SBU’s Caroline Mota Fernandes shows fungal vaccine protection in animal models of the immunocompromised

By Daniel Dunaieff

Fungal infections pose a significant health risk to some patients, killing an estimated 1.5 million people worldwide each year. Doctors struggle to provide medical help to some of these patients, especially those whose weakened immune systems offer insufficient protection against the development of pathogens.

Invasive fungal infections, which people typically contract by inhaling them as spores, account for about half of all AIDS-related deaths.

Maurizio del Poeta, professor emeritus at Stony Brook University’s Renaissance School of Medicine, has studied ways to strengthen the body’s defenses against these life-threatening infections, even in people with weakened immunity.

Recently, Caroline Mota Fernandes, a postdoctoral researcher in del Poeta’s lab, published research in the journal mBIO, a publication of the American Society for Microbiology, which demonstrated that a mutated, heat-killed version of the fungus Aspergillus transmitted protection in an animal model. of an immunocompromised individual.

“The biggest news is that we can just use the ‘autoclaved’ mutated version,” del Poeta explained in an email. “This version couldn’t be more dead!”

An autoclave is like a scientific oven: it raises the temperature or the pressure. In this case, it can kill the mutated fungus, leaving only the mutated signal that primes the immune system.

The mutated, heat-killed version of the fungus, however, still offered full protection in a state in a weakened immune system model.

“That means this formulation is very stable and resistant to heat degradation,” added del Poeta.

Del Poeta’s lab had done similar research with another fungus called Cryptococcus.

Demonstrating that this approach also works with Aspergillus, del Poeta said the result “validates the cryptococcal vaccine (after all, it uses a mutant of the homologous gene, Sg11 in Crypto and SglA in Aspergillus.”

It also shows that there is protection under an additional type of immunosuppression different from that used in the cryptococcal vaccine.

The encouraging results, although in the preliminary phase, are relevant not only for immunocompromised people in general, but also for those who have fought Covid, since Aspergillus was the cause of death for many patients during the worst of the pandemic.

Homologous genes

Del Poeta’s lab focused on genes that catalyze the breakdown of steryl glycosides, which scientists have also studied in the context of plants. Crops attacked by various fungi become less productive, increasing the need to understand and disrupt these pathways.

“People working with plants began to observe that these molecules had some sort of immunomodulatory property,” Fernandes said. “That’s where the idea for these steryl glycosides came from, which are also drugs against fungal virulence.”

The mutation studied by Fernandes deleted the sglA gene for sterylglucosidase. Without the enzyme that breaks down steryl glucose, the fungus had fewer hyphae, which are needed for the fungus to grow. The mutation also altered cell wall polysaccharides. Mice vaccinated with this heat-killed mutation had a hundred percent survival rate in response to exposure to the live fungus.

“What was a very big achievement of our work was getting 100% protection,” Fernandes said. For immunocompromised people for whom a live attenuated fungus could threaten their health, the effectiveness of the heat-killed mutation has shown particular promise.

In the experiment, she administered the vaccine 30 days before exposure, while providing boosters as often as every 10 days.

Fernandes, who began postdoctoral research in del Poeta’s lab in 2018, said several questions remain. “After this study, we will try to characterize exactly how this strain induces immunity and protection against a secondary Aspergillus challenge,” she said. Dr. Veronica Brauer, another postdoctoral researcher in del Poeta’s lab, is leading this research.

At this point, it is not known how long the protection against a fungal infection might last.

“For us to be able to estimate the duration of protection, we need to have a more precise understanding of the immune components involved in the response,” Fernandes said.

As of now, mice vaccinated with the mutated, heat-killed fungus had no off-target effects for up to 75 days after vaccination.

Fernandes is also working to characterize the mechanism of action of a new class of antifungal drugs previously identified by the lab, called acylhydrazones. She also hopes to identify a new virulence protein in Cryptococcus.

Origins of the collaboration

Fernandes, who was born and raised in Rio de Janeiro, Brazil, first worked in del Poeta’s lab in 2013, while conducting her doctoral research at the Federal University of Rio de Janeiro. She was studying antifungal peptides and explained to the Brazilian government why coming to Stony Brook would help her research.

Fernandes began studying mushrooms when she was in her second year of university at the Federal University of Rio de Janeiro.

The daughter of two chemists, Fernandes said she grew up in a home in which she had pH strips, which she used to test the acidity of shampoo, water and anything else she could test. . She has also participated in many science fairs.

Fernandes met her husband Jonas Conde, who is a virologist at Stony Brook University and has studied Covid-19, while they were in nearby labs during their doctoral research.

Port Jefferson residents Fernandes and Conde have a four-month-old son named Lucas.

Having a child “motivates me to be better at my job and to lead by example so that he is committed to doing good for others,” Fernandes said.

Del Poeta described Fernandes as “extremely efficient” at managing his time and has “extraordinary motivation”. He appreciates her commitment to his work, which is evident in the additional articles she reads.

Fernandes enjoys being part of del Poeta’s lab. She described him as an “incredible” researcher and supervisor and said being part of his group was “an honor”.

Del Poeta said Fernandes would continue to make mutants for other fungi, including Mucorales and Rhizopous, for which antifungal therapy is not particularly effective.

Del Poeta added that the urgency of this work remains high. Along with several other Stony Brook professors, he submitted grants to study Sgl1 as a vaccine and antifungal target.

“To imagine [making] a drug that not only can treat the primary infection, but in doing so can potentially prevent the recurrence of a secondary infection? he asked rhetorically. “Exciting!”

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