Research at the Iovino Laboratory

We investigate host-pathogen interactions during pathogenesis of bacterial invasive infectious disease of the brain.

Focus

Among unsolved causes of neurological dysfunctions in both children and adults there are Central Nervous System (CNS) bacterial infections and bacterial meningitis, a severe inflammation of the meninges occurring as a consequence of a bacterial infection of the brain. The main etiological cause of these bacterial infections is Streptococcus pneumoniae, also known as the pneumococcus.

Pneumococcal infections of the brain can be cured with antibiotics, however, the major burden of these infectious diseases is that, once bacteria invade the brain after trafficking across the blood-brain barrier, they interact with neurons causing neuronal death. Most of neurons cannot be either repaired or replaced.

World Health Organization (WHO) defines bacterial meningitis as a devastating disorder of the CNS primarily because, even if the bacterial infection is adequately cured, permanent neurological deficiencies, such as motor and intellectual delay, hearing loss, seizures, psychiatric disorders, occur in fifty percent of the cases, and they are all due to a neuronal injury caused by the infection. Finding the correct antibiotic therapy for a patient with bacterial meningitis could take a few days. In the meantime, bacteria in the brain kill and damage neurons in the brain. Successful treatments do not only have to eliminate the bacterial infection but must also protect neurons.

Our goal is to understand the molecular mechanisms of neuronal damage caused by pneumococcal infection to develop a new therapeutic strategy to block pneumococcal-neuron interaction and protect neurons. The pneumococcal conjugated vaccine (PCV) is the only prophylactic tool we currently have to prevent pneumococcal infections, however PCV is based on capsular polysaccharides which surround the bacterial cells and are poorly immunogenic; moreover, the protection is conferred only towards the pneumococcal serotypes included in the vaccine (thirteen serotypes in the PCV13), and there is no protection towards all the other serotypes, which are more than 100 in total. Since the introduction of PCV, cases of pneumococcal infections, including meningitis, caused by all serotypes not included in PCV, have increased.

Our goal is to identify the bacterial molecules that are “sensed” by microglia, the immune sentinels of the brain, and trigger the immune response which culminates with the killing of the bacteria by phagocytosis; we then want to use these molecules as immune-stimulatory agents to boost microglial immune response towards pneumococcal pathogens.  
Bacterial meningitis is routinely treated with β-lactamic-antibiotics, like penicillin.

There are two main problems related to the antibiotic treatment in the management of bacterial meningitis:

  1. β-lactam antibiotics have a poor penetration of the BBB due to their huge molecular size
  2. Because of the overuse and misuse of antibiotics in the last decades, the problem of antibiotic-resistance is a constant threat to face in clinics.

Bacteria are highly-versatile microorganisms and can change in response to antibiotics, new antibiotics can be discovered but bacteria can rapidly adapt and develop resistance.

Our goal is to establish a new antimicrobial treatment against antibiotic-resistant S. pneumoniae strains, especially the ones causing meningitis. 

Illustration of Pneumococcal infections of the brain.
Pneumococcal infections of the brain. Photo: Federico Iovino

After trafficking across the blood-brain barrier endothelium, S. pneumoniae in the brain encounters neurons and microglia. Neuronal damage can be caused by a direct interaction with the bacteria as a consequence of bacterial adhesion and invasion of neuronal cells, but also by an indirect interaction through the release of the toxin pneumolysin; microglia, the resident immune cells of the brain, have the fundamental function of eliminating bacteria by phagocytosis, on the other hand bacteria can also use microglia as niche to survive in the brain.

Projects

Support

  • Swedish Research Council 
  • Karolinska Institutet Committee of Research 
  • Karolinska Institutet Research Foundation Grants
  • Bjarne Ahlström Memorial Fund
  • European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
  • StratNeuro
  • Petrus and Augusta Hedlund Foundation
  • Jeansson Foundation
  • Åke Wiberg Foundation
  • Clas Groschinsky Foundation
  • HKH Kronprinsessan Lovisa Association for Child Care
  • Magnus Bergvall Foundation
  • Tore Nilson Foundation
  • Loo and Hans Osterman Foundation
  • Fredrik and Ingrid Thuring Foundation
  • Stiftelsen Längmanska Kulturfonden
  • Swedish Foundation for Elderly (Stiftelsen för Gamla Tjänarinnor)
  • Wera Ekströms Fund for Pediatric Research
  • Åhlén Foundation
  • MSD Sverige

Collaborations

At Karolinska Institutet

Research news

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Content reviewer:
02-02-2023