Microsporidian obligate intracellular parasites subvert autophagy of infected mammalian cells to promote their own growth

ABSTRACT Intracellular pathogens such as Microsporidia can interfere with host proteostasis pathways, including autophagy. While the manipulation of host autophagy has been demonstrated in a nematode-infecting species, and autophagic activity was also observed in tardigrade midgut infections, it remains unclear whether this strategy extends to mammalian-infecting Microsporidia. Here, we investigated interactions between host autophagy and two human-pathogenic Microsporidian species representing distinct evolutionary lineages. Using immunochemistry, super-resolution fluorescence microscopy, and modulation of autophagy via siRNA silencing and chemical agents, we show that Encephalitozoon cuniculi is tagged by early autophagy markers (ubiquitin and p62) but escapes clearance via autolysosomes. Instead of restricting the parasite, autophagy induction significantly enhances Microsporidia proliferation in two mammalian cell models. Conversely, autophagy suppression—via siRNA or treatment with microbiota-derived metabolites important for gut epithelial homeostasis—reduces parasite growth. These findings demonstrate that the ability to evade and exploit host autophagy is not restricted to nematode-infecting species but is conserved across diverse Microsporidia infecting mammals. Together with adaptations such as NTT nucleotide transporters, the hijacking of autophagy emerges as a core strategy supporting the obligate intracellular lifestyle of these pathogens. IMPORTANCE Microsporidia are tiny parasites that must live inside other cells to survive. In animals like worms and tardigrades, they’ve been seen to interact with a cell’s recycling system called autophagy, which usually helps the host defend itself. But what about Microsporidia that infect mammals, including humans? Our research shows that instead of being destroyed by autophagy, human-infecting Microsporidia use it to grow faster. We studied two different species in mammalian cells and found that when we boosted the host’s autophagy system, the parasites multiplied more. When we slowed down autophagy, parasite growth dropped. This means that Microsporidia have evolved clever ways to turn the host’s defences into a resource. Understanding how they do this could lead to better treatments for infections, especially for people with weakened immune systems. It also reveals a surprising twist in how these unusual parasites survive across a broad range of hosts.