In my PhD thesis, I characterised an essential enzyme for Trypanosoma cruzi, identifying inhibitors that could be used for treating chagas disease (PMID: 7969266 & 8144647). In the Department of Biochemistry of the University of Cambridge, I conducted work recognising that the tertiary structure and shape of apo-proteins, rather than the primary structure, determines their post-translational modification with lipoic acid or biotin (PMID: 10981714, 10329614, 9445386 & 976586). In the DNAX Research Institute, I played a relevant role in the discovery and functional characterisation of a novel cytokine, TSLP, which promotes Th2-allergic inflammation (PMID: 11418668 & 1205562). This discovery is cited in text books and it is protected by several patents, with me as co-inventor (US Patent 8,075,886, US Patent 6,890,734 & US Patent 7,071,308). Moreover, the work has found application in the treatment of asthma in the form of monoclonal antibodies against TSLP (Tezepelumab). 

I am a competent figure in Immunoinformatics. I initiated my activity in Immunoinformatics in 2001 in the Dana-Farber Cancer Institute and I have continued it until today in the University Complutense of Madrid (2007-present). Through the years, I have developed over a dozen of highly popular web-based bioinformatics tools, many for epitope prediction and epitope-vaccine design, that are available for free public use at http://imed.med.ucm.es/Tools/. I have also utilized computational biology to address different issues, test hypothesis and/or arrive to interesting biological conclusions. At the Dana-Farber, I devised the design of epitope-based vaccines using legacy experimentation available in databases (PMID: 16674822) and since then I have participated in the design of several epitope vaccines for different pathogens (PMID: 31823715, 29567319, 29100164, 29119120 & 31824493), including an universal flu vaccine (PMID: 27402904). By analysing viral T cell epitopes, we determined that T cell epitope immunogenicity is influenced by their position in the source antigens.  Moreover, we proposed that position-enhanced immunogenicity is related to preferential protein translation/biosynthesis (PMID: 22952734). I have a great interest in cytokines and through a structural bioinformatics analysis I discovered that the tertiary structure of gc-cytokines determines receptor usage (PMID: 30716660). In a recent work, my group has identified that, despite the common believe, most antibodies elicited during an infection recognise hidden antigens and non-accessible epitopes, which can only be explained if pathogens/antigens undergo ample degradation prior to recognition by B cells (PMID: 38994930). Such degradation likely serves to amplify the breath of the B cell response and to limit the reach of the antigen sin. We also hypothesized that antibodies and memory cells recognizing degradation-exposed epitopes may be cross-reactive with unrelated pathogens. In a systematic analysis of the sequence similarity of virus-specific epitopes and the human proteome, we proved that T cells preferentially target epitopes that are similar to self-antigens (PMID: 40649820). This finding challenges the classical self/non-self discrimination paradigm of T cell recognition, but is consistent with the process of positive selection ocurring during T cell development, in which T cell precursors incapable of recognizing self-MHC–peptide complexes are eliminiated. In parallel, we found that epitopes derived from viruses associated with autoimmune diseases exhibit a high degree of sequence similarity to self-antigens, thereby supporting the role of molecular mimicry in the induction of autoimmunity. Furthermore, we identified human coronaviruses, including SARS-CoV-2, as well as several flaviviruses, as major sources of epitopes displaying a high degree of molecular mimicry with self-antigens involved in motility, membrane projections, and neural synapses. These findings support the hypothesis that post-infectious sequelae associated with these viruses, including long COVID, may be linked to autoimmunity.

My formal training is however as experimental researcher and with my group at the UCM I have made several relevant contributions in Immunology. Thus, research from my group determined that epithelial cells have an inherent immunosuppressive capacity, which has likely evolved to avoid harmful over reactions against resident bacteria (PMID: 31316504). The inhibition of T cells by epithelial cells is dramatic and I argued that it may explain the need to transport antigen and eliciting antigen-specific responses away from the influence of epithelial cells, in secondary lymphoid tissues (PMID: 35126344). Likewise, the immunosuppressive capacity of epithelial cells may explain why most tumors derive from epithelial cells (PMID: 35126344). Indeed, my group has recently identified that oral sarcoma cells, which derive from epithelial cells, release proteins that induce the differentiation of immunosuppressive macrophages and promote tumor growth (PMID: 39437531). This knowledge shall be instrumental to develop novel anti-tumoral therapies. 

I have also carried out other investigations with relevant practical implications. My group has identified highly conserved T cell epitopes in human Rhinovirus (HRV) which could be used for epitope-vaccine development against HRV (PMID: 33230881 & 34571943). Early during the COVID-19 pandemic, I concluded through a computational analysis that vaccines with tetanus and diphtheria toxoids could induce protective cross-reactive immunity against SARS-CoV-2 (PMID: 33178220). Many benefited from this early discovery. Protection against COVID-19 by these vaccines was latter corroborated by independent epidemiological studies (PMID: 33972940, 37441187 & 34691063) and my group has shown that Tetanus-diphtheria (Td) vaccine can induce SARS-CoV-2 cross-reactive responses in antigen unexperienced naïve T cells (PMID: 39091504). This study formally proves that vaccines with tetanus and diphtheria toxoids represent an original source of cross-reactive immunity to SARS-CoV-2 and perhaps also to common cold coronavirus. My group has also shown that essential eucalyptus oil (EEO) can inhibit infection by SARS-CoV-2-like viruses. EEO is known for its anti-inflammatory properties, which, all together, calls for testing/adopting EEO aromatherapy as a cost-effective easy-to-implement anti-COVID-19 measure (PMID: 39200349).