exacerbates pericellular fibrosis in visceral WAT. Change in WAT architecture correlates with increased infiltration of macrophages with tissue-reparative, fibrotic features. We uncover that autophagy regulates purine nucleoside metabolism in obese adipocytes, preventing excessive release of the purine catabolites xanthine and hypoxanthine. Purines signal cell-extrinsically for fibrosis by driving macrophage polarisation towards a tissue reparative phenotype. Our findings reveal a novel role for adipocyte autophagy in regulating tissue purine nucleoside metabolism, thereby limiting obesity-associated fibrosis and maintaining the functional integrity of visceral WAT. Purine signals may serve as a critical balance checkpoint and therapeutic target in fibrotic diseases.

cell biology↗

bioRxiv2024

Inheritance of old mitochondria controls early CD8+ T cell fate commitment and is regulated by autophagy

T cell immunity is impaired during ageing, particularly in memory responses needed for efficient vaccination. Autophagy and asymmetric cell division (ACD) are cell biological mechanisms key to memory formation, which undergo a decline upon ageing. However, despite the fundamental importance of these processes in cellular function, the link between ACD and in vivo fate decisions has remained highly correlative in T cells and in the field of mammalian ACD overall. Here we provide robust causal evidence linking ACD to in vivo T cell fate decisions and our data are consistent with the concept that initiation of asymmetric T cell fates is regulated by autophagy. Analysing the proteome of first-daughter CD8+ T cells following TCR-triggered activation, we reveal that mitochondrial proteins rely on autophagy for their asymmetric inheritance and that damaged mitochondria are polarized upon first division. These results led us to evaluate whether mitochondria were asymmetrically inherited and to functionally address their impact on T cell fate. For this we used a novel mouse model that allows sequential tagging of mitochondria in mother and daughter cells, enabling their isolation and subsequent in vivo analysis of CD8+ T cell progenies based on pre-mitotic cell cargo. Autophagy-deficient CD8+ T cells showed impaired clearance and symmetric inheritance of old mitochondria, suggesting that degradation events promote asymmetry and are needed to generate T cells devoid of old organelles. Daughter cells inheriting old mitochondria are more glycolytic and upon adoptive transfer show reduced memory potential, whereas daughter cells that have not inherited old mitochondria from the mother cell are long-lived and expand upon cognate-antigen challenge. Proteomic and single-cell transcriptomic analysis of cells inheriting aged mitochondria suggest that their early fate divergence relies on one carbon metabolism as a consequence of poor mitochondrial quality and function. These findings increase our understanding of how T cell diversity is early-imprinted during division and will help foster the development of strategies to modulate T cell function. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/577412v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@526135org.highwire.dtl.DTLVardef@6c04b1org.highwire.dtl.DTLVardef@1a834fforg.highwire.dtl.DTLVardef@2f70f8_HPS_FORMAT_FIGEXP M_FIG The MitoSnap model allows tracking of pre-mitotic and post-mitotic cell cargoes. Both segregation and degradation (autophagy) contribute to the asymmetric inheritance of old mitochondria. Old mitochondria impact cell metabolism and function. Cells devoid of old mitochondria exhibit better memory potential in vivo. C_FIG

cell biology↗

bioRxiv2023

Cellular iron governs the host response to malaria

Malaria and iron deficiency are major global health problems with extensive epidemiological overlap. Iron deficiency-induced anaemia can protect the host from malaria by limiting parasite growth. On the other hand, iron deficiency can significantly disrupt immune cell function. However, the impact of host cell iron scarcity beyond anaemia remains elusive in malaria. To address this, we employed a transgenic mouse model carrying a mutation in the transferrin receptor (TfrcY20H/Y20H), which limits the ability of cells to internalise iron from plasma. At homeostasis TfrcY20H/Y20H mice appear healthy and are not anaemic. However, TfrcY20H/Y20H mice infected with Plasmodium chabaudi chabaudi AS showed significantly higher peak parasitaemia and body weight loss. We found that TfrcY20H/Y20H mice displayed a similar trajectory of malaria-induced anaemia as wild-type mice, and elevated circulating iron did not increase peak parasitaemia. Instead, P. chabaudi infected TfrcY20H/Y20H mice had an impaired innate and adaptive immune response, marked by decreased cell proliferation and cytokine production. Moreover, we demonstrated that these immune cell impairments were cell-intrinsic, as ex vivo iron supplementation fully recovered CD4 T cell and B cell function. Despite the inhibited immune response and increased parasitaemia, TfrcY20H/Y20H mice displayed mitigated liver damage, characterised by decreased parasite sequestration in the liver and an attenuated hepatic immune response. Together, these results show that host cell iron scarcity inhibits the immune response but prevents excessive hepatic tissue damage during malaria infection. These divergent effects shed light on the role of iron in the complex balance between protection and pathology in malaria.

immunology↗

bioRxiv2023

The Preprint Club - A cross-institutional, community-based approach to peer reviewing

The academic community has been increasingly using preprints to disseminate their latest research findings quickly and openly. This early and open access of non-peer reviewed research warrants new means from the scientific community to efficiently assess and provide feedback to preprints. Yet, most peer review of scientific studies performed today are still managed by journals, each having their own peer review policy and transparency. However, approaches to uncouple the peer review process from journal publication are emerging. Additionally, formal education of early career researchers (ECRs) in peer reviewing is rarely available, hampering the quality of peer review feedback. Here, we introduce the Preprint Club, a cross-institutional, community-based approach to peer reviewing, founded by ECRs from the University of Oxford, Karolinska Institutet and Icahn School of Medicine at Mount Sinai. Over the past two years and using the collaborative setting of the Preprint Club, we have been discussing, assessing, and providing feedback on recent preprints in the field of immunology. In this article, we provide a blueprint of the Preprint Club basic structure, demonstrate its effectiveness, and detail the lessons we learned on its impact on peer review training and preprint authors perception.

scientific communication and education↗

bioRxiv2021

Cell-extrinsic autophagy in mature adipocytes regulates anti-inflammatory response to intestinal tissue injury through lipid mobilization

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, through their use as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti- inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an altered oxylipin balance, driven through an NRF2-mediated upregulation of Ephx1. This was accompanied by a shift in adipose tissue macrophage polarization with reduced secretion of IL-10, leading to lower circulating levels of IL-10. These results suggest an underappreciated fat-gut crosstalk through an autophagy- dependent regulation of anti-inflammatory oxylipins, indicating a protective effect of adipose tissues for distant inflammation.

immunology↗

bioRxiv2017

An antisense RNA capable of modulating the expression of the tumour suppressor microRNA-34a

The microRNA-34a is a well-studied tumor suppressor microRNA (miRNA) and a direct downstream target of TP53 with roles in several pathways associated with oncogenesis, such as proliferation, cellular growth, and differentiation. Due to its broad tumor suppressive activity, it is not surprising that miR34a expression is altered in a wide variety of solid tumors and hematological malignancies. However, the mechanisms by which miR34a is regulated in these cancers is largely unknown. In this study, we find that a long non-coding RNA transcribed antisense to the miR34a host gene, is critical for miR34a expression and mediation of its cellular functions in multiple types of human cancer. We name this long non-coding RNA lncTAM34a, and characterize its ability to facilitate miR34a expression under different types of cellular stress in both TP53 deficient and wild type settings.

cancer biology↗