When the brain becomes a target
Meningitis, encephalitis… When the brain comes under attack
The brain is one of the best-defended organs in the body: the skull, the meninges (the membranes enveloping the brain and spinal cord) and the blood-brain barrier form a defence in depth. The latter is made up of cells sealed tightly together to form a virtually impermeable barrier. By continuously filtering what comes from the blood, it forms a virtually inviolable frontier.
Yet so-called “neurotropic” pathogens do manage to breach these barriers and reach the brain or spinal cord directly. These infections chiefly present as meningitis (inflammation of the meninges) or encephalitis (inflammation of the brain).
They represent a major public health issue, both in terms of severity and the diversity of the microbes responsible. Their consequences are devastating: every year they leave severe neurological after-effects and can prove fatal, particularly in immunocompromised patients and young children. The global impact is considerable: in 2019, encephalitis accounted for 1.4 million new cases worldwide, resulting in almost 90,000 deaths.
Enteroviruses - A viral family under surveillance
Poliomyelitis is a formidable viral disease, caused by an enterovirus that attacks the central nervous system. This invasion can destroy motor neurons, leading to irreversible acute flaccid paralysis (a rare clinical syndrome characterised by sudden muscle weakness), or even death through involvement of the respiratory muscles. Although eradication appears close, the threat persists.
Maël Bessaud, head of the National Reference Centre (CNR) for Enteroviruses and Parechoviruses, is studying the fundamental mechanisms of this disease by comparing the viruses in primates and in humans. “The aim is to identify what determines a virus's ability to infect the nervous system”, he explains.
Despite decades of efforts, total eradication is running into difficulties on the ground. In endemic areas such as the Democratic Republic of the Congo or Nigeria, vaccination coverage remains stuck below 50%. For the researcher, the obstacle is not scientific. “Coverage is below 50% because of insecurity and limited access to health centres.” As long as the virus circulates anywhere, the risk of its spreading elsewhere remains. In 2024, poliovirus strains were detected in wastewater in French Guiana, a reminder of how a reminder of how easily health threats can cross borders. “Even French territory is exposed”, warns the researcher. While mainland France benefits from excellent vaccination coverage, the overseas departments remain vulnerable in the face of local distrust and migratory flows.
Beyond historic poliomyelitis, the enterovirus family continues to evolve. Relatives such as EV-D68 are now causing severe encephalitis in children.
Surveillance therefore needs to be broadened. The Pasteur Network, with its front-line laboratories in Africa and its diagnostic and molecular expertise in Paris, is at the forefront of tracking these emerging threats.
Scientific questions remain unanswered to this day, particularly regarding how the virus specifically targets motor neurons. Understanding this mechanism is crucial for anticipating future threats.
In the meantime, vigilance remains essential. With the disappearance of historic cases, “younger clinicians may no longer consider poliomyelitis in the differential diagnosis when faced with acute flaccid paralysis”, making it essential to maintain high vaccination coverage in order to prevent the return of a scourge once thought to have been defeated.
Neurotropic pathogens: microbial diversity
The infectious agents capable of reaching the brain belong to several categories:
• viruses occupy a prominent place, chiefly in encephalitis: enteroviruses (poliomyelitis virus), arboviruses (West Nile virus, dengue, chikungunya), herpesviruses (herpes, glandular fever, shingles) or lyssaviruses (rabies). The emergence or re-emergence of several of these viruses makes such infections a global research priority;
• bacteria: Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Listeria monocytogenes… ;
• fungi: Cryptococcus neoformans, Aspergillus spp., Candida spp. ;
• parasites: Toxoplasma gondii, Plasmodium falciparum, Trypanosoma cruzi...
Among all these infections, bacterial meningitis – particularly that caused by meningococcus – remains especially formidable. Beyond acute infections, viruses warrant particular attention. Not only are they responsible for numerous cases of encephalitis, but they are also suspected of contributing to neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, by activating shared mechanisms: chronic inflammation and damage to axons (the projections of neurons). Studying these viruses could thus open up new therapeutic avenues against these diseases.
Microbes: masters of infiltration
To invade the brain, microbes exploit every possible weakness. Some attack the blood-brain barrier head-on: they hijack its transport systems or take advantage of local inflammation to increase its permeability. Others bypass it altogether, using the olfactory mucosa as a direct point of entry, or quietly travelling up along peripheral nerves. The most insidious strategy remains the "Trojan horse" approach: the microbe conceals itself inside white blood cells that naturally cross the barrier. The infectious agent thus enters the brain incognito, shielded from surveillance.
Listeria - A pathogen that “walks through walls”
The bacterium Listeria monocytogenes causes listeriosis, an invasive infection that can present as septicaemia or as a severe infection of the central nervous system, known as neurolisteriosis. With a mortality rate of between 30% and 45%, it is one of the deadliest foodborne infections (a notifiable disease since 1998). Pregnant women are highly vulnerable: the infection can lead to miscarriage, premature birth or severe neonatal infection. “This bacterium can cross the intestinal mucosa to reach the bloodstream, but it can also cross the blood-brain barrier and the placental barrier”, explains Marc Lecuit, head of the Biology of Infection Unit, the National Reference Centre and the WHO Collaborating Centre for Listeria.
In the food industry, this microbe is responsible for numerous product recalls and withdrawals. Unlike many other agents, this bacterium is capable of surviving and multiplying at low temperatures, earning it the nickname “the refrigerator bacterium”.
In France, there are 500 to 600 cases of listeriosis every year, of which almost 40 occur in newborns. “We are studying this disease in order to understand and combat it, but also as a model for identifying the host-pathogen interactions that allow a microbe to target specific cells and cross various barriers in order to spread throughout the body”, the researcher explains.
A model using strains isolated from patients with neurolisteriosis enabled the team to elucidate the mechanism by which the bacterium infects the brain. “Listeria infects a type of white blood cell known as inflammatory monocytes. These infected cells circulate in the blood, adhere to the walls of the brain's blood vessels, and allow the bacterium to reach brain tissue”, says Marc Lecuit. A surface protein of Listeria enables infected cells to evade the immune system, allowing the infection to spread throughout the body, notably to the brain. Uncovering the strategies used by Listeria will help to better prevent and treat an infection that remains 'one of the deadliest foodborne infections.
Interview - Guilherme Dias de Melo
Rabies is an ancient disease that remains fatal once symptoms appear. Why is it so distinctive?
Guilherme Dias de Melo: Unlike many pathogens that infect the brain, the rabies virus does not travel through the blood. Its mode of operation has surgical precision: it enters through peripheral nerve endings, often at neuromuscular junctions, and travels up along the axons (the projections of neurons) to reach the central nervous system. Other viruses, such as herpes simplex or even SARS-CoV-2, also use this route to reach the brain.
What is the global impact of rabies today?
GDdM: Rabies is 100% preventable through pre-exposure vaccination or post-exposure treatment. The latter approach was pioneered by Louis Pasteur. But once symptoms appear, the disease is almost invariably fatal, with a mortality rate of over 99%. It is estimated to cause around 60,000 deaths a year worldwide, 40% of them in children under 15 – a figure that is probably an underestimate. The worst-affected areas are Africa and South-East Asia, where rural communities far from healthcare centres are most exposed. Mainland France is free of terrestrial rabies (in dogs and foxes), but lyssaviruses (viruses related to rabies) circulate among bats. The residual risk comes from travel to endemic areas or the illegal importation of animals. The WHO aims to eliminate human rabies transmitted by dogs worldwide by 2030, chiefly through canine vaccination, but the target is proving difficult to reach for economic, social, anthropological and political reasons.
Transmission mainly occurs through bites, but are there other routes?
GDdM: The virus is usually transmitted through infected saliva, via a bite, a scratch, or licking on broken skin. There is no human-to-human transmission under ordinary circumstances. However, extremely rare cases of transmission through organ transplantation or through aerosols in caves with very high densities of bats have been documented.
Rabies is far from being an infectious relic of the past – it helps us understand other viruses too.
Your team is working on the mechanisms by which the virus spreads through neurons. What are the major unanswered questions?
GDdM: Despite long-standing clinical knowledge, the mechanisms underlying rabies remain poorly understood. For example, we still do not know in what form the virus moves within neurons: is it enclosed within a vesicle? Is its genetic material transported unenveloped? Another mystery is how it passes from one neuron to another. Using cryo-electron microscopy, we are attempting to answer these fundamental questions.
The virus even evades the immune system without triggering a strong inflammatory response. This explains the absence of early symptoms. We believe that its pathogenicity may instead result from a disruption of communication between neurons, causing symptoms such as aggression, anxiety or hydrophobia.
Until recently, curing a symptomatic patient seemed impossible. What are the new therapeutic avenues?
GDdM: Experimentally, we have recently shown that continuous administration of monoclonal antibodies (defence proteins synthesised in the laboratory) directly into the brains of mice enabled them to recover. If treatment is started as soon as the first symptoms appear, the survival rate is 100%. Even at a late stage, we can still save 40% of the animals. However, intracerebral injection is invasive and cannot be applied to humans.
The current challenge is the route of administration. The team is evaluating monoclonal antibodies capable of crossing the blood-brain barrier, as well as a simpler method of administration such as intravenous injection. These initial results are highly encouraging for the development of a curative treatment in humans.
Beyond rabies, how does this work benefit the fight against other emerging diseases?
GDdM: Our expertise on the mechanisms by which the rabies virus infects the brain has directly benefited research into SARS-CoV-2, particularly in understanding loss of smell, viral persistence in the brain, and the symptoms of long Covid. Rabies remains a unique model for studying brain infection.
Towards faster, more precise diagnostic tests
Despite extensive investigations, the cause of many brain infections remains unidentified. Improving diagnosis requires further research. Today, PCR tests (detecting the microbe by amplifying its genetic material) performed on CSF (cerebrospinal fluid, in which the brain and spinal cord are bathed) can detect pathogens within a matter of hours with high sensitivity. However, this technique only works when part of the genome being sought is already known. To detect variants or emerging pathogens, genetic targets need to be defined and testing broadened. A major advance lies in broad-spectrum sequencing of CSF: this technique, capable of analyzing the full range of microbes in a single test, makes it possible to identify unsuspected infectious agents that might otherwise escape conventional diagnosis. Recent progress in experimental in vitro models and organoids is enabling closer study of host-pathogen interactions and the identification of new diagnostic targets.
Meningococcus - Understanding the pathogen behind certain infectious meningitis cases
Within the Invasive Bacterial Infections Unit, Ala-Eddine Deghmane, deputy head of the National Reference Centre (CNR) for Meningococci and Haemophilus influenzae, studies the bacterium Neisseria meningitidis. Also known as meningococcus, this pathogen is responsible for certain forms of meningitis. It is carried asymptomatically in the throat by 10 to 15% of the population, particularly adolescents.
“Invasive meningococcal disease affects around one million people worldwide every year. In France, around 500 to 600 people develop this serious infection each year”, the researcher explains. The bacterium crosses the epithelial barrier and then invades the bloodstream. As it multiplies there, the bacterium releases toxins, causes septicaemia, and can cross the blood-brain barrier to reach the meninges. Its invasion of the cerebrospinal fluid then triggers meningitis, an infection that is 100% fatal without antibiotics, and around 10% fatal even with early treatment.
How does the bacterium manage to cross these barriers? The mechanism by which it enters the central nervous system remains uncertain and is the subject of several hypotheses. “We are working on the host-pathogen interaction and on developing diagnostic and characterization tools”, says Ala-Eddine Deghmane. “Our aim is to understand how the bacterium crosses cellular barriers, so that we can block it.”
Vaccines are not available for all twelve identified meningococcal types. “To date, two vaccines exist in France: the ACWY vaccine, which protects against these four serogroups, and the vaccine against meningococcus B, which is responsible for 50% of invasive meningococcal infections in France”, the researcher explains. Vaccination has become mandatory for infants. By the end of 2025, 88.2% of babies under one year old had received a first dose of the ACWY vaccine, and 96.8% had received the vaccine against meningococcus B.
A booster dose of the ACWY vaccine is also recommended for adolescents aged 11 to 14, who can catch up on vaccination at secondary school.
Innovative treatments and vaccination
Two complementary approaches are used to combat brain infections: treatment and prevention. Brain infections (viral, bacterial or fungal) require specific treatments, but all face a common obstacle: the blood-brain barrier, which restricts drug access to the brain. Effective antivirals, such as aciclovir for herpes, remain few in number. For bacterial infections, antibiotics are the treatment of choice, although their penetration into the brain is uneven, often requiring high doses. Fungal infections require treatment over prolonged periods.
To improve therapeutic effectiveness, researchers are developing several approaches: repurposing existing drugs, optimized for better diffusion into the brain; nano-particles designed to deliver active molecules directly to infected areas; and natural antimicrobial compounds with targeted properties. Even as treatments advance, vaccination remains the most effective strategy, where available.
New vaccine platforms – messenger RNA, viral vectors, nanoparticles – are now accelerating the development of vaccines targeting viruses, bacteria and fungi. The challenge is to greatly expand this protection in order to prevent severe cases and their heavy neurological after-effects.
See also
Cryptococcosis - An overlooked but formidable fungus
Ranked in the “critical priority group” of fungi of critical importance by the WHO in 2022, Cryptococcus neoformans is the cause of cryptococcosis, a neglected disease. “This is a fungus found in the environment, commonly found in pigeon droppings or dead trees”, explains Guilhem Janbon, director of the Mycology Department and head of the RNA and Extracellular Vesicles Unit. Humans are most likely infected through inhalation, developing cryptococcosis, which is rare in France, with around 200 cases a year, but it kills more than 150,000 people worldwide each year. This pathogenic yeast chiefly targets immunocompromised individuals (people with HIV, transplant recipients, cancer patients), but can also affect apparently healthy people. “It is thought that spores or dried-out cells are inhaled. Once inside the body, the fungus can remain dormant within white blood cells for 20 years before reactivating”, he explains. It is the only pathogenic fungus to possess a capsule, a genuine suit of armour that protects it and allows it to survive in the environment. In the laboratory, a simple drop of Indian ink staining is enough to diagnose it: the ink cannot cross the capsule, revealing a characteristic white halo.
This fungus crosses the blood-brain barrier, attacks the central nervous system and causes meningoencephalitis, with abscesses. “Without treatment, it is fatal. Even with the best antifungal treatments, mortality reaches 20 to 40%”, warns the researcher. Moreover, resistance to these antifungal treatments is being amplified by their extensive use in agriculture, and no vaccine is available.
His team is studying extracellular vesicles, tiny particles produced by the fungus, in order to uncover its mechanisms of virulence. “They contain RNA and proteins, which could play a role in virulence or drug resistance”, he explains. Ultimately, he hopes to develop organoid models to elucidate how the fungus crosses the blood-brain barrier.
Protecting our brain: a rapidly expanding field of research
The continued emergence of new pathogens, some of which are capable of reaching the brain (as seen with SARS-CoV-2), makes active epidemiological surveillance and ever more sophisticated experimental models essential. These tools are vital for decoding the complex interactions between pathogens and the brain, and for developing targeted diagnostics and treatments. For while our understanding is advancing, much remains to be clarified: the true diversity of neurotropic pathogens, their precise infiltration mechanisms, and their lasting impact on the nervous system. This is the whole challenge of a rapidly evolving field of research.
