Research Sergio Araujo

Abstract

This BOF-SRG project aims to support my independent research line, exploring host-pathogen interactions and unraveling pathophysiological mechanisms involved in the intracellular invasion of the olfactory network by understudied neurotropic infectious agents of various aetiologies, that have been found to infect the upper respiratory tract and cause neuropathological manifestations. Currently, as a senior postdoc at the Laboratory of Microbiology, Parasitology, and Hygiene (LMPH), I am leveraging my extensive experience on Hansen's Disease (HD) to investigate the causative pathogen of HD, Mycobacterium leprae. My research in the field of HD has been internationally recognized, and I have published four first-author papers on HD, including two fundamental studies that have shifted the paradigm on the infection mechanism: one unveiling asymptomatic carriage of bacilli in the nose with a potential role in the chain of transmission; and the other on the aerial route as the predominant mode of infection and transmission. The evidence of nasal mucosa infection and high incidence of olfactory dysfunction in HD, as well as the knowledge gap regarding the cellular mechanisms of infection, warrant further investigation. My hypothesis is that M. leprae can infect olfactory ensheathing cells (OECs) and this unexplored niche can be an undisclosed route for the initial invasion of nerve tissues, play a role in immune evasion, and contribute to the colonization of nasal mucosa and the persistence of chronic infection. The development of this project will increase our understanding of this debilitating disease and shed light on the unknown mechanisms by which it can evade immune responses, colonize nerve tissues, and develop chronic disease. It will also provide the cornerstone for establishing an international partnership with research groups in the Global South (Brazil) working on HD and other neglected tropical diseases (NTDs). In the short term, I also plan to explore the infection of OECs by other neurotropic parasitic, viral, and bacterial pathogens under investigation at LMPH, such as Leishmania, RSV, and Streptococcus, which can also invade and damage the PNS and/or use the olfactory pathway as a route of entry into the CNS. In the middle term, I envisage investigating co-infections with pathogens of different aetiologies in the established infection model of OECs. In the long term and beyond infectious diseases, this project will open opportunities for collaboration on regenerative medicine studies, as the use of OECs is also a promising strategy for neuroprotection and the regeneration of neural tissues.

Researcher(s)

• Promoter: Araujo Sergio

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Human respiratory infections lead to a spectrum of respiratory symptoms and variable disease severity, contributing to substantial morbidity, mortality and economic losses worldwide. Respiratory pathogens can spread easily in the population and are specifically prone to cause large scale outbreaks, epidemics and even pandemics. While such pandemics have devastating impact on human health and cause major socio-economic disruptions, the annual burden of respiratory infections such as Respiratory Syncytial Virus (RSV), Mycobacterium tuberculosis and Streptococcus pneumoniae is also substantial. Respiratory infections are worldwide the number one cause of death in children below five years of age, with ~650.000 annual deaths. The disease burden however goes beyond this staggering number, with an overall effect on morbidity and mortality in the general population worldwide (~2.5 million deaths annually). Of particular interest, it has become very clear that severe disease upon respiratory infections not only depends on one particular pathogen, but also depends on other previous or simultaneous co-infections. The importance and impact of co-infection are however not yet fully clear. Therefore, there is an urgent need to enhance our understanding of host-pathogen interactions at the lung (immune) interface and to develop clinically relevant animal models. Laboratory animal studies are a cornerstone of basic research and the development of novel prophylactic, diagnostic and therapeutic modalities. However, the development of suitable infection models can be notoriously daunting, often resulting in very narrow assay windows due to rapid pathogen clearance or early mortality of the host. The research teams involved in this challenge have longstanding expertise with infection models, both in vitro and in rodents. Three PIs focus their research on parasitic (prof. Caljon), viral (Prof. Delputte) and bacterial infections (Prof. Cos) to gain understanding of protective innate and adaptive immune responses, and of (immune) pathology. A recent study in which LMPH was involved demonstrated that some lung bacteria have an immune modulatory role in chronic respiratory diseases (Rigauts et al., Eur. Resp. J., 2022). Very recent parasitological observations show that African trypanosomes rapidly and permanently colonize the lung tissue with substantial changes in the immunological repertoire (reductions in B cells and eosinophils) but without overt respiratory dysfunction or pathology. Surprisingly, RSV challenge revealed a higher susceptibility with an enhanced and sustained viral replication, hinting at complex in vivo interactions that cannot be modelled in vitro (Mabille et al., Nat. Commun., pending acceptance). Exploiting the expertise with parasitic, viral and bacterial infections at LMPH, the established high-end platforms for evaluating lung function and immunological correlates and initiatives of biobanking, this challenge aims to functionally and immunologically characterize pulmonary infections and co-infections of parasitic, viral and bacterial origin. This will provide invaluable information on virulence and pathogenicity of selected strains from in-house collections, establishment of in vivo read-out assays and immunological correlates of induced pathology. Besides progressing basic scientific insights in host-pathogen interactions, the applications are numerous including the development and evaluation of diagnostics and medicinal compounds.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Cos Paul
• Co-promoter: Delputte Peter
• Fellow: Araujo Sergio

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project