Cell and developmental mechanisms of animal responses to intracellular beneficial microbes

Microbes shape animal physiology, evolution, and can cause or protect against disease. Extensive studies on animal-pathogen relationships have enhanced our understanding of immunity, cell biology, and disease therapies. In recent years, the importance of beneficial microbes in animal health has become clear. However, the complexity of microbes associated with animals has made it difficult to both identify beneficial microbes and to discover the cell biology underlying their benefit, severely limiting progress in the field. These knowledge gaps can be addressed by using simple, genetically tractable animal models with well-defined symbionts. Over the past four years, my lab has developed genetic tools in the small anemone, Aiptasia, that has an intracellular endosymbiotic relationship with dinoflagellate algae. These dinoflagellate algal symbionts are re- established in each generation and reside inside the gastrodermal cells of the animal in a novel phagolysosome- like organelle. Aiptasia is a powerful model for beneficial microbial relationships relevant to biomedicine for several reasons. First, the structure and content of sea anemone genomes are more conserved to humans than in other models (e.g., insects and nematodes), enabling the study of conserved pathways of host-microbe interactions. Second, the dinoflagellate symbionts are closely related to well-studied apicomplexan parasites (e.g., Plasmodium falciparum), allowing for comparisons of the mechanisms used by intracellular pathogens and beneficial microbes to modulate animal cell biology. These new genetic tools in an experimentally tractable symbiotic animal offers a powerful untapped opportunity to dissect the mechanisms of beneficial animal-microbe interactions. Over the next five years, we aim to understand how the innate immune system is regulated to select for and tolerate endosymbiotic microbes while still allowing defense against pathogenic infections, how gastrodermal cells respond to beneficial microbes to generate a novel cell type in the animal gut, and how core and conserved cellular processes are co-opted to support a symbiotic microbe in a novel organelle. This research will uncover underexplored fundamental processes that govern beneficial host-microbe interactions including cellular signaling, developmental genetics, and organelle dynamics, providing insights relevant to NIGMS priorities. Importantly, this research will provide a new avenue to explore how animals respond to beneficial microbes and how microbes impact animal health. Project Number: 1R35GM162274-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Phillip Cleves | Institution: UNIVERSITY OF CALIFORNIA BERKELEY, BERKELEY, CA | Award Amount: $441,375 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11271589