Mark Gresnigt wins NVVI thesis award 2015

The encounter between Aspergillus fumigatus and the immune system

Aspergillus fumigatus is one of the hundreds of variants in the aspergillus family of fungi. Its spores are very common in the air around. They are harmless to healthy people, but in patients with a weakened immune function these spores can cause a possibly lethal infection. Mark Gresnigt PhD wrote the story of the encounter between Aspergillus fumigatus and the immune system entitled 'Recognition and cytokine signalling pathways in host defence against Aspergillus fumigatus', which won him the NVVI Thesis Award.

Aspergillus fumigatus spores frequently enter the human respiratory tract. They are recognised by Pathogen Recognition Receptors (PRRs) and are subsequently killed by macrophages and neutrophils. Simultaneously, these innate immune cells produce cytokines (such as Interleukin IL1 or IL36)  to also induce an adaptive immune response against the trespasser. This defence mechanism is highly effective - except when the immune system is weakened by for instance stem cell transplantation, corticosteroid or chemo therapy. Estimates indicate that 200,000 people worldwide annually struggle to overcome aspergillosis. As under-diagnosis is quite a problem, the real numbers are probably higher.

Furthermore, helper cell Th2 can induce an allergic reaction against Aspergillus fumingatus in severe asthma patients: Allergic Broncho-Pulmonary Aspergillosis (ABPA). “It turned out that, in contrast to T-cells in mice, there was little known about the human T-cell response against Aspergillus fumigatus”, says Gresnigt. 

Protective deficiency and other approaches
An amazing find featured in the thesis is that the NOD1 pathway, involved in the protection against bacteria and mutated in individuals with inflammatory bowel disease, interferes with aspergillosis. A study in mice at the Paris Institut Pasteur confirmed that NOD1 deficiency actually protects against aspergillosis – possibly the first ever deficiency with an established protective function. Gresnigt: “This led to the idea to develop a receptor-inhibiting drug for treatment of aspergillosis. In patients with aspergillosis the main question is, whether their immune system can recover quickly enough to beat the fungus. Inhibiting NOD1 could tip the balance positively.” 

Another approach is offered by immuno therapy with interferon-gamma (IFNγ), a cytokine with known antifungal properties. Gresnigt: “In a series of cases of invasive fungal infections we showed that IFNγ indeed strengthened patient cells against fungi” The role of the cytokine IL1, another actor in the complex interplay between fungus and immune system and known for its attraction of neutrophils after infection, was also taken into account by Gresnigt. “Boosting IL1 in aspergillosis patients could have a decisive impact against the fungus. We also found that a new member of the IL1 family, IL 36 which is known to play a role in psoriasis, is also induced by Aspergillus fumigatus. It could in this case take over IL1's role when that interleukin is lacking, as it seems to manage the Aspergillus-induced T-cell responses.”

Colitis
Gresnigt and researchers at the Institut Pasteur found in another collaboration project that a polysaccharide molecule in the cell wall of Aspergillus fumigatus induced the anti-inflammatory cytokine IL1Ra. This anti-inflammatory effect correlated with a poor outcome of aspergillosis. The researchers hypothesized that the anti-inflammatory properties of this polysaccharide could be put to good use. “It could help to boost an anti-inflammatory response in Colitis Ulcerosa patients”, Gresnigt comments. “Preclinical research in this direction is now carried out at the Institut Pasteur. If the present expensive recombinant receptor antagonists could be replaced by drugs cheaply synthesized by fungi, this would be great.”

Gresnigt is presently working on postdoc research about reprogramming of cells during sepsis. But fungi have captured him and he is applying for a VENI on mucormycosis, a type of fungal infection with even more severe infective impact. “My preliminary data suggest that the immune reactions are entirely different from that to Aspergillus fumigatus. There is hardly any other research published to corroborate this, so I would very much like to chart this terra incognita.”

 

Leendert van der Ent

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