Biology subjects

Singh, A.

Publications and source records attributed to Singh, A..

At least 469 records · Page 26Linked to original sources

bioRxiv2022

Stromal Hippo-YAP signaling in stem cell niche controls intestinal homeostasis

Intestinal homeostasis is tightly regulated by the reciprocal interaction between gut epithelium and adjacent mesenchyme. The mammalian Hippo-YAP pathway is intimately associated with intestinal epithelial homeostasis and re-generation; however, its role in postnatal gut mesenchyme remains poorly defined. We find that, although removal of the core Hippo kinases Lats1/2 or activation of YAP in adult intestinal smooth muscle has largely no effect; Hippo-YAP signaling in Gli1/PDGFR-expressing intestinal stromal cells is critical to maintain the stem cell niche. We show that YAP/TAZ activation drives over-proliferation and suppresses smooth muscle actin expression in the niche-forming Gli1+ mesenchymal progenitors. In addition, mesenchymal YAP/TAZ activation disrupts the epithelial-mesenchymal crosstalk by promoting Wnt ligand production, leading to epithelial Wnt pathway activation. Our data also reveal that YAP/TAZ are upregulated in the stroma during DSS-induced injury and stromal YAP activation promotes intestinal epithelial regeneration. Altogether, our data identify an essential requirement for stromal Hippo-YAP signaling in the stem cell niche during intestinal homeostasis. HIGHTLIGHTSO_LILats1/2 control proliferation and differentiation of adult gut mesenchymal progenitors. C_LIO_LIMesenchymal YAP/TAZ promotes Wnt ligand production in intestinal stem cell niche. C_LIO_LIYAP/TAZ is up-regulated in the mesenchyme during intestinal injury. C_LIO_LIStromal YAP activation promotes intestinal epithelial regeneration. C_LI

developmental biology↗

bioRxiv2022

CaV1 and CaV2 calcium channels mediate the release of distinct pools of synaptic vesicles

Activation of voltage-gated calcium channels at synapses leads to local increases in calcium and the fusion of synaptic vesicles. However, presynaptic output will be determined by the density of calcium channels, the dynamic properties of the channel, the distance to docked vesicles, and the release probability at the docking site. We demonstrate that at C. elegans neuromuscular junctions two different classes of voltage-gated calcium channels, CaV2 and CaV1, mediate the release of distinct pools of synaptic vesicles. CaV2 channels are concentrated in densely packed clusters [~]300 nm in diameter with the active zone proteins Neurexin, -Liprin, SYDE, ELKS/CAST, RIM-BP, -Catulin, and MAGI1. CaV2 channels mediate the fusion of vesicles docked adjacent to the dense projection and are colocalized with the synaptic vesicle priming protein UNC-13L. By contrast, CaV1 channels are dispersed in the synaptic varicosity and are coupled to internal calcium stores via the ryanodine receptor. CaV1 and ryanodine receptor mediate the fusion of vesicles docked broadly in the synaptic varicosity and are colocalized with the vesicle priming protein UNC-13S. Distinct synaptic vesicle pools, released by different calcium channels, could be used to tune the speed, voltage-dependence, and quantal content of neurotransmitter release.

neuroscience↗

bioRxiv2022

MITE infestation of germline accommodated by genome editing in Blepharisma

During a sophisticated developmental process, ciliates excise numerous internally eliminated sequences (IESs) from a germline genome copy, producing a functional somatic genome. Most IESs ultimately originate from transposons but homology is obscured by sequence decay. To obtain more representative perspectives on ciliate genome editing, we assembled forty thousand IESs of Blepharisma stoltei, from a much earlier-diverging lineage than existing models. Short IESs (< 115 bp) were largely non-repetitive, with a pronounced ~10 bp length periodicity, whereas longer IESs (max 7 kbp) were non-periodic and contained abundant interspersed repeats. Contrary to current models, the Blepharisma germline genome encodes few transposases. Instead, its most abundant repeat (8000 copies) was a Miniature Inverted-repeat Transposable Element (MITE), apparently a deletion derivative of a germline-limited Pogo-family transposon. We propose MITEs as an important and eventually self-limiting IES source. Rather than defending germline genomes against mobile elements, we argue that transposase domestication actually facilitates junk DNA accumulation.

genomics↗

bioRxiv2022

Discordant effects of resource limitation on host survival and systemic pathogen growth in Drosophila-bacteria infection models: resistance vs. tolerance

In the experiments presented here, we explore the effect of resource limitation, in form of starvation (which leads to decrease in accessible resources and depletion of reserves) and sexual activity (which leads to reallocation of resources from somatic defence towards reproduction), on immune function of female Drosophila melanogaster flies. We infected females with five bacterial pathogens and measured their post-infection survival when subjected to either starvation or sexual activity (mating). Additionally, we measured within host pathogen levels in case of three of these pathogens. Based on previous literature, we predicted that both modes of resource limitation will increase post-infection mortality, but only sexual activity will lead to increase of pathogen load (because of compromised immune function), while starvation will either not affect or reduce pathogen loads (because of reduced availability of resources for the pathogen to proliferate within the host). Our results indicate that both starvation and sexual activity can lead to increased within-host pathogen levels, in addition to increased post-infection mortality, but in a pathogen-specific manner.

ecology↗

bioRxiv2022

TopoGAN: Unsupervised manifold alignment of single-cell data

MotivationSingle-cell technologies allow deep characterization of different molecular aspects of cells. Integrating these modalities provides a comprehensive view of cellular identity. Current integration methods rely on overlapping features or cells to link datasets measuring different modalities, limiting their application to experiments where different molecular layers are profiled in different subsets of cells. ResultsWe present scTopoGAN, a method for unsupervised manifold alignment of single-cell datasets with non-overlapping cells or features. We use topological autoencoders to obtain latent representations of each modality separately. A topology-guided Generative Adversarial Network then aligns these latent representations into a common space. We show that scTopoGAN outperforms state-of-the-art manifold alignment methods in complete unsupervised settings. Interestingly, the topological autoencoder for individual modalities also showed better performance in preserving the original structure of the data in the low-dimensional representations when compared to other manifold projection methods. Taken together, we show that the concept of topology preservation might be a powerful tool to align multiple single modality datasets, unleashing the potential of multi-omic interpretations of cells. Availability and implementationImplementation available on GitHub (https://github.com/AkashCiel/scTopoGAN). All datasets used in this study are publicly available. Contactt.r.m.abdelaal@lumc.nl

bioinformatics↗

bioRxiv2022

Induction of Sis1 promotes fitness but not feedback in the heat shock response

Previously, we combined modeling and experiments to demonstrate that the heat shock response (HSR) functions as a negative feedback loop in which undefined chaperone clients activate the HSR by sequestering Hsp70, and subsequent induction of Hsp70 deactivates the response (Zheng et al., 2016; Krakowiak et al., 2018). Here, we formally define newly synthesized proteins (NSPs) as a major class of HSR activators and determine the role of Sis1, a co-chaperone of Hsp70, in HSR regulation. We develop and experimentally validate a new mathematical model that incorporates NSPs and Sis1. Unexpectedly, genetic decoupling and pulse-labeling experiments reveal that Sis1 induction promotes fitness during prolonged stress rather than providing negative feedback to the HSR. These results support an overall model in which NSPs signal the HSR by sequestering Sis1 and Hsp70, while induction of Hsp70 - but not Sis1 - attenuates the response.

cell biology↗

bioRxiv2022

Gene regulation by synergism between mRNA decay and gene transcription

It has become increasingly clear in the last few years that gene expression in eukaryotes is not a linear process starting from transcription in the nucleus to the cytoplasm, but a circular one where the mRNA level is controlled by crosstalk between nuclear transcription and cytoplasmic decay pathways. One of the possible purposes of this crosstalk is to keep the mRNA level approximately constant. This is called mRNA buffering and happens when transcription and mRNA degradation act at compensatory rates. However, if transcription and mRNA degradation act synergistically, enhanced gene expression regulation would occur. In this work we mathematically modeled the effects of RNA binding proteins (RBP) when they have positive or negative effects on mRNA synthesis and decay rates. We found that they can buffer or enhance gene expression responses depending on their respective effects on transcription and mRNA stability. Then we analyzed new and previously published genomic datasets obtained for several yeast mutants related to either transcription or mRNA decay, but they are not known to possess activity in the other process. We show that some of them, which were presumed only transcription factors (Sfp1) or only decay factors (Puf3, Upf2/3), may represent examples of RBPs that make specific synergistic crosstalk to enhance the control of the mRNA levels of their target genes by combining antagonistic effects on transcriptional and mRNA stability.

molecular biology↗

bioRxiv2022

Karyorelict ciliates use an ambiguous genetic code with context-dependent stop/sense codons

AO_SCPLOWBSTRACTC_SCPLOWIn ambiguous stop/sense genetic codes, the stop codon(s) not only terminate translation but can also encode amino acids. Such codes have evolved at least four times in eukaryotes, twice among ciliates (Condylostoma magnum and Parduczia sp.). These have appeared to be isolated cases whose next closest relatives use conventional stop codons. However, little genomic data have been published for the Karyorelictea, the ciliate class that contains Parduczia sp., and previous studies may have overlooked ambiguous codes because of their apparent rarity. We therefore analyzed single-cell transcriptomes from four of the six karyorelict families to determine their genetic codes. Reassignment of canonical stops to sense codons was inferred from codon frequencies in conserved protein domains, while the actual stop codon was predicted from full-length transcripts with intact 3-untranslated regions (3-UTRs). We found that all available karyorelicts use the Parduczia code, where canonical stops UAA and UAG are reassigned to glutamine, and UGA encodes either tryptophan or stop. Furthermore, a small minority of transcripts may use an ambiguous stop-UAA instead of stop-UGA. Given the ubiquity of karyorelicts in marine coastal sediments, ambiguous genetic codes are not mere marginal curiosities but a defining feature of a globally distributed and diverse group of eukaryotes.

genomics↗

bioRxiv2022

Stochastic analysis of frequency bandwidth and noise attenuation in neurotransmission

Action potential (AP)-triggered neurotransmitter release forms the key basis of inter-neuronal communication. We present a stochastic hybrid system model that captures the release of neurotransmitter-filled vesicles from a presynaptic neuron. More specifically, vesicles arrive as a Poisson process to attach at a given number of docking sites, and each docked vesicle has a certain probability of release when an AP is generated in the presynaptic neuron. The released neurotransmitters enhance the membrane potential of the postsynaptic neuron, and this increase is coupled to the continuous exponential decay of the membrane potential. The buildup of potential to a critical threshold level results in an AP firing in the postsynaptic neuron, with the potential subsequently resetting back to its resting level. Our model analysis develops formulas that quantify the fluctuations in the number of released vesicles and mechanistically connects them to fluctuations in both the postsynaptic membrane potential and the AP firing times. Increasing the frequency of APs in the presynaptic neuron leads to saturation effects on the postsynaptic side, resulting in a limiting frequency range of neurotransmission. Interestingly, AP firing in the postsynaptic neuron becomes more precise with increasing AP frequency in the presynaptic neuron. We also investigate how noise in AP timing varies with different parameters, such as the probability of releases, the number of docking sites, the voltage threshold for AP firing, and the timescale of voltage decay. In summary, our results provide a systematic understanding of how stochastic mechanisms in neurotransmission enhance or impinge the precision of AP fringing times.

neuroscience↗

bioRxiv2022

Moxifloxacin-mediated killing of Mycobacterium tuberculosis involves respiratory downshift, reductive stress, and ROS accumulation

Moxifloxacin is central to treatment of multidrug-resistant tuberculosis. Effects of moxifloxacin on Mycobacterium tuberculosis redox state were explored to identify strategies for increasing lethality and reducing the prevalence of extensively resistant tuberculosis. A non-invasive redox biosensor and an ROS-sensitive dye revealed that moxifloxacin induces oxidative stress correlated with M. tuberculosis death. Moxifloxacin lethality was mitigated by supplementing bacterial cultures with an ROS scavenger (thiourea), an iron chelator (bipyridyl), and, after drug removal, an antioxidant enzyme (catalase). Lethality was also reduced by hypoxia and nutrient starvation. Moxifloxacin increased the expression of genes involved in the oxidative stress response, iron-sulfur cluster biogenesis, and DNA repair. Surprisingly, and in contrast with Escherichia coli studies, moxifloxacin decreased expression of genes involved in respiration, suppressed oxygen consumption, increased the NADH/NAD+ ratio, and increased the labile iron pool in M. tuberculosis. Lowering the NADH/NAD+ ratio in M. tuberculosis revealed that NADH-reductive stress facilitates an iron-mediated ROS surge and moxifloxacin lethality. Treatment with N-acetyl cysteine (NAC) accelerated respiration and ROS production, increased moxifloxacin lethality, and lowered the mutant prevention concentration. Moxifloxacin induced redox stress in M. tuberculosis inside macrophages, and co-treatment with NAC potentiated the anti-mycobacterial efficacy of moxifloxacin during nutrient starvation, inside macrophages, and in mice where NAC restricted the emergence of resistance. Thus, oxidative stress, generated in a novel way, contributes to moxifloxacin-mediated killing of M. tuberculosis. The results open a way to make fluoroquinolones more effective anti-tuberculosis agents and provide a mechanistic basis for NAC-mediated enhancement of fluoroquinolone lethality in vitro and in vivo. Author Summary A new paradigm was revealed for stress-mediated bacterial death in which moxifloxacin treatment of M. tuberculosis decreases respiration rate (respiration increases in E. coli). Although moxifloxacin-induced, ROS-mediated bacterial death was observed, it derived from elevated levels of NADH and iron, a phenomenon not seen with antibiotic-treated E. coli. Nevertheless, stimulation of respiration and ROS by N-acetyl cysteine (NAC) enhanced moxifloxacin-mediated killing of M. tuberculosis, thereby reinforcing involvement of ROS in killing. NAC stimulation of moxifloxacin-mediated killing of M. tuberculosis and restriction of the emergence of resistance in a murine model of infection emphasize the importance of lethal action against pathogens. The work, plus published benefits of NAC to TB patients, encourage studies of NAC-based enhancement of fluoroquinolones.

microbiology↗

bioRxiv2022

Dietary αKG inhibits SARS CoV-2 infection and rescues inflamed lungs to restore normal O2 saturation in animals

Our recent works described the rescue effect of -ketoglutarate (KG, a metabolite of Krebs cycle) on thrombosis and inflammation in animals. KG augments activity of prolyl hydroxylase 2 (PHD2), which in turn degrades proline residues of substrates like phosphorylated Akt (pAkt) and hypoxia inducible factor (HIF). Here we describe the inhibitory effect of octyl KG on pAkt as well as on HIF1/HIF2, and in turn decreasing SARS CoV-2 replication in Vero E6 cells. KG failed to inhibit the viral replication and Akt phosphorylation in PHD2-knockdown U937 cells transiently expressing ACE2. Contrastingly, triciribine (TCN, an Akt-inhibitor) inhibited viral replication alongside a downmodulation of pAkt in PHD2-KD cells. Dietary KG significantly inhibited viral infection and rescued hamsters from thrombus formation and inflammation in lungs, the known causes of acute respiratory distress syndrome (ARDS) in COVID-19. KG supplementation also reduced the apoptotic death of lung tissues in infected animals, alongside a downmodulation of pAkt and HIF2. KG supplementation neither affected IgG levels against SARS CoV-2 RBD protein nor altered the neutralization antibody response against SARS CoV-2. It did not interfere with the percentage of interferon-{gamma} positive (IFN{gamma}+) CD4+ and IFN{gamma}+CD8+ T cells in infected animals. The extended work in balb/c mice transiently expressing ACE2 showed a similar effect of KG in reducing accumulation of inflammatory immune cells and cytokines, including IL6, IL1{beta} and TNF, in lungs as well as in circulation of infected animals. Pro-thrombotic markers like platelet microparticles and platelet-leukocyte aggregates were reduced significantly in infected mice after KG supplementation. Importantly, KG supplementation restored the O2 saturation (SpO2) in circulation of SARS CoV-2 infected hamsters and mice, suggesting a potential therapeutic role of this metabolite in COVID-19 treatment.

pathology↗

bioRxiv2022

A fluctuation-based approach to infer kinetics and topology of cell-state switching

In the noisy cellular environment, RNAs and proteins are subject to considerable stochastic fluctuations in copy numbers over time. As a consequence, single cells within the same isoclonal population can differ in their expression profile and reside in different phenotypic states. The dynamic nature of this intercellular variation, where individual cells can transition between different states over time makes it a particularly hard phenomenon to characterize. Here we propose a novel fluctuation-test approach to infer the kinetics of transitions between cell states. More specifically, single cells are randomly drawn from the population and grown into cell colonies. After growth for a fixed number of generations, the number of cells residing in different states is assayed for each colony. In a simple system with reversible switching between two cell states, our analysis shows that the extent of colony-to-colony fluctuations in the fraction of cells in a given state is monotonically related to the switching kinetics. Several closed-form formulas for inferring the switching rates from experimentally quantified fluctuations are presented. We further extend this approach to multiple cell states where harnessing fluctuation signatures can reveal both the topology and the rates of cell-state switching. In summary, our analysis provides a powerful approach for dissecting cell-state transitions based on a single time point measurement. This is especially important for scenarios where a measurement involves killing the cell (for example, performing single-cell RNA-seq or assaying whether a microbial/cancer cell is in a drug-sensitive or drug-tolerant state), and hence the state of the same cell cannot be measured at different time points.

systems biology↗

bioRxiv2022

Relative stability of mRNA and protein severely limits inference of gene networks from single-cell mRNA measurements

Inference of gene regulatory networks from single-cell expression data, such as single-cell RNA sequencing, is a popular problem in computational biology. Despite diverse methods spanning information theory, machine learning, and statistics, it is unsolved. This shortcoming can be attributed to measurement errors, lack of perturbation data, or difficulty in causal inference. Yet, it is not known if kinetic properties of gene expression also cause an issue. We show how the relative stability of mRNA and protein hampers inference. Available inference methods perform benchmarking on synthetic data lacking protein species, which is biologically incorrect. We use a simple model of gene expression, incorporating both mRNA and protein, to show that a more stable protein than mRNA can cause loss in correlation between the mRNA of a transcription factor and its target gene. This can also happen when mRNA and protein are on the same timescale. The relative difference in timescales affects true interactions more strongly than false positives, which may not be suppressed. Besides correlation, we find that information-theoretic nonlinear measures are also prone to this problem. Finally, we demonstrate these principles in real single-cell RNA sequencing data for over 1700 yeast genes.

systems biology↗

bioRxiv2022

Dynamic analysis of sequestration-based feedbacks in cellular and biomolecular circuits

Nonlinear feedback controllers are ubiquitous features of biological systems at different scales. A key motif arising in these systems is a sequestration-based feedback. As a physiological example of this type of feedback architecture, platelets (specialized cells involved in blood clotting) differentiate from stem cells, and this process is activated by a protein called Thrombopoietin (TPO). Platelets actively sequester and degrade TPO, creating negative feedback whereby any depletion of platelets increases the levels of freely available TPO that upregulates platelet production. We show similar examples of sequestration-based feedback in intracellular biomolecular circuits involved in heat-shock response and microRNA regulation. Our systematic analysis of this feedback motif reveals that platelets induced degradation of TPO is critical in enhancing system robustness to external disturbances. In contrast, reversible sequestration of TPO without degradation results in poor robustness to disturbances. We develop exact analytical results quantifying the limits to which the sensitivity to disturbances can be attenuated by sequestration-based feedback. Next, we consider the stochastic formulation of the circuit that takes into account low-copy number fluctuations in feedback components. Interestingly, our results show that the extent of random fluctuations are enhanced with increasing feedback strength, but can exhibit local maxima and minima across parameter regimes. In summary, our systematic analysis highlights design principles for enhancing the robustness of sequestration-based feedback mechanisms to external disturbances and inherent noise in molecular counts.

physiology↗

bioRxiv2022

Stimulus-Response signaling dynamics characterize macrophage polarization states

Macrophages show remarkable functional pleiotropy that is dependent on microenvironmental context. Prior studies have characterized how polarizing cytokines alter the transcriptomic and epigenetic landscape. Here we characterized the immune-threat appropriate responses of polarized macrophages by measuring the single-cell signaling dynamics of transcription factor NF{kappa}B. Leveraging a fluorescent protein reporter mouse, primary macrophages were polarized into 6 states and stimulated with 8 different stimuli resulting in a vast dataset. Linear Discriminant Analysis revealed how NF{kappa}B signaling codons compose the immune threat level of stimuli, placing polarization states along a linear continuum between the M1/M2 dichotomy. Machine learning classification revealed losses of stimulus distinguishability with polarization, which reflect a switch from sentinel to more canalized effector functions. However, the stimulus-response dynamics and discrimination patterns did not fit the M1/M2 continuum. Instead, our analysis suggests macrophage functional niches within a multi-dimensional polarization landscape. HighlightsO_LIPolarization of macrophages affects stimulus-response NF{kappa}B dynamics C_LIO_LIFor each condition, NF{kappa}B signaling codons quantify the "immune threat" level C_LIO_LIMachine Learning reveals polarization-induced canalization of stimulus-responses C_LIO_LINF{kappa}B stimulus-responses may define a landscape of macrophage states C_LI eTOC blurbMacrophages are profoundly responsive to their tissue microenvironment, but how that affects their pathogen response functions has not been investigated systematically. Here we studied how their signaling response is affected by six polarizing cytokines. We found each modulates their stimulus-responses highly specifically, producing distinct patterns of stimulus-discrimination. Thereby, these stimulus-response specificities may be used to describe a landscape of functional macrophage states. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/485991v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@1d34d5forg.highwire.dtl.DTLVardef@17cc0eaorg.highwire.dtl.DTLVardef@15d6022org.highwire.dtl.DTLVardef@1526f72_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2022

A Novel High-Throughput Single B-Cell Cloning Platform for Isolation and Characterization of High-Affinity and potent SARS-CoV-2 Neutralizing Antibodies

Monoclonal antibodies (mAbs) that are specific to SARS-CoV-2 can be useful in diagnosing, preventing, and treating the coronavirus (COVID-19) illness. Strategies for the high-throughput and rapid isolation of these potent neutralizing antibodies are critical toward the development of therapeutically targeting COVID-19 as well as other infectious diseases. In the present study, a single B-cell cloning method was used to screen SARS-CoV-2 receptor-binding domain (RBD) specific, high affinity, and neutralizing mAbs from patients blood samples. An RBD-specific antibody, SAR03, was discovered that showed high binding (ELISA and SPR) and neutralizing activity (competitive ELISA and pseudovirus-based reporter assay) against Sars-CoV-2. Mechanistic studies on human cells revealed that SAR03 competes with the ACE-2 receptor for binding with the RBD domain (S1 subunit) present in the spike protein of Sars-CoV-2. This study highlights the potential of the single B cell cloning method for the rapid and efficient screening of high-affinity and effective neutralizing antibodies for Sars-CoV-2 and other emerging infectious diseases. HighlightsO_LISingle B-cell cloning is a high-throughput and efficient method of generating high affinity neutralizing antibodies C_LIO_LISingle B-cell cloning method was used to screen SARS-CoV-2 receptor-binding domain (RBD) specific, high affinity, and neutralizing monoclonal antibodies from patients blood samples. C_LIO_LIAn RBD-specific antibody, SAR03, was discovered that showed high binding and neutralizing activity against SARS-CoV-2. C_LI

immunology↗

bioRxiv2022

Discovery of anti-SARS-CoV-2 molecules using structure-assisted repurposing approach targeting N-protein

The N-terminal (NTD) and the C-terminal (CTD) domains comprises the structure of the SARS-CoV-2 Nucleocapsid (N) protein. Crystal structure of the SARS-CoV-2 N protein determined by Kang et al, 2020, reveals the N-terminal RNA binding domain as a unique drug binding site. The present study targets this unique pocket with identified antivirals using structure-based drug repurposing approach. The high-affinity binding of potential molecules was characterised thermodynamically using Isothermal titration calorimetry. The selected molecules showed an inhibitory RNA binding potential between 8.8 M and 15.7 M IC50 when evaluated with a fluorescent-based assay. Furthermore, in an in vitro cell-based antiviral assay, these ten antiviral molecules demonstrated high effectiveness in halting SARS-CoV-2 replication. Telmisartan and BMS-189453, the two highly potent antivirals, have [~]0.98M and 1.02 M EC50 values with the selective index of >102, and >98, respectively. For the first time, this study presents drug molecules specifically targeting the NTD of SARS-CoV-2, offering essential insights for the development of therapeutic interventions against this virus, which is still a potential global threat to public health.

molecular biology↗

bioRxiv2022

Effect of larval diet on adult immune function is contingent upon selection history and host sex in Drosophila melanogaster

Mounting an immune response requires a considerable energy investment by the host. This makes expression of immune phenotypes susceptible to changes in availability of resources. There is ample evidence in scientific literature to suggest that hosts become more vulnerable to infection by pathogens and parasites when access to nutrition is limited. Using populations of Drosophila melanogaster experimentally evolved to better survive bacterial infections, we explore if host selection history influences host response to resource deprivation in terms of immune function. We find that when reared on a suboptimal diet (both in larval and adult stages), adult flies from evolved populations are still more immune to infections compared to flies from control populations. Furthermore, we observe a sex-dependent effect of interaction between selection history and diet on immune function. We thus conclude that immune function of hosts adapted to pathogen challenge is less affected by resource limitation compared to non-adapted hosts.

evolutionary biology↗