Biology subjects

Milazzo, J.

Publications and source records attributed to Milazzo, J..

6 recordsLinked to original sources

bioRxiv2023

Wild and cultivated rice host different populations of the blast fungus, Pyricularia oryzae, in Mali

Blast is a devastating disease of rice caused by the fungus Pyricularia oryzae. The role of infected straw and seed as sources of primary inoculum in blast disease epidemics is well known. The role of alternative hosts is yet to be confirmed. The current study sought to assess if wild rice is a major source of inoculum for cultivated rice by comparing the genetic structure of P. oryzae populations from both hosts. Cross infectivity of P. oryzae isolates was also assessed using pathogenicity tests. Samples were collected from cultivated and wild rice organs with blast symptoms in irrigated and lowland areas of Mali in Koulikoro, Sikasso, and Segou regions. Under controlled conditions, P. oryzae isolates from wild rice were pathogenic to cultivated rice but, on average, had a narrower range of cultivar compatibility. Results of pathogenicity tests suggest that P. oryzae isolates from wild rice have the potential to attack cultivated rice in the field. However, populations of P. oryzae on cultivated and wild rice were genetically differentiated. Thus, although physically close, each host plant hosts a different population of the pathogen, and our results support the hypothesis that wild rice is not a major source of blast inoculum for cultivated rice.

microbiology↗

bioRxiv2023

Engrailed-1 Promotes Pancreatic Cancer Metastasis

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

cancer biology↗

bioRxiv2021

COEVOLUTION WITH SPATIALLY STRUCTURED RICE LANDRACES MAINTAINS MULTIPLE GENERALIST LINEAGES IN THE RICE BLAST PATHOGEN

Traditional agrosystems, where humans, crops and microbes have coevolved over long periods, can serve as models to understand the eco-evolutionary determinants of disease dynamics and help the engineering of durably resistant agrosystems. Here, we investigated the genetic and phenotypic relationship between rice (Oryza sativa) landraces and their rice blast pathogen (Magnaporthe oryzae) in the traditional Yuanyang terraces of flooded rice paddies in China, where rice landraces have been grown and bred over centuries without significant disease outbreaks. Analyses of genetic subdivision revealed that indica rice plants clustered according to landrace names. Three new diverse lineages of rice blast specific to the Yuanyang terraces coexisted with lineages previously detected at the worldwide scale. Population subdivision in the pathogen population did not mirror pattern of population subdivision in the host. Measuring the pathogenicity of rice blast isolates on landraces revealed generalist life histories. Our results suggest that the implementation of disease control strategies based on the emergence or maintenance of a generalist lifestyle in pathogens may sustainably reduce the burden of disease in crops.

evolutionary biology↗

bioRxiv2020

Ecological differentiation and incipient speciation in the fungal pathogen causing rice blast

Many invasive fungal species coexist as multiple lineages on the same host, but the factors underlying the origin and maintenance of population structure remain largely unknown. Here, we analyzed genetic and phenotypic diversity in isolates of the rice blast fungus (Pyricularia oryzae) covering a broad geographical range. We showed that the four lineages of P. oryzae were found in areas with different prevailing environmental conditions and types of rice grown, indicating niche separation. Pathogenicity tests revealed that specialization to rice subspecies contributed to niche separation between lineages, and differences in repertoires of putative virulence effectors were consistent with differences in host range. Experimental crosses revealed that female sterility and early post-mating genetic incompatibilities acted as strong barriers to gene flow between these lineages. Our results demonstrate that the spread of a pathogen across heterogeneous habitats and divergent populations of a crop species can lead to niche separation and reproductive isolation between distinct invasive lineages.

evolutionary biology↗

bioRxiv2019

The Salt-Inducible Kinase inhibitor YKL-05-099 suppresses MEF2C function and acute myeloid leukemia progression in vivo

Lineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a Salt-Inducible Kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF MEF2C. In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C. Here, we evaluated whether inhibition of SIK3 with the tool compound YKL-05-099 can suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells under in vitro and in vivo conditions. Similar phenotypes were obtained when exposing cells to YKL-05-099, which caused cell cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. Using a gatekeeper allele of SIK3, we found that the anti-proliferative effects of YKL-05-099 occurred through on-target inhibition of SIK3 kinase activity. Based on these findings, we treated two different mouse models of MLL-AF9 AML with YKL-05-099, which attenuated disease progression in vivo and extended animal survival at well-tolerated doses. These findings validate SIK3 as a therapeutic target in MEF2C-positive AML and provide a rationale for developing drug-like inhibitors of SIK3 for definitive pre-clinical investigation and for studies in human patients with leukemia.\n\nKey PointsAML cells are uniquely sensitive to genetic or chemical inhibition of Salt-Inducible Kinase 3 in vitro and in vivo.\n\nA SIK inhibitor YKL-05-099 suppresses MEF2C function and AML in vivo.

cancer biology↗

bioRxiv2017

Coexistence of multiple endemic and pandemic lineages of the rice blast pathogen

The rice blast fungus Magnaporthe oryzae (syn. Pyricularia oryzae) is both a threat to global food security and a model for plant pathology. Molecular pathologists need an accurate understanding of the origins and line of descent of M. oryzae populations, to identify the genetic and functional bases of pathogen adaptation, and to guide the development of more effective control strategies. We used a whole-genome sequence analysis of samples from different times and places to infer details about the genetic makeup of M. oryzae from a global collection of isolates. Analyses of population structure identified six lineages within M. oryzae, including two pandemic on japonica and indica rice, respectively, and four lineages with more restricted distributions. Tip-dating calibration indicated that M. oryzae lineages separated about a millenium ago, long after the initial domestication of rice. The major lineage endemic to continental Southeast Asia displayed signatures of sexual recombination and evidence of DNA acquisition from multiple lineages. Tests for weak natural selection revealed that the pandemic spread of clonal lineages entailed an evolutionary cost, in terms of the accumulation of deleterious mutations. Our findings reveal the coexistence of multiple endemic and pandemic lineages with contrasting population and genetic characteristics within a widely distributed pathogen.\n\nImportanceThe rice blast fungus Magnaporthe oryzae (syn. Pyricularia oryzae) is a textbook example of a rapidly adapting pathogen, and is responsible for one of the most damaging diseases of rice. Improvements in our understanding of Magnaporthe oryzae diversity and evolution are required, to guide the development of more effective control strategies. We used genome sequencing data for samples from around the world to infer the evolutionary history of M. oryzae. We found that M. oryzae diversified about a thousand years ago ago, separating into six main lineages: two pandemic on japonica and indica rice, respectively, and four with more restricted distributions. We also found that a lineage endemic to continental Southeast Asia displayed signatures of sexual recombination and the acquisition of genetic material from multiple lineages. This work provides a population-level genomic framework for defining molecular markers for the control of rice blast and investigations of the molecular basis of differences in pathogenicity between M. oryzae lineages.

evolutionary biology↗