Peripheral Neuroimmunology

Nociceptors as controllers of immunity

Pain has been recognized as a cardinal sign of inflammation ever since the time of the Roman physician Celsus. Yet, only in the past decade has it become clear that such neuroimmune communication is bidirectional: it’s not just that inflammation begets pain, but pain and, specifically, nociceptors – the neurons that mediate the sensation – can also shape immune responses in many different contexts.

Understanding this neuroimmune dialogue represents one of the most exciting frontiers in modern biomedical research. However, the inherent complexity of neuroimmune interactions complicates systematic dissection of the underlying molecular mechanisms. Thus, we have recently developed an in vitro co-culture system that enables the exploration of neuroimmune interactions under defined conditions. In this manner, we identified three molecularly distinct communication modalities through which nociceptors fine-tune the functions of dendritic cells (DCs) – myeloid leukocytes essential for the initiation and regulation of immune responses.

Similarly, in a parallel line of investigation, we found that nociceptors communicate with another subset of myeloid leukocytes – monocytes – and promote their differentiation into immunosuppressive cells with pro-tumorigenic properties.

The successful candidate will build on these observations and utilize a combination of in vitro and in vivo techniques, integrating immunology, neuroscience, genomics, and cancer/cell biology, to conduct research that broadens our understanding of how nociceptors influence immunity. Based on their interests, the specific project may be focused on the dissection of molecular communication mechanisms between nociceptors and DCs, the role of the nociceptor : monocyte dialog in tumorigenesis, or the identification of novel communication modalities between nociceptors and other immune cells.

While the project will primarily generate conceptual insights into the mechanisms of neuroimmune interactions, it may also identify “druggable” targets with translational potential in various clinically relevant settings, including cancer, inflammatory disorders, or vaccination.

Epithelial Biology of Apicomplexan Infections

Investigating host epithelial cell-parasite interactions

What makes the host-pathogen relationship so special? How have obligate parasites evolved to survive and thrive within the hosts they have chosen? What is it about host cells that the parasites can’t live without, and how might host cells respond in return? The Epi-Api lab at GIMM is interested in answering these questions, and more, initially through the lens of the intestinal parasite Cryptosporidium (‘Crypto’).

Crypto is in the same family of deadly apicomplexan parasites as Plasmodium and Toxoplasma. However, unlike its relatives, Crypto only infects epithelial cells, completing its full life cycle in one host. No stranger to disease, it is one of the leading causes of diarrheal disease and deaths in young children worldwide (Kotloff et al, 2017, Lancet; PMID: 23680352). There is no vaccine or effective treatment for this parasite.

We are interested in studying Crypto not only to potentially find better therapies, but also to better understand host and apicomplexan cell biologies. We will initially leverage results from a powerful microscopy-based genome-wide CRISPR-Cas9 screen that was recently conducted (Marzook et al, 2025, Cell; PMID: 40706591). Hits from this screen will be starting points for several possible projects to better understand the epithelial cell-parasite relationship. We are also interested in understanding the host immune response to Crypto infections, particularly the role of certain immune cell types that we know are important to fight Crypto infections in vivo (Maradana & Marzook et al, 2023, Cell Host & Microbe; PMID: 38052207). We believe this is crucial to developing effective treatments and vaccines against this deadly disease.

If these research topics interest you, consider applying to the Epi-Api lab!

Bishara Marzook is joining GIMM in 2026 (currently at the Francis Crick Institute)

Innate Immune Cell Biology

Myddosome Signaling: Defining the spatiotemporal rules of innate immune activation

Mammalian immune systems are comprised of interconnected layers: Barriers, the innate and the adaptive immune system. We study the cell biology of innate immune cells and how these special cells contribute to the detection of microbes and defense against pathogens. For this, innate immune cells employ a range of pattern-recognition receptors, that upon their activation “ring the alarm” and initiate inflammation and an immune response. One class of pattern-recognition receptors, the Toll-like receptors (TLRs) are central to this innate immune activation. Canonical models of TLR signaling describe ligand-induced assembly of MyD88-dependent signaling complexes (“myddosomes”) at the plasma membrane or endosomal compartments. This receptor-proximal clustering of MyD88 nucleates a highly complex signaling assembly and activates diverse signaling pathways (e.g. NF-κB and MAPKs). Emerging evidence suggests that myddosomes are not limited to the receptor-proximal compartment where they were seeded (proto-myddosomes). Instead, the updated model of TLR signaling supports that myddosomes can assemble and persist in the cytosol. The mechanistic basis, molecular composition, and functional consequences of these cytosolic assemblies remain incompletely understood.

This project seeks to further characterize cytosolic myddosomes and define the rules and factors that govern their assembly. The central hypothesis is that cytosolic myddosomes are structurally and compositionally distinct from receptor-bound proto-myddosomes and that their spatial reorganization modulates signaling amplitude, duration, and transcriptional output; altogether shaping the subsequent immune response. To test this, the project will combine quantitative (live-cell) imaging, genetic engineering to externally control MyD88 and its complexes, and transcriptional profiling:

1. We will investigate the assembly dynamics of cytosolic myddosomes using CRISPR-engineered knock-in innate immune cell lines (e.g. macrophages) and high-resolution live-cell imaging. By comparing ligand-induced receptor-proximal complexes with cytosolic puncta that emerge after receptor disengagement, we will determine how the cytosolic assemblies arise from membrane-proximal complexes. Quantitative and biochemical analysis will further characterize their properties.
2. We will determine and manipulate the molecular composition of cytosolic myddosomes using inducible clustering of MyD88 combined with biochemical and imaging-based quantifications. We will explore biosynthetic approaches to control MyD88 independently of the receptors and to target MyD88-assemblies to different cellular compartments. By spatially restricting MyD88, we will identify proteins selectively enriched in each context and define whether canonical components such as IRAK kinases are differentially recruited.
3. The functional consequences of cytosolic MyD88 signaling will be assessed through time-resolved transcriptomic analysis and quantitative measurements of signaling dynamics and cytokine production. Comparing acute receptor-driven activation with persistent cytosolic clustering will determine the impact of cytosolic myddosomes on innate immune cell activation.

By integrating mechanistic cell biology with systems-level analysis, we will learn how TLRs and their associated signaling pathways govern the inflammatory output of innate immune cells. Given the central role of TLRs and MyD88 in infection, autoimmunity, and inflammatory diseases, uncovering these principles may reveal new strategies for modulating pathological inflammation.

Daniel Fisch is joining GIMM as a Group Leader in 2026. Currently at the Boston Children’s Hospital & Harvard Medical School, Boston MA, US

Chromatin & Epigenetics

DNA Damage-Driven Genome Remodelling and Inflammation in Ageing

How do some cells sustain their functions for decades without dividing? Skeletal muscle fibers and neurons are designed to last, yet over time, they undergo ongoing DNA damage and cellular stress. How these long-lived cells maintain their function despite such stress is a compelling question in modern biology. Unlike dividing cells, these specialized cells have limited options for repairing DNA damage, yet they must stay functional for years.

This PhD project will explore how post-mitotic cells respond to genomic stress and how these responses may influence ageing and age-related diseases. It addresses key questions: How do long-lived cells manage
persistent DNA damage? Do they handle different genomic lesions in the same way, or do they adopt varying strategies based on context? Can defective responses to genome stress contribute to inflammation and decline in ageing tissues? The student will use various experimental models of human post-mitotic cells, employing advanced cell biology,
microscopy, molecular techniques, and genomic analysis.

The research will examine how damaged DNA is detected, processed, and repaired in differentiated cells, and how these processes intersect with pathways involved in cellular maintenance and inflammatory signalling. Understanding these mechanisms is crucial beyond basic science. As tissues age, they accumulate molecular damage, and failures in cellular maintenance are linked to chronic inflammation, functional decline, and degenerative diseases. By revealing how post-mitotic cells safeguard genomic integrity, or why they fail, the project could offer new insights into tissue ageing and age-associated disorders, especially in systems like muscle and the nervous system, where cell longevity is vital for lifelong function.

Telomeres & Telomere Transcription in Cancer and Aging

Telomeres and telomere transcription in cancer and aging

Telomeres are specialized nucleoprotein structures that protect chromosome ends and preserve genome stability. Because conventional DNA replication cannot fully copy chromosome termini, telomeres progressively shorten with each cell division. When they reach a critical length, cells enter replicative senescence, a stable proliferation arrest that prevents further proliferation. Cellular senescence is a double-edged sword: on one hand, it acts as a potent barrier against cancer by averting immortalization; on the other, the accumulation of senescent cells contributes to tissue dysfunction and is thought to drive organismal aging. Understanding how cells sense telomere shortening and trigger senescence is therefore a central question at the intersection of cancer biology and aging research.

Our laboratory studies TERRA, an RNA transcribed by RNA polymerase II from telomeric regions. TERRA levels increase when telomeres become short or dysfunctional, suggesting it may act as a signal communicating telomere status to the cell. While TERRA has been extensively studied in cultuted cancer cells, its roles in normal aging cells, particularly in multicellular model organisms, remain largely unexplored.

We have found that primary human fibroblasts approaching replicative senescence produce higher levels of TERRA. Moreover, we recently developed a novel experimental toolkit that allows induction of TERRA transcription from long telomeres in young cells. Remarkably, this is sufficient to trigger proliferation arrest and the accumulation of cellular features resembling senescence. These findings suggest that telomere transcription itself may initiate premature aging-like responses and point to TERRA as a molecule linking cellular aging and cancer prevention.

The goal of this PhD project is to uncover how telomere transcription influences cellular proliferation, aging and protection against oncogenic transformation. We will investigate how TERRA production is regulated, how it affects telomere structure and signaling pathways, and how it contributes to senescence. Studies will be conducted primarily in cultured primary human cells and may also extend to zebrafish transgenic models currently under development. This provides a unique opportunity to study telomere transcription in vivo, the interplay between cancer development and aging at both cellular and organismal levels, and the conservation of these processes across different eukaryotes.

The project will employ a broad range of state-of-the-art techniques, including molecular biology, biochemistry, advanced imaging, long-read sequencing and bioinformatics. The student will gain training in both experimental and computational approaches within a collaborative and interdisciplinary environment.

This PhD project offers the chance to explore a fundamental and emerging aspect of telomere biology at the crossroads of genome stability, aging and cancer. This work will uncover how telomere transcription signals cellular state and shapes senescence responses, reveal novel mechanisms controlling cellular lifespan and disease susceptibility, and likely inform new strategies for cancer therapy and healthy aging.

Plant Molecular Biology

Alternative Splicing in Plant Immunity: The Role of SR Proteins

Plants rely on a highly dynamic defense system to detect and respond to pathogens, which requires rapid and precise reprogramming of gene expression. Alternative splicing, a process by which a single gene can produce multiple transcript variants, has emerged as an important mechanism contributing to this flexibility.

During pathogen infection, widespread changes in alternative splicing affect genes involved in both major layers of plant immunity: pattern-triggered immunity (PTI), activated by recognition of conserved microbial molecules, and effector-triggered immunity (ETI), which depends on intracellular detection of pathogen virulence proteins. Despite this, the mechanisms that regulate these splicing changes and their impact on disease resistance remain poorly understood.

Serine/arginine-rich (SR) proteins are key regulators of alternative splicing. While their roles in abiotic stress responses are well established, their function during pathogen infection is largely unexplored. Interestingly, pathogen effectors can target components of the host splicing machinery, suggesting that SR proteins may play an important role in shaping immune responses.

In this project, the student will use the Arabidopsis thaliana–Pseudomonas syringae pathosystem, together with a collection of SR protein mutants available in the lab, to investigate how alternative splicing contributes to plant immunity.

The work will begin by identifying splicing changes controlled by SR proteins during infection. RNA-seq will be used to compare splicing profiles of wild-type and SR protein mutant plants under control and infection conditions to identify alternative splicing events that depend on specific SR proteins. Based on these datasets, candidate genes with potential roles in immunity will be selected using functional annotation and enrichment analyses. Their contribution to plant defense will then be tested using reverse genetics and pathogen infection assays, linking specific splicing events to disease resistance or susceptibility.

To further investigate how SR proteins contribute to immune signaling, the student will analyze their role in both PTI and ETI using well-established assays, including flagellin treatment and infections with Pseudomonas strains carrying different effector repertoires. These experiments will reveal how loss of specific SR proteins affects early immune responses and disease progression.

Finally, the project will explore whether pathogen effectors directly target SR proteins. Protein–protein interaction approaches, such as co-immunoprecipitation and yeast two-hybrid assays, will be used to assess whether effectors interact with SR proteins and modulate their function.

This project combines transcriptomics, molecular biology, and plant–microbe interaction studies. The student will gain experience in RNA-seq and alternative splicing analysis, plant genetics, infection assays, and protein interaction techniques.

Overall, this work will reveal how alternative splicing contributes to plant defense and how pathogens may exploit this layer of regulation, establishing SR proteins as key regulators of gene expression during stress.

Cell Architecture

Dynamic Regulation of Microtubule-Nucleus Connections in Myofiber Nuclear Positioning

Precise positioning of nuclei within skeletal muscle fibers is essential for muscle development, function, and overall health. Disruption of nuclear placement is a hallmark of several muscle diseases, including muscular dystrophies. However, the mechanisms that regulate nuclear positioning, particularly the role of microtubule (MT)-nucleus connections, remain poorly understood. The student’s project aims to investigate how MT-nucleus connections are dynamically regulated to control nuclear movement and positioning in myofibers.

To address this, the student will employ a combination of advanced techniques, including high-resolution immunofluorescence microscopy to map the localization of key centrosomal proteins at the nuclear envelope, and optogenetic tools to selectively sever microtubules near nuclei and directly assess their role in nuclear movement. Live-cell imaging will be used to compare the dynamics of MT-nucleus connections in central versus peripheral nuclei. The student will also manipulate muscle fiber contraction and nuclear stiffness to explore upstream signals that may trigger changes in MT-nucleus interactions. During muscle growth, newly fused nuclei will be isolated using EdU labeling and FACS sorting, followed by single nuclei RNA sequencing and protein mass spectrometry to profile their gene expression and proteome over time.

By integrating these approaches with the laboratory’s primary myofiber organoid system, the student’s project will provide new insights into the molecular machinery controlling nuclear positioning in muscle. This work will also train the student in state-of-the-art experimental techniques and data management skills, which are essential for future research careers in the life sciences. Ultimately, the findings could reveal novel therapeutic targets for muscle diseases characterized by nuclear mispositioning, contributing to improved understanding and treatment of these conditions.

Ageing & Tissue Repair

Project I: Stem Cells in Aging and Rejuvenation

Aging is the single greatest risk factor for the chronic diseases that dominate modern medicine, yet its biology remains incompletely understood. A major challenge for regenerative medicine is that the organs that most need repair in old age are also those least able to respond to it. Adult stem cells are central to this challenge. These cells sustain tissue maintenance and repair, and their therapeutic potential has been recognized as a path toward restoring organ function in aging. However, translating this potential into effective therapies requires a better understanding of how stem cells respond to aged tissues, which profoundly shape stem cell function, identity and regenerative competence.

Our lab addresses this problem using skeletal muscle, one of the best-studied models of stem cell-driven tissue repair. We investigate how aging alters the relationship between stem cells and their tissue environment, how stem cell identity and regenerative potential are maintained or eroded across the lifespan, and whether these processes can be targeted to restore repair capacity. This PhD project will explore how aging is translated into a loss of stem cell function and regenerative capacity, and whether this process can be reversed. The student will join an ERC-funded research program aimed at uncovering fundamental mechanisms of tissue aging and leveraging this knowledge to design regenerative strategies for old age.

Aging & Tissue Repair

Project II: Immune aging and the loss of regenerative capacity

Adult stem cells sustain organ renewal and repair throughout life, but this capacity declines with age. One of the central challenges in aging biology is to understand why organs progressively lose their ability to recover from stress and injury, and how this decline might be reversed. Increasing evidence suggests that these failures cannot be explained by stem cells alone. Instead, they emerge from age-related alterations in the tissue environment, including changes in immune signaling that may reshape the behavior and regenerative potential of stem cells.

Our lab studies this problem using skeletal muscle, one of the best-studied models of tissue repair. Muscle regeneration is sustained by resident muscle stem cells but depends on a highly coordinated interaction with immune cells and other niche populations. We are particularly interested in understanding how immune populations and immune-derived signals regulate stem-cell activity during regeneration, how these interactions are altered in aging, and how this ultimately drives regenerative decline.

This PhD project will investigate how immune aging drives regenerative failure. The student will join an ERC-funded research program aimed at uncovering specific immune alterations involved in age-associated regenerative decline and developing immune modulatory strategies to improve regenerative success in aging. The project will address fundamental questions at the interface of immunology, stem cell biology and aging, while contributing to a broader effort to develop regenerative medicine strategies that improve tissue repair in later life.

Integrative Behavioural Biology

Molecular and cellular evolution of the social brain: a comparative approach

The brain, with its large diversity of cell types (>3000 in the human brain) that establish multiple connections among them (86 billion neurons establish approximately 1014 synapses in the human brain) to form functionally specialized neural circuits, is the most complex organ known. How and why such complexity has evolved is a central question in evolutionary biology ever since Darwin. The social environment has been postulated as a major selective pressure that led to enhanced cognition and brain complexity. According to the “social brain hypothesis” (SBH) , living in social groups with differentiated relationships between individuals imposes a demand for enhanced cognitive abilities that require more computational power and hence enlarged executive brain regions. Although the SBH has received widespread support from comparative studies in different vertebrate taxa, contradictory results have been reported when trying to generalize it across a broader range of taxa,and in recent years it has been the focus of much debate.

The main aim of this project is to investigate the role of sociality in brain evolution at the molecular and cellular levels. Cichlid fishes were chosen as a vertebrate study model, given the unparalleled naturally occurring variation in social behavior in this group of fish. The specific goals of this project are:

(1) to test the implicit assumptions and predictions of the social brain hypothesis (SBH) and to contrast its explanatory power with other hypotheses (ecological, life-history) for brain evolution.

(2) to characterize sociality-driven brain evolution at the transcriptomic and cellular levels with single cell resolution.

(3) to characterize the genetic basis of sociality-driven brain evolution.

To achieve these goals our research plan is organized into 3 tasks.

In Task 1 we will test the SBH comparatively at the inter-specific level, using the adaptive radiation of cichlids in Lake Tanganyika, which comprises repeated evolutionary transitions towards sociality. The effect on increased sociality on measures of brain computational power (i.e. volume/ mass, neuron numbers, potential connectivity) across brain regions will be tested. The effects of other ecological (e.g. diet, ecological niche) and life-history variables will also be tested, allowing to assess the relative contribution of social, ecological, and life-history factors on brain evolution.

In Task 2 we will characterize brain evolution at the transcriptomic and cellular levels using single cell sequencing combined with spatial transcriptomics, which allows for the identification of the cell types and their allocation to specific brain regions, across paiwise comparisons of solitary vs. social cichlid species. As a result, the test of the SBH will be, for the first time, extended beyond brain size/ neuron numbers to cellular and molecular levels.

In Task 3 we will investigate the genetic basis of variation in brain measures and of their response to the evolution of sociality. We will search for genetic variants associated with the brain phenotypes, already characterized in Task 1, using an interspecific GWAS based on the database of whole genome sequences available for all Lake Tanganyika cichlids.

Biomembranes & Nanomedicine

A biophysical and computational approach for the development of peptide-nanoparticle conjugates as new effective antimicrobials

The critical multidrug-resistant ESKAPE pathogens have in common the formation of biofilms that form a barrier for most common antibiotics, thereby exacerbating chronic infections and contributing to the emerging of multidrug resistant strains. In response to these recalcitrant infections, the project proposes the targeting of biofilms with AI-optimized antimicrobial peptides (AMPs), both by themselves and combined with nanoparticles: metal nanoparticles, for a synergistic effect, and lipid nanocarriers (LNCs), for targeting and controlled release. Advanced artificial intelligence approaches will be used to design new peptides inspired by natural AMPs. Selected AMPs with improved therapeutic potential and scalable biotechnological production will be encapsulated in LNCs for peptide stability and reduced off-target activity. The exploration of metallic nanoparticles, such as silver nanostars (AgNS), will be explored as adjuvants for synergistic antimicrobial effects. The formulations most effective in vitro will be further tested in vivo using a murine model of infection. This project will bring together microbiology and computational approaches, with a strong biophysical component, including fluorescence spectroscopy, circular dichroism, flow cytometry, advanced optical microscopies, atomic force microscopy, transmission and scanning electron microscopy, dynamic light scattering and zeta potential measurements. The new antimicrobial strategies to be developed are envisaged for human health application, but also with a broader One Health perspective.

Cell Biology of Host – Pathogen Interaction

Species-specific host-pathogen interaction of Toxoplasma gondii

Toxoplasma is a generalist parasite that infects a wide range of hosts and cell types. This is in stark contrast to many other intracellular pathogens. How Toxoplasma is able to infect such a broad host range and survive in many different cell types is not clearly understood. In the past we have developed CRISPR screening methods to identify proteins the parasite utalizes to modify the infected cell to ensure its own survival. Using this method, we identified that the parasite probably uses different proteins in human, vs mouse cells. In this project we will look at a range of species and Toxoplasma strains to gain a broad understanding of protective mechanisms across warm-blooded animals, and how the parasite adapts to these innate immune mechanisms. We are looking for candidates with interest in the cell biology of infection. A strong understanding of molecular biology techniques is essential and candidates with a solid understanding of cell biology and image analysis are preferred.