The research group "Immunology of fungal infections" has focused its research over the last fifteen years on the study of the host immune response to Candida albicans. The group has a multidisciplinary background, both in Microbiology and Immunology, so it has an ideal profile to study the interactions between pathogenic fungi and cells of the immune system both in vitro and in vivo. Although the research conducted is primarily basic in nature, it has clear applied potential in the development of new immunotherapeutic approaches for the treatment of fungal infections.
C. albicans is an opportunistic pathogen that, depending on the underlying host defect, is capable of causing a variety of infections ranging from superficial mucocutaneous candidiasis to severe invasive candidiasis. The frequency and severity of the latter has increased considerably in recent decades, due to the increase in the at-risk population that is immunocompromised or weakened by various causes.
Resistance to candidiasis requires the coordinated action of innate and acquired immune defences. Mature cells of the innate immune system use different PRRs (pattern recognition receptors) to directly recognise MAMPs (molecular patterns associated with micro-organisms), so that with a limited number of these receptors they can recognise a wide range of pathogens. The most important families of PRRs in C. albicans recognition are Toll-like receptors (TLRs) and C-type lectins (CLRs, such as dectin-1). In this context, our group demonstrated that the TLR2 receptor is involved in the recognition of C. albicans, both yeast and hyphae, inducing cytokine and chemokine secretion through a pathway dependent on the adaptor molecule MyD88 and that such recognition is critical for protection against invasive candidiasis in a mouse model of infection.
In 2006 it was described that haematopoietic stem and progenitor cells (HSPCs), from which all immune system cells are derived, express functional TLRs, and that signalling via TLRs in haematopoietic stem cells (HSCs) triggers their entry into the cell cycle and their differentiation into the myeloid lineage. This discovery opened new perspectives on pathogen-host interactions, as these receptors could be involved in modulating haematopoiesis in response to micro-organisms during infection. At that time our group decided to study the involvement of PRRs in the interaction of C. albicans with HSPCs and its consequences for the resolution of the infection. Working along these lines, we have shown that C. albicans induces the proliferation of HSPCs and their differentiation towards the myeloid lineage, both in vitro and in vivo. This response requires signalling via TLR2 and dectin-1, and results in functional macrophages that are able to internalise and destroy yeast, as well as secrete inflammatory cytokines. These results indicate that pathogens can be directly recognised by HSPCs through PRRs, thereby promoting the replenishment capacity of the innate immune system during infection. These receptors may therefore be at least partly responsible for the emergency myelopoiesis that occurs during most infections, including invasive candidiasis.
On the other hand, numerous recent studies have challenged the dogma that immunological memory is an exclusive feature of specific immunity, as cells of innate immunity can exhibit some "memory" and respond differently to a second encounter with the same or another microbial stimulus. For example, exposure of monocytes and macrophages to C. albicans increases their response to a second encounter (trained, dectin-1-dependent immunity), while TLR4 or TLR2 ligands confer a reduced inflammatory response to macrophages (tolerance).
In parallel to the studies on the memory of innate immunity, our group set itself the new goal of studying the function of phagocytes formed after HSPCs contact with microbial ligands. Using in vitro and in vivo models, we have shown that stimulation of PRRs in HSPCs affects the functional phenotype of the macrophages they subsequently generate. Therefore, our results show that this new concept of "memory" of innate immunity can be applied not only to mature myeloid cells, but also to HSPCs, which contributes to increase the durability of innate memory over time.
Based on these results, and those of other authors in the same line, an active role is now assigned to HSPCs in the fight against infection. The hypothesis we are currently working on is that HSPCs can directly detect microorganisms and contribute to protection against infection by different mechanisms, including their ability to differentiate into myeloid cells with an enhanced phenotype to confront the pathogen and initiate the immune response.
The results already obtained open up new perspectives, which may be of great interest at the intersection between Immunology, Microbiology and Haematology. The existence of new mechanisms in the host-pathogen interaction, and their consequences in modulating the immune response during infection, may represent a new target for intervention against serious infections by enhancing the immune response. In addition, modulation of haematopoiesis by microorganisms could reveal new strategies for the treatment of diseases with alterations in myeloid cell production, such as myeloid leukaemias.
- Identify the molecular and cellular mechanisms activated in haematopoietic stem and progenitor cells (HSPCs) in emergency myelopoiesis during candidiasis.
- Reveal the mechanisms involved in trained innate immunity during fungal infections.
... in emergency myelopoiesis during candidiasis and reveal the mechanisms involved in trained innate immunity during fungal infections.
The hypothesis we are currently working on is that HSPCs can directly detect microorganisms and contribute to protection against infection by different mechanisms, including their ability to differentiate into myeloid cells with an enhanced (trained) phenotype to face the pathogen and initiate the immune response.
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- GIL HERRERO, M LUISA
- PDI-Catedratic/a d'Universitat
- GOZALBO FLOR, DANIEL
- PDI-Catedratic/a d'Universitat
Contributors
- Victoria Eugenia Maneu Flores - University of Alacant
Burjassot/Paterna Campus
C/ Doctor Moliner, 50
46100 Burjassot (Valencia)
- GIL HERRERO, M LUISA
- PDI-Catedratic/a d'Universitat
