Biology subjects

Jenkins, B.

Publications and source records attributed to Jenkins, B..

23 records · Page 2Linked to original sources

bioRxiv2020

A high affinity human monoclonal antibody against Pfs230 binds multiple parasite stages and blocks oocyst formation in mosquitoes

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterized B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230kDa gamete surface protein Pfs2301-3 to neutralize sexual stage P. falciparum parasites and halt their further spread. We generated nine Pfs230 human monoclonal antibodies (mAbs). One mAb potently blocked transmission to mosquitoes in a complement-dependent manner and reacted strongly to gamete surface while eight mAbs showed only low or no blocking activity. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination.

immunology↗

bioRxiv2019

C. elegans transgenerationally adapts to bacterial infection by increasing the expression of cysteine synthases in progeny

Parental exposure to pathogens can prime offspring immunity in diverse organisms. The mechanisms by which this heritable priming occurs are largely unknown. Here we report that the soil bacteria Pseudomonas vranovensis is a natural pathogen of the nematode Caenorhabditis elegans and that parental exposure of animals to P. vranovensis promotes offspring resistance to infection. Furthermore, we demonstrate a transgenerational enhancement of progeny survival when three consecutive generations of animals are exposed to P. vranovensis. By investigating the mechanisms by which animals heritably adapt to P. vranovensis infection, we found that parental infection by P. vranovensis results in increased expression of the cysteine synthases CYSL-1 and CYSL-2 and the regulator of hypoxia inducible factor RHY-1 in progeny and that these three genes are required for adaptation to P. vranovensis. To our knowledge, these observations represent the largest heritable increase in offspring survival in response to a pathogen infection reported in any organism to date and establish a new CYSL-1, CYSL-2, and RHY-1 dependent mechanism by which animals adapt to infection.

genetics↗

bioRxiv2019

Accelerated phosphatidylcholine turnover in macrophages promotes adipose tissue inflammation in obesity

White adipose tissue (WAT) inflammation contributes to the development of insulin resistance in obesity. While the role of adipose tissue macrophage (ATM) pro-inflammatory signalling in the development of insulin resistance has been established, it is less clear how WAT inflammation is initiated. Here, we show that ATMs from obese mice and humans exhibit markers of increased de novo phosphatidylcholine (PC) biosynthesis rate. Macrophage-specific knockout of phosphocholine-cytidylyltransferase A (CCT), the rate-limiting enzyme of de novo PC biosynthesis pathway, alleviated obesity-induced WAT inflammation and insulin resistance. Mechanistically, CCT-deficient macrophages showed reduced ER stress and inflammation in response to palmitate. Surprisingly, this was not due to lower exogenous palmitate incorporation into cellular PCs. Instead, CCT-null macrophages had lower PC turnover, leading to elevated membrane polyunsaturated fatty acids that negated the pro-inflammatory effects of palmitate. Our results reveal a link between obesity-associated increase in PC synthesis, accelerated PC turnover and pro-inflammatory activation of ATMs.

cell biology↗

bioRxiv2018

Microtubule acetylation is required for mechanosensation in Drosophila

At the cellular level, -tubulin acetylation alters the structure of microtubules to render them mechanically resistant to compressive forces. How this biochemical property of microtubule acetylation relates to mechanosensation remains unknown, though prior studies have shown that microtubule acetylation plays a role in touch perception. Here, we identify the major Drosophila -tubulin acetylase (dTAT) and show that it plays key roles in several forms of mechanosensation while exerting little effect on other sensory modalities. dTAT is highly expressed in neurons of the larval peripheral nervous system (PNS), but is not required for normal neuronal morphogenesis. We show that mutation of the acetylase gene or the K40 acetylation site in -tubulin impairs mechanical sensitivity in sensory neurons and behavioral responses to gentle touch, harsh touch, gravity, and sound stimulus, but not thermal stimulus. Finally, we show that dTAT is required for mechanically-induced activation of NOMPC, a microtubule-associated transient receptor potential channel, and functions to maintain integrity of the microtubule cytoskeleton in response to mechanical stimulation.

cell biology↗

bioRxiv2017

Effects of mutating α-tubulin lysine 40 on sensory dendrite development

Microtubules are essential to neuronal structure and function. Axonal and dendritic microtubules are enriched in post-translational modifications that impact microtubule dynamics, transport, and microtubule-associated proteins. Acetylation of -tubulin lysine 40 (K40) is a prominent, conserved modification of neuronal microtubules. However, the cellular role of microtubule acetylation remains controversial. To resolve how microtubule acetylation might affect neuronal morphogenesis we mutated endogenous -tubulin in vivo using a new fly strain that facilitates the rapid knock-in of designer -tubulin alleles. Leveraging our new strain, we found that microtubule acetylation, as well as polyglutamylation and (de)tyrosination, is not essential for survival. However, we found that dendrite branch refinement in sensory neurons relies on -tubulin K40. Mutagenesis of K40 reveals moderate yet significant changes in dendritic lysosome transport, microtubule polymerization, and Futsch distribution in dendrites but not axons. Our studies point to an unappreciated role for -tubulin K40 and acetylation in dendrite morphogenesis. While our results are consistent with the idea that microtubule acetylation patterns microtubule function within neurons, they also suggest there may be a structural requirement for -tubulin K40.\n\nSummary StatementNeurons are enriched in post-translationally modified microtubules. Targeted mutagenesis of endogenous -tubulin in flies reveals that dendrite branch refinement is altered by acetylation-blocking mutations.

cell biology↗