Biology subjects

Lazzaro, B. P.

Publications and source records attributed to Lazzaro, B. P..

8 recordsLinked to original sources

bioRxiv2026

Shielded by the dead: how killed bacteria shape the dynamics and evolution of innate immunity

The outcome of an infection is determined by the dynamic interplay between microbial growth and host immunity. During a bacterial infection, bacteria killed by innate immune effectors can accumulate as corpses in the extracelluar space, where they can continue to bind (and thus sequester) immune effectors. The impacts on infection outcomes of continued biochemical activity ("sponginess") by the dead have been generally overlooked in theoretical and empirical studies of within-host disease dynamics. We develop a mechanism-based mathematical model of within-host dynamics that incorporates host microbial sensing, the production of immune effectors, the interaction of those effectors with microbes, and shutdown of the immune response after an infection has been controlled. Corpse sponginess impedes the hosts ability to control infection, but at the same time, the rapid mopping up of effectors by bacterial corpses also protects host tissue against autoimmune self-harm from immune effectors still circulating after the infection has been resolved. This dual impact of bacterial sponginess alters the trade-off between damage done by infecting bacteria versus autoimmune damage, consequently shifting the evolutionarily optimal immune activation and shutdown kinetics. Thus, the sponginess of bacterial corpses likely shapes both short-term infection dynamics and the long-term evolution of immune systems.

immunology↗

bioRxiv2025

Host plant nutrition drives fitness outcomes in the cactus specialist Drosophila mettleri

Organisms must navigate complex interactions with host plants, microbial communities, and environmental cues to ensure their survival and reproductive success when adapting to novel environments. Host plant specialists can be used to study how these interactions affect fitness due to their ecological constraints. In specialist species, such as cactophilic Drosophila, it remains unclear how feeding preferences, nutritional value of the substrate, and microbial interactions collectively shape fitness outcomes. We used diverse laboratory media formulations to examine the fitness implications in Drosophila mettleri, a species that exclusively uses Saguaro cactus (Carnegiea gigantea) as its natural host plant. We found that D. mettleri did not preferentially feed on one medium compared to others, nor on C. gigantea supplemented media compared to controls. Microbial communities, especially on banana media with C. gigantea additives, appear to improve developmental success and can influence D. mettleri post-pupation success. Taken together, our results highlight the behavioral and environmental interplay between host plant substrate and microbial communities.

ecology↗

bioRxiv2025

Strong GAL4 expression compromises Drosophila fat body function

The ability to direct tissue-specific overexpression of transgenic proteins in genetically tractable organisms like Drosophila melanogaster has facilitated innumerable biological discoveries. However, transgenic proteins can themselves impact cellular and physiological processes in ways that are often ignored or poorly defined. Here we discovered that the yolk-GAL4 transgene, which directs strong expression of the yeast GAL4 transcription factor in the Drosophila fat body, induces significant physiological defects in adult female flies. We found that yolk-GAL4 disrupts adipose tissue integrity and reduces fat body lipid stores, egg production, and resistance to systemic bacterial infections. Knocking down GAL4 expression in yolk-GAL4 heterozygotes using RNAi fully suppressed each of these defects, thus confirming that the GAL4 transgene product induces these phenotypes. Comparing a panel of additional fat body driver lines, we found that GAL4 expression levels directly correlate infection susceptibility, but not with fat levels or egg production. To determine whether other transgenic proteins can impair fat body function, we constructed new fly lines in which the yolk enhancer directs expression of either cytoplasmic or nuclear-localized mCherry, or an alternative transactivator, LexA. We found that only nuclear-localized mCherry and LexA increased infection susceptibility similarly to GAL4, suggesting that intranuclear transgenic proteins in general can curtail the fat bodys induced immune response in a manner highly sensitive to transgene expression strength. Additionally, these new lines can be valuable tools for future studies. More broadly, our findings highlight the potential for transgenes to substantially impact organismal biology and emphasize the importance of rigorously characterizing genetic tools to optimally leverage model systems like Drosophila.

genetics↗

bioRxiv2023

High sugar diets can increase susceptibility to bacterial infection in Drosophila melanogaster

Overnutrition with dietary sugar can worsen infection outcomes in diverse organisms including insects and humans, generally through unknown mechanisms. In the present study, we show that adult Drosophila melanogaster fed high-sugar diets became more susceptible to infection by the Gram-negative bacteria Providencia rettgeri and Serratia marcescens, although diet had no significant effect on infection by Gram-positive bacteria Enterococcus faecalis or Lactococcus lactis. We found that P. rettgeri and S. marcescens proliferate more rapidly in D. melanogaster fed a high-sugar diet, resulting in increased probability of host death. D. melanogaster become hyperglycemic on the high-sugar diet, and we find evidence that the extra carbon availability may promote S. marcescens growth within the host. However, we found no evidence that increased carbon availability directly supports greater P. rettgeri growth. D. melanogaster on both diets fully induce transcription of antimicrobial peptide (AMP) genes in response to infection, but D. melanogaster provided with high-sugar diets show reduced production of AMP protein. Thus, overnutrition with dietary sugar may impair host immunity at the level of AMP translation. Our results demonstrate that dietary sugar can shape infection dynamics by impacting both host and pathogen, depending on the nutritional requirements of the pathogen and by altering the physiological capacity of the host to sustain an immune response. Author SummaryDiet has critical impact on the quality of immune defense, and high-sugar diets increase susceptibility to bacterial infection in many animals. Yet it is unknown which aspects of host and pathogen physiology are impacted by diet to influence infection dynamics. Here we show that high-sugar diets increase susceptibility to some, but not all, bacterial infections in Drosophila. We find that feeding on high sugar diet impairs the host immune response by reducing the level of antimicrobial peptides produced. The expression of genes encoding these peptides is not affected, so we infer that protein translation is impaired. We further show that flies on high-sugar diets are hyperglycemic, and that some pathogens may use the excess sugar in the host to promote growth during the infection. Thus, our study demonstrates that dietary impacts on infection outcome arise through physiological effects on both the host and pathogen.

immunology↗

bioRxiv2023

No evidence for trans-generational immune priming inDrosophila melanogaster

Most organisms are under constant and repeated exposure to pathogens, leading to perpetual natural selection for more effective ways to fight-off infections. This could include the evolution of memory-based immunity to increase protection from repeatedly-encountered pathogens both within and across generations. There is mixed evidence for intra- and trans-generational priming in non-vertebrates, which lack the antibody-mediated acquired immunity characteristic of vertebrates. In this work, we tested for trans-generational immune priming in adult offspring of the fruit fly, Drosophila melanogaster, after maternal challenge with 10 different bacterial pathogens. We focused on natural opportunistic pathogens of Drosophila spanning a range of virulence from 10% to 100% host mortality. We infected mothers via septic injury and tested for enhanced resistance to infection in their adult offspring, measured as the ability to suppress bacterial proliferation and survive infection. We categorized the mothers into four classes for each bacterium tested: those that survived infection, those that succumbed to infection, sterile-injury controls, and uninjured controls. We found no evidence for trans-generational priming by any class of mother in response to any of the bacteria.

immunology↗

bioRxiv2021

The genetic basis of Drosophila melanogaster defense against Beauveria bassiana explored through evolve and resequence and quantitative trait locus mapping

Many of the molecular mechanisms for antifungal immunity in Drosophila melanogaster have been defined, but relatively little is known about the genetic basis for variation in antifungal immunity in natural populations. Using two population genetic approaches, Quantitative Trait Locus (QTL) Mapping and Evolve and Resequence (E&R), we explored the genetics underlying D. melanogaster immune defense against infection with the fungus Beauveria bassiana. Immune defense was highly variable both in the recombinant inbred lines from the Drosophila Synthetic Population Resource used for our QTL Mapping and in the synthetic outbred populations used in our E&R study. Survivorship of infection improved dramatically over just 10 generations in the E&R study, and continued to increase for an additional 9 generations, revealing a trade-off with uninfected longevity. Populations selected for increased defense against B. bassiana evolved cross resistance to a second, distinct B. bassiana strain but not to bacterial pathogens. The QTL mapping study revealed that sexual dimorphism in defense depends on host genotype, and the E&R study indicated that dimorphism also depends on the specific pathogen to which the host is exposed. Both the QTL Mapping and E&R experiments generated lists of potentially causal candidate genes, although these lists were non-overlapping.

genomics↗

bioRxiv2021

Host-pathogen Immune Feedbacks Can Explain Widely Divergent Outcomes from Similar Infections

A longstanding question in infection biology is why two very similar individuals, with very similar pathogen exposures, may have very different outcomes. Recent experiments have found that even isogenic Drosophila melanogaster hosts, given identical inoculations of some bacterial pathogens at suitable doses, can experience very similar initial bacteria proliferation but then diverge to either a lethal infection or a sustained chronic infection with much lower pathogen load. We hypothesized that divergent infection outcomes are a natural result of mutual negative feedbacks between pathogens and the host immune response. Here we test this hypothesis in silico by constructing process-based dynamic models for bacterial population growth, host immune induction, and the feedbacks between them, based on common mechanisms of immune system response. Mathematical analysis of a minimal conceptual model confirms our qualitative hypothesis that mutual negative feedbacks can magnify small differences among hosts into life-or-death differences in outcome. However, explaining observed features of chronic infections requires an extension of the model to include induced pathogen modifications that shield themselves from host immune responses at the cost of reduced proliferation rate. Our analysis thus generates new, testable predictions about the mechanisms underlying bimodal infection outcomes.

systems biology↗

bioRxiv2017

Rapid seasonal evolution in innate immunity of wild Drosophila melanogaster

Understanding the rate of evolutionary change and the genetic architecture that facilitates rapid adaptation is a current challenge in evolutionary biology. Comparative studies show that genes with immune function are among the most rapidly evolving genes in a range of taxa. Here, we use immune defense in natural populations of D. melanogaster to understand the rate of evolution in natural populations and the genetics underlying the rapid change. We probed the immune system using the natural pathogens Enterococcus faecalis and Providencia rettgeri to measure post-infection survival and bacterial load of wild D. melanogaster populations collected across seasonal time along a latitudinal transect on the eastern North America (Massachusetts, Pennsylvania, and Virginia). There are pronounced and repeatable changes in the immune response over approximately 10 generations between the spring and fall populations with a significant but less distinct difference among geographic locations. Genes with known immune function are not enriched among alleles that cycle with seasonal time, but the immune function of a subset of seasonally cycling alleles in immune genes was tested using reconstructed outbred populations. We find that flies containing seasonal alleles in Thioester-containing protein 3 (Tep3) have different functional responses to infection and that epistatic interactions among seasonal Tep3 and Drosomycin-like 6 (Dro6) alleles produce the immune phenotypes observed in natural populations. This rapid, cyclic response to seasonal environmental pressure broadens our understanding of the complex ecological and genetic interactions determining the evolution of immune defense in natural populations.

evolutionary biology↗