Biology subjects

Latre de Late, P.

Publications and source records attributed to Latre de Late, P..

3 recordsLinked to original sources

bioRxiv2026

Targeted mutagenesis in Ehrlichia canis deleting the phage head-to-tail connector protein gene and its assessment as a vaccine candidate preventing canine ehrlichiosis

Ehrlichia canis is primarily a Rhipicephalus sanguineus tick-borne rickettsial pathogen initially identified as causing canine monocytic ehrlichiosis, and infections in people have also been reported in Venezuela, Mexico, and parts of Europe. It is of high importance to have a vaccine suitable in protecting the canine host, which will aid in lessening E. canis infections also in people. Gene inactivation mutations in the phage head-to-tail connector protein genes (phtcp) from E. chaffeensis and A. marginale caused attenuated growth, and prior infection with the mutated bacteria induced protective immunity against wild-type bacterial infections in natural hosts, independent of blood-borne infection or tick-transmission infection. In the current study, we describe the development of targeted mutagenesis for the first time in E. canis genome and with a novel modification to avoid introducing antibiotic resistance cassettes to delete the phtcp ortholog from E. canis. The mutated E. canis was then assessed for its in vivo growth and the induction of host immunity exerted following the mutant infection aiding to protect against wild-type infection challenge in the canine host. We assessed systemic pathogen loads, hematological parameters, IgG immune responses, and plasma cytokines following the mutant infection relative to uninfected dogs. Similarly, the assessments were carried out following wild-type pathogen infections in dogs with or without prior mutant infection challenges. The study demonstrates that prior infection of dogs with the mutant induces immunity to prevent infection establishment by wild-type E. canis. Similarly, the mutant infection resulted in clear biological differences compared to the wild-type infection. This study establishes that the molecular genetic methods are broadly applicable to pathogens belonging to the family Anaplasmataceae and that the modified live vaccines with phtcp gene orthologs are valuable in reducing the diseases caused by the tick-borne rickettsial pathogens belong to Anaplasmataceae, including E. canis.

microbiology↗

bioRxiv2021

A locus conferring tolerance to Theileria infection in African cattle

East Coast fever, a tick-borne cattle disease caused by the Theileria parva parasite, is among the biggest natural killers of cattle in East Africa, leading to over 1 million deaths annually. Here we report on the genetic analysis of a cohort of Boran cattle demonstrating heritable tolerance to infection by T. parva (h2 = 0.65, s.e. 0.57). Through a linkage analysis we identify a 6 Mb genomic region on Bos taurus chromosome 15 that is significantly associated with survival outcome following T. parva exposure. Testing this locus in an independent cohort of animals replicates this association with survival following T. parva infection. A stop gained polymorphism in this region was found to be highly associated with survival across both related and unrelated animals, with only one of the 20 homozygote carriers (T/T) of this change succumbing to the disease in contrast to 44 out of 97 animals homozygote for the reference allele (C/C). Consequently, we present a genetic locus linked to tolerance of one of Africas most important cattle diseases, raising the promise of marker-assisted selection for cattle that are less susceptible to infection by T. parva. Author SummaryMore than a million cattle die of East Coast fever in Africa each year, the impact of which disproportionately falls onto low-income, smallholder farmers. The lack of a widely accessible vaccine, heavy reliance on chemicals to control the tick vector and inadequate drug treatments means that new approaches for controlling the disease are urgently required. Through a genetic study of an extended pedigree of Boran cattle that are more than three times less likely to succumb to the disease than matched controls, we identify a region on chromosome 15 of the cattle genome associated with a high level of tolerance to the disease. We show that a variant in this region is also associated with survival in an independent cohort, and is linked to rates of cell expansion during infection. This genetic variant can therefore support marker-assisted selection, allowing farmers to breed tolerant cattle and offers a route to introduce this beneficial DNA to non-native breeds, enabling reduced disease incidence and increased productivity, which would be of benefit to millions of rural smallholder farmers across Africa.

genetics↗

bioRxiv2018

Theileria highjacks JNK2 into a complex with the macroschizont GPI-anchored surface protein p104

Theileria is a unique apicomplexan parasite capable of transforming its host cell into a disseminating tumour. Constitutive JNK activity characterizes bovine T and B cells infected with T. parva, and B cells and macrophages infected with T. annulata. Here, we show that T. annulata manipulates JNK activation by recruiting JNK2, and not JNK1, to the parasite surface, whereas JNK1 is found predominantly in the host cell nucleus. In silico analysis identified 3 potential JNK-binding motifs in the previously characterized GPI-anchored macroschizont surface protein (p104), and we demonstrate here that JNK2 is recruited to the parasite via physical interaction with p104. A cell penetrating peptide harbouring a p104 JNK-binding motif also conserved in T. parva p104 competitively ablated binding, whereupon liberated JNK2 became ubiquitinated and degraded. Sequestration of JNK2 depended on PKA-mediated phosphorylation of the conserved JNK-binding motif and upon disruption of the p104/JNK2 complex loss of JNK2 resulted in diminished matrigel traversal of T. annulata-transformed macrophages. Loss of JNK2 also resulted in upregulation of small mitochondrial ARF that promoted autophagy consistent with cytosolic sequestration of JNK2 sustaininf not only JNK2, but also nuclear JNK1 levels that combined contribute to both survival and dissemination of Theileria-transformed macrophages.\n\nAuthor SummaryTheileria annulata parasites infect and transform their host bovine leukocytes into tumourlike cells that disseminate throughout infected animals causing a widespread disease called tropical theileriosis. Virulence has been ascribed to the parasites ability to constitutively activate leukocyte c-Jun N-terminal Kinase (JNK) leading to permanent induction of Matrix Metallo-Proteinase 9 (MMP9) that promotes transformed macrophage dissemination. In attenuated live vaccines JNK-mediated AP-1-driven transcriptional activity is reduced so dampening dissemination. However, in leukocytes JNK exists as two isoforms JNK1 and JNK2 and here, we show for the first time that in T. annulata-transformed macrophages they have different subcellular localisations and perform separate functions. Surprisingly, JNK2 associates with the parasite and is not in the nucleus like JNK1. JNK2 is hijacked by the parasite and sequestered in a complex with a macroschizont surface protein called p104. Upon forced complex dissociation JNK2 gets degraded and its loss negatively affects infected macrophage survival and ability to disseminate.

microbiology↗