Rudzki, E. N. | bioRxiv Science

bioRxiv2025

Phylosymbiosis in the making: Host-associated microbiota and host gene expression profiles exhibit discordant timing of phylogenetic congruence over early mammalian development

Gut microbial communities often mirror host phylogenetic relationships, an eco-evolutionary pattern known as phylosymbiosis. While phylosymbiosis is well documented in adult mammals, the developmental timing and mechanisms underlying its emergence remain unknown. Here, we use four captive-bred species of Peromyscus mice, a powerful model for studying natural variation in animal biology, to investigate the assembly of the intestinal microbiota and the emergence of phylosymbiotic signatures from birth through weaning. We combine 16S rRNA microbiome profiling with whole-tissue transcriptomics across three developmental stages (newborn, pre-weaning, and weaning) to test when during development the microbiome and host transcriptome exhibit evolutionary signatures. While parental feces and maternal mammary skin harbored phylosymbiotic communities, the intestines of newborn pups did not. Phylosymbiosis only emerged in pups at the pre-weaning stage of development and was sustained through weaning. Gut microbial diversity increased with age across species, and developmental stage was a stronger driver of community composition than host species identity, with a 1.5-2x larger effect size. Strikingly, host gene expression profiles showed the opposite pattern: transcriptome-based dendrograms were congruent with host phylogeny only at birth, not at later stages. Gene co-expression modules that showed correlation with host phylogenetic distance at birth were mainly enriched for metabolic pathways, such as lysosome activity, fat and vitamin digestion and absorption, and glycan metabolism. This work provides the first evidence, to our knowledge, in vertebrates that phylosymbiosis is not a fixed property of host-microbiome systems, but an emergent feature with distinct developmental dynamics in both the microbiome and the host transcriptome. Our results begin to reveal the complex and dynamic nature by which mammalian host-microbiome relationships are established and maintained across both evolutionary and developmental and time scales.

evolutionary biology↗

bioRxiv2020

Toxoplasma gondii GRA28 is required for specific induction of the regulatory chemokine CCL22 in human and mouse cells.

Toxoplasma gondii is an intracellular protozoan pathogen of humans that can cross the placenta and result in adverse pregnancy outcomes and long-term birth defects. The mechanism used by T. gondii to cross the placenta are unknown but complex interactions with the host immune response are likely to play a role in dictating infection outcomes during pregnancy. Prior work showed that T. gondii infection dramatically and specifically increases the secretion of the immunomodulatory chemokine CCL22 in human placental cells during infection.. Given the important role of this chemokine during pregnancy, we hypothesized that CCL22 induction was driven by a specific T. gondii-secreted effector. Using a combination of bioinformatics and molecular genetics, we have now identified T. gondii GRA28 as the gene product required for CCL22 induction. GRA28 is secreted into the host cell where it localizes to the nucleus, and deletion of this gene results in reduced CCL22 placental cells as well as a human monocyte cell line. The impact of GRA28 on CCL22 production is also conserved in mouse immune and placental cells both in vitro and in vivo. Moreover, parasites lacking GRA28 are impaired in their ability to disseminate throughout the animal, suggesting a link between CCL22 induction and the ability of the parasite to cause disease. Overall these data demonstrate a clear function for GRA28 in altering the immunomodulatory landscape during infection of both placental and peripheral immune cells, and show a clear impact of this immunomodulation on infection outcome. AUTHOR SUMMARYToxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in HIV/AIDS patients and can also cross the placenta and infect the developing fetus. We have found that placental and immune cells infected with T. gondii secrete significant amounts of a chemokine (called "CCL22") that is critical for immune tolerance during pregnancy. In order to better understand whether this is a response by the host or a process that is driven by the parasite, we have identified a T. gondii gene that is absolutely required to induce CCL22 production in human cells, indicating that CCL22 production is a process driven almost entirely by the parasite rather than the host. Consistent with its role in immune tolerance, we also found that T. gondii parasites lacking this gene are less able to proliferate and disseminate throughout the host. Taken together these data illustrate a direct relationship between CCL22 levels in the infected host and a key parasite effector, and provide an interesting example of how T. gondii can directly modulate host signaling pathways in order to facilitate its growth and dissemination.

microbiology↗