Tuberculosis Makes a Lethal Fungus More Dangerous, Lab Study Finds

Two of the world's most dangerous infectious pathogens often share the same patient. Tuberculosis infects roughly 10 million people per year globally and killed 1.25 million in 2023. Cryptococcus neoformans, a fungus that colonizes the lungs and can spread to the brain causing meningitis, caused an estimated 112,000 deaths in 2020 alone - and disproportionately kills people whose immune systems have already been weakened, including by tuberculosis. In regions where both pathogens are endemic, co-infection is common.

What has not been studied until now is whether the two pathogens interact - whether the presence of one changes the behavior of the other in ways that worsen disease. A research team at the MRC Centre for Medical Mycology at the University of Exeter has provided the first direct experimental evidence that they do. Their findings, from a study led by PhD candidate Orlando Ross, show that C. neoformans exposed to tuberculosis bacteria becomes structurally altered in ways associated with increased pathogenicity. The work is preliminary - all in cell and culture models - but it opens a new lens on co-infection biology. The study represents early-stage laboratory research; no animal or human clinical data are yet available.

A WHO Critical Priority Pathogen

Cryptococcus neoformans occupies one of four positions on the WHO's Fungal Pathogens Priority List as a "critical priority" organism - a designation intended to draw the same level of research and policy attention that bacterial and viral critical priority pathogens receive. The fungus spreads by inhalation of spores or yeast cells present in soil and pigeon droppings. In immunocompetent people, infection is usually contained; in people with impaired immunity - including those with HIV, organ transplant recipients, or patients on high-dose corticosteroids - it can spread to the central nervous system and cause cryptococcal meningitis, which is fatal without treatment and carries high mortality even with it.

What Changes When the Two Pathogens Meet

The Exeter team co-incubated C. neoformans with Mycobacterium species in culture and examined whether the fungus changed in ways relevant to pathogenicity. The hypothesis going in was specific: the researchers predicted that exposure to mycobacteria would drive C. neoformans toward larger cell size and altered morphology - changes previously linked to worse outcomes in infected hosts.

What they found confirmed the hypothesis. In the presence of mycobacteria, the fungal cells showed changes in cell density, in the diversity of cell types within the population, and in capsule size. The capsule is a protective polysaccharide outer coating that surrounds C. neoformans cells - it is a key virulence factor that helps the fungus evade immune attack and persist inside host cells. Larger capsules are associated with greater resistance to phagocytosis and more severe infection.

Some of these changes are known from other research to correlate with increased harmfulness to infected hosts - they point toward a more pathogenic fungal phenotype emerging specifically in the context of co-infection.

Immune Cell Invasion Under Co-Infection Conditions

The team went a step further and replicated a co-infected lung environment in the laboratory to examine how the two pathogens together affect immune cell function. In this model, they found that immune cells - specifically macrophages, the primary innate immune cells that patrol the lungs - were more likely to be invaded by C. neoformans when tuberculosis bacteria were also present, compared with fungal infection in the absence of tuberculosis.

This is significant because C. neoformans is known to survive inside macrophages rather than being destroyed by them - a key mechanism by which the fungus evades clearance and persists in the body. If tuberculosis infection increases the frequency with which C. neoformans successfully invades macrophages, co-infected patients could face a more aggressive and less controllable fungal infection than those infected with the fungus alone.

"This shows that the presence of both bacterial and fungal pathogens together in the lung could worsen disease outcome for patients," said Ross.

What This Study Does Not Yet Show

The study is entirely in vitro - conducted in cell culture and controlled co-incubation experiments outside of a living organism. Whether the same interactions occur in a full mammalian immune system, with its complex network of cellular and humoral defenses, feedback loops, and tissue-specific environments, remains to be demonstrated. The researchers identify mouse model experiments as the immediate next step for validation.

"We're really proud of the physiological modelling we've carried out in this project, but we're excited to validate these findings in the context of a full immune system and more complex host environments," said Ross.

If confirmed in animal models, the findings would carry clinical implications. Patients co-infected with tuberculosis and C. neoformans might warrant more aggressive antifungal treatment than current guidelines recommend for fungal infection alone. The mechanisms by which tuberculosis drives the fungal phenotype changes also represent potential targets for intervention - disrupting that interaction could represent a new strategy for managing co-infection outcomes in high-burden settings where both pathogens are endemic.