Early Career Awards

ESMOPH | Exploring Novel SNVs and viral population dynamics in mpox outbreak: implications for pathogenesis and public health 

Awardee: Michela Deiana, IRCCS Sacro Cuore Don Calabria 

Since 2022, the spread of mpox in several nations, has raised a relevant concern. Viral evolution may have allowed the co-transmission of multiple variants. To date, numerous Single Nucleotide Variations have been reported, however, it is unclear whether they represent the result of local mutagenesis or possible co-infections. Our previous findings have revealed the coexistence of mutated and wild-type alleles in unrelated patients, albeit with divergent frequencies, supporting the co-infection hypothesis. In this project, my objective is to further explore the co-infection hypothesis, through the in-depth genetic analysis of viral sub-populations in different biological matrices from mpox patient. The current epidemiological situation underscores the importance of mpox as a re-emerging zoonotic threat. Potential co-infection with multiple viral sub-populations could have a major impact.

B19-CAT | Human B19-like parvovirus in domestic cats 

Awardee: Georgia Diakoudi, Università degli Studi di Bari

Parvovirus B19 (family Parvoviridae, genus Erythroparvovirus) is the only pathogenic parvovirus in humans causing mild-to-severe symptoms, including infectious erythema, anaemia and foetal hydrops or demise. Recently a novel B19-like parvovirus was identified in a cat with non-regenerative anaemia by our laboratories (unpublished). Following the objectives of INF-ACT, the current project aims to study the presence and gather data on the epidemiology of this emerging virus in the feline population. The objective is to create a complete diagnostic pipeline that will allow to understand the prevalence of the virus, its pathology and plan efficient prevention measures. Understanding the pathology of the virus in the feline population will offer the opportunity to explore possible parallelisms with human parvovirus B19 infection in humans and offer an animal model for the study of erythroparvoviruses.

EMERGENT | Exploring redox-related pathogenic mechanisms underlying respiratory virus infections

Awardee: Marta De Angelis, Università degli Studi di Roma La Sapienza

Understanding the pathogenic mechanisms of respiratory virus infections is crucial for addressing the emergence of novel viral strains. Changes in the intracellular redox state have been identified as a key event in regulating viral replication and inflammatory response, impacting on the severity of infection. Dysfunction of the pulmonary epithelial-endothelial barrier is an event associated with severe cases, however, the underlying mechanisms remain unclear. This proposal aims to define the redox pathways involved in the pathogenic mechanisms during different respiratory virus infections. Particularly, it will be investigated the modulation of the antioxidant factors related to the inflammatory response during viral infections in different respiratory tracts, and their role in the epithelial-endothelial barrier damage. The study will be pursued by using "Air Liquid Interface" monoculture and co-culture cell models that are representative of the in vivo upper and lower respiratory tract. The findings will provide insights into the events underlying severe conditions of respiratory virus infections and pave the way for the development of novel "cell-targeted" therapeutic approaches against viral infections.

LSI | Leishmania vs Sauroleishmania in the mediterranean basin: isolation, molecular characterization and metagenomics of Leishmania spp in Italy 

Awardee: Jairo Mendoza Roldan, Università degli Studi di Bari Aldo Moro

Zoonotic canine leishmaniasis (CanL) caused by Leishmania infantum is endemic in southern Europe. In these areas other Leishmania species occur in sympatry, such as Leishmania tarentolae, a non-pathogenic protozoan of reptiles. Recent molecular diagnostics and serological positivity to L. tarentolae in humans and dogs have spurred interest in the interactions between these mammalian hosts, reptiles, and L. infantum. The aim of this project is to confirm the circulation of L. infantum and L. tarentolae in non-permissive hosts and to isolate new strains of these protists. After, strains will be molecularly characterized through whole genome sequencing to identify new strains and/or hybrids. Results from this study will allow to depict the changing epidemiology of Leishmania in Italy, as well as to evaluate the possible usefulness of L. tarentolae for new vaccination strategies.

ClimaVec | Impact of global climate change on vectors and emerging arboviruses

Awardee: Ayda Khorramnejad, Università degli Studi di Pavia

How arboviral vectors respond in the face of rapid anthropogenic climate warming is a key open question of ecological and public health concern because mosquitoes are ectotherms and temperature impacts nearly all aspects of their life cycle. Climate warming is expected to cause large shifts in mosquito distributions and dynamics, thus resulting in the expansion of the transmission risk, also to temperate regions of the world. However, how temperature influences mosquito interaction with viruses remains largely unknown. In this proposal, I will address this knowledge gap by studying if and how the interaction of the Asian tiger mosquito, Aedes albopictus, the main arboviral vector in Europe, with viruses changes when mosquitoes are exposed to a hot thermal regime, mimicking Italian summer. I will address this question using the arbovirus Semliki Forest Virus (SFV) and the insect-restricted Cell Fusing Agent Virus (CFAV). CFAV was proposed as a novel control agent based on its ability to restrict arbovirus infection in mosquitoes. I designed three independent, but inter-related aims to answer the following detailed questions: does short vs long-term exposure to a hot thermal regime alters how mosquitoes respond to SFV and CFAV infections? Can CFAV restrict SFV infection in thermally challenged Ae. albopictus? Acquiring this knowledge is essential to derive climate-refined predictions of arboviral risks and develop CFAV-based control strategies.

LION | Exploring the interactions between the mammalian host and Leishmania parasites at the mucosal level: insights from organoid models

Awardee: Ilaria Varotto Boccazzi, Università degli Studi di Milano

Leishmaniases are neglected vector-borne diseases caused by Leishmania parasites and transmitted to the host by the bite of sandflies. With this project I intend to answer to the following questions: i) could this parasite be transmitted to the mammalian host through the oral route? ii) can this microorganism be exploited as an antigen vehicle, in oral vaccination? To address these questions, it is crucial to investigate the interaction/internalisation of Leishmania within the intestinal epithelium and the stimulation of immune response at the mucosal level. Gut organoids will be exploited to study the host-parasite interaction instead of animal models, using Leishmania tarentolae as a model parasite. The obtained results could clarify the possible oral/mucosal transmission route of Leishmania and the dynamics of its internalisation/localisation.In prospect, a better knowledge of the interaction of Leishmania parasites with the intestinal epithelium and immune system will possibly permit to develop novel tools to modulate the immune response toward these parasites, that still impact the life of millions of people around the world.

PRE-STA-MD-AI | Predicting Statistics of Molecular Descriptors by Employing AI 

Awardee: Stefan Milenkovic, Università degli Studi di Cagliari

In this project, our primary objective is to develop a machine-learning model designed to predict the statistical parameters of small-molecule molecular descriptors. Traditionally, these parameters are obtained by running molecular dynamics (MD) simulations of solvated molecules and then explicitly extracting the statistics of molecules. However, with a model capable of predicting these parameters, we can bypass the need for MD simulations. This advancement will facilitate virtual screening of huge databases for searching molecules with favorable accumulation/permeability characteristics, leveraging existing machine learning models where molecular statistics are pivotal. Consequently, this approach will significantly reduce computational time, shrinking the processing time from several hours per molecule to under a second. Moreover, it will contribute to environmental preservation by lowering energy consumption.

FOS | Molecular characterization of fosfomycin resistance emerging Enterobacterales strains 

Awardee: Vittoria Mattioni Marchetti, Università degli Studi di Pavia 

Fosfomycin (FOS) regained clinical interest against multi-drug resistant bacteria, but it is affected by the global increasing of resistance. Since FOS resistant Enterobacterales epidemiology in Italy is scarce, the project will be focused on i) epidemiological typing of clinical FOS resistant Enterobacterales, ii) characterization of fosA genes, iii) investigation of mutations in FOS transporters/regulators, and iv) implementing an alternative methodology in FOS resistance profiles? detection. During the one-year project, FOS resistant Enterobacterales strains will be collected from different Northern Italy Hospitals, subjected to long-reads sequencing and analyzed on molecular level for the presence of fosA-like genes and mutations in FOS intake proteins. The built collection will be evaluated using a novel agar-based test. The project aims to analyze and prevent the diffusion of FOS resistance feature and to elucidate the epidemiology of FOS resistant Enterobacterales in Italy, contributing in specific guidelines for prevention, control and managing.

PROMISING | PROMotIng StewardshIp iN General practice 

Awardee: Costanza Vicentini, Università degli Studi di Torino

Promoting the prudent use of antibiotics, in order to preserve their effectiveness and safeguard patient safety, is one of the main objectives of the Italian National action plan to contrast AMR (PNCAR). Antibiotic stewardship (AMS) interventions aim to promote the responsible use of antimicrobials, balancing the individual need for appropriate treatment and the long-term societal need to maintain access to effective treatments. The majority of AMS interventions mainly focus on acute-care hospitals. However, a significant proportion of all antibiotic use is prescribed in the outpatient setting.The project’s objective is to develop an AMS intervention aimed at enhancing prescribing skills of general practitioners (GPs). The impact of the AMS intervention will be evaluated through a pilot study. GPs will be invited to participate in an AMS educational program, further, a number will be randomly assigned to receive enhanced guidance from acute-care hospital AMS experts, provided via a web-based telemedicine platform. The service will ensure the delivery of the most appropriate treatment based on epidemiological, microbiological, and clinical data. In line with the INF-ACT holistic approach from basic to clinical research, the project aims to explore innovative strategies for health services delivery. In particular, the project complements the objectives of the INF-ACT Research Node 3, by assessing the clinical relevance of personalized medicine outside the acute-care setting. The project will strengthen relationships between health professionals operating at hospital and outpatient levels, allowing to optimize and share patient management.

PAMIR | Preclinical in vitro Airway Models for studying Infectious Risk in chronic respiratory diseases 

Awardee: Serena Di Vincenzo, Consiglio Nazionale delle Ricerche

Patients with chronic respiratory diseases experience recurrent infections caused by bacteria, viruses or atypical bacteria. This increases the frequency of disease exacerbations which leads to a faster progression of the disease to more severe forms. Cigarette smoke is a major risk factor for chronic respiratory disease and increases susceptibility to infections inducing structural changes and alterations in the immune defences. Current therapies are not very effective in the prevention or treatment of exacerbations, and it is important to find new therapeutic strategies that can reduce the risk of infections in these patients. The present study aims to evaluate whether the use of nutraceutical drugs (apigenin, resveratrol, curcumin and probiotics), in addition to traditional therapy, can respond to this need. A complex in vitro experimental model consisting of a bronchial pseudostratified epithelium, fibroblasts and macrophages will be used for the study. This in vitro model will be exposed to cigarette smoke and infection-simulating molecules. It will be evaluated the effects of these insults on: oxidative stress, the loss of epithelial integrity, the activation of inflammatory mechanisms, the phagocytosis activity and cytokine release of macrophages. The in vitro model exposed to these insults will be treated with the selected drugs and the ability to restore tissue homeostasis will be evaluated. This would reduce respiratory infections in subjects most at risk and prevent the frequent exacerbations of the disease

BREATH | Development of antimicroBial platfoRms basEd on natural biomAterials for acuTe and cHronic lung diseases

Awardee: Francesca Della Sala, Consiglio Nazionale delle Ricerche

Bacterial infections, including the ones originated from Pseudomonas aeruginosa, Streptococcus pneumonia and Staphylococcus aureus, represent a significant challenge in the field of respiratory diseases. Indeed, these are responsible for severe exacerbations in chronic obstructive pulmonary diseases (COPD) and acute respiratory distress syndrome (ARDS), dramatically accelerating the deterioration of lung function. Nowadays, persistent infections are treated with high doses of antibiotics, causing side effects and increasing the growing problem of multidrug-resistance by microorganisms. In this context, BREATH project aims to develop an antimicrobial platform, based on natural biomaterials, such as Hyaluronic acid (HA) and chitosan, forming nanogel (NG) incorporated with antimicrobial agents, such as Folic Acid-Carbon Dots (FA-CDs). This antimicrobial platform will synergistically combine the HA and chitosan intrinsic bacteriostatic and bactericidal properties with the antimicrobial activity of FA-CDs, enhancing their release. FA-CDs will be synthetized using a simple and rapid one-step microwave-assisted system, optimizing reaction parameters (i.e. temperature and pH) to control their structural properties and consequently their functional antimicrobial features. The HA/chitosan NGs will be produced using the ionic gelation method. In order to design the best candidate to incorporate FA-CDs, able to reach lung site avoiding alveolar clearance, polymers’ molecular weights and concentrations will be optimized to control NGs size and stability. To validate such systems physical-chemical characterization and biological response on lung cells along with evaluation of antimicrobial activities will be performed. Such platforms, exploiting the tunable structural properties of biomaterials, can provide new strategies to fight bacteria in pulmonary infections, evading their natural defense mechanisms.

TARGET-UTR | Targeting the 3’-UTR of West Nile Virus: a Novel Peptide-Based Antiviral Strategy

Awardee: Riccardo Rigo, Università degli Studi di Padova

West Nile virus (WNV), a mosquito-borne virus from the Flaviviridae family, can cause severe neuroinflammatory symptoms, particularly in immunocompromised and elderly individuals. Recent outbreaks in Africa, North America, and Europe have highlighted WNV as a significant public health threat. Despite the urgent need for treatments, no vaccines or specific antiviral drugs are available. This project aims to develop new pharmaceutical strategies targeting the WNV genome to disrupt its replication and reduce its virulence. We focus on a unique RNA structure in the 3’-UTR of the WNV genome, crucial for viral replication and immune evasion. By utilizing phage display technology, we aim to identify peptide ligands that specifically bind and stabilize this RNA domain, potentially impairing viral enzyme activity. This approach could lead to broad-spectrum anti-flavivirus treatments and advance nucleic acid-targeting strategies.

PHAGOMED | PHAGe therapy cOmbined with CutiMED Sorbact for the treatment of infected skin ulcers: an epidemiological and in vitro study 

Awardee: Matteo Passerini, Università degli Studi di Milano

Infected cutaneous ulcers present a significant clinical challenge, often exacerbated by poor tissue penetration of antibiotics and the development of bacterial resistance. This project aims to address this challenge through two parallel experimental studies. Firstly, consecutive bacterial samples from patients with infected ulcers will be collected to select and assess phages capable of in vitro killing isolated bacteria. Secondly, the in vitro antimicrobial activity of phages combined with Cutimed Sorbact dressing will be evaluated. This interdisciplinary approach integrates microbiology, wound care, and phage therapy to develop a novel treatment strategy, by addressing the objective of the INF-ACT research program. Successful outcomes of this study could pave the way for a subsequent clinical application of phage therapy by providing important data on efficacy and the optimal dressing to combine with it.