Navas A et al. (2007) Proc Natl Acad Sci U S A "Experimental validation of Haldane's hypothesis on the role of infection as an evolutionary force for Metazoans."

Cobas G, Ayala JA, Talavera M, Lopez JA, Navas A, Martinez JL

[Proc Natl Acad Sci U S A, 2007]

A common drawback in evolutionary science is the fact that the evolution of organisms occurs in geological timing, completely out of the time scale of laboratory experimental work. For this reason, some relevant hypotheses on evolution of Metazoans are based on correlations more than on experimental data obtained for testing the robustness of those hypotheses. In the current work, we implement an experimental methodology to analyze the role of infections as a driving force in the evolution of Metazoans (Haldane''s hypothesis). To that goal, we have used simple models of virulence with short reproduction times, large populations, and that are easily testable in the laboratory. Using the bacteriovirus nematode Caenorhabditis elegans as a model organism under evolution and their infection by the environmental opportunistic bacterial pathogen Pseudomonas aeruginosa as the selective force, we have demonstrated that bacterial infection selects an evolved nematode lineage resistant to infection, with changes in its respiration and capability of consuming novel food resources. Using an experimental approach, we show that infection is a selective force in the evolution of Metazoans as proposed earlier by Haldane.

Nava S et al. (2023) Proc Natl Acad Sci U S A "A cGAL-UAS bipartite expression toolkit for Caenorhabditis elegans sensory neurons."

Chen CH, Lee JS, Liu J, Tan M, Revanna JS, Wang H, Zhang M, Wan X, Perry B, Palma W, Gharib S, Oh JY, Sternberg PW, Nava S

[Proc Natl Acad Sci U S A, 2023]

Animals integrate sensory information from the environment and display various behaviors in response to external stimuli. In <i>Caenorhabditis elegans</i> hermaphrodites, 33 types of sensory neurons are responsible for chemosensation, olfaction, and mechanosensation. However, the functional roles of all sensory neurons have not been systematically studied due to the lack of facile genetic accessibility. A bipartite cGAL-UAS system has been previously developed to study tissue- or cell-specific functions in <i>C. elegans</i>. Here, we report a toolkit of new cGAL drivers that can facilitate the analysis of a vast majority of the 60 sensory neurons in <i>C. elegans</i> hermaphrodites. We generated 37 sensory neuronal cGAL drivers that drive cGAL expression by cell-specific regulatory sequences or intersection of two distinct regulatory regions with overlapping expression (split cGAL). Most cGAL-drivers exhibit expression in single types of cells. We also constructed 28 UAS effectors that allow expression of proteins to perturb or interrogate sensory neurons of choice. This cGAL-UAS sensory neuron toolkit provides a genetic platform to systematically study the functions of <i>C. elegans</i> sensory neurons.

Sanchez P et al. (2002) J Antimicrob Chemother "Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants."

Campanario E, Navas A, Ruiz-Diez B, Baquero F, Linares JF, Martinez JL, Sanchez P

[J Antimicrob Chemother, 2002]

Overproduction of multidrug resistance (MDR) efflux pumps is involved in the resistance to a wide range of compounds in bacteria. These determinants extrude antibiotics, but also bacterial metabolites like quorum-sensing signals. Non-regulated extrusion of bacterial metabolites might produce a metabolic burden, so that MDR-overproducing mutants could have a reduced fitness when compared with their parental strains. To test such a possibility, we have compared the behaviour of two MDR Pseudomonas aeruginosa in vitro selected mutants (nalB and nfxB) with their isogenic parental strain with respect to some properties with potential relevance for the survival in the environment and the virulence of this bacterial species. Overproduction of the MDR determinants MexABOprM (nalB mutant) and MexCDOprJ (nfxB mutant) decreased the survival in water, the production of phenazines and proteases, and the virulence (using a Caenorhabditis elegans model system) of the P. aeruginosa mutants. In contrast, the capability of forming biofilms was not impaired. The simple models tested in the present work can enable the analysis of the fitness of large numbers of antibiotic-resistant bacteria by using more realistic approaches than the in vitro competition assays currently used.

Ruiz-Diez B et al. (2003) J Theor Biol "Differential interactions within the Caenorhabditis elegans-Pseudomonas aeruginosa pathogenesis model."

Sanchez P, Baquero F, Ruiz-Diez B, Martinez JL, Navas A

[J Theor Biol, 2003]

A pathogenesis model based on the interaction between Caenorhabditis elegans and bacterial opportunistic pathogens has recently been developed. In the case of Pseudomonas aeruginosa, the model is based on three different modes of nematode killing (fast killing, slow killing and lethal paralysis) by virulent bacteria that has been incubated in different nutrient media. Using parametric statistics and Probit analysis, we test the reliability of the three different killing systems with respect to bacterial virulence. To accomplish this, we use three P. aeruginosa strains, each with a different level of virulence and one strain of non-virulent Escherichia coli. Probit function proved to be effective in quantifying the virulence of P. aeruginosa. The results of the killing curve analysis using the Probit function demonstrates that the slow-killing test is the most reliable method for quantifying virulence using the C elegans model of bacterial pathogenesis. Although the greatest virulence differences are observed after long periods of incubation, the Probit analysis clearly shows that the death kinetics of C elegans depend on the first hours of nematode/bacteria interaction. In contrast, fast killing seems to be non-specific, at least under our experimental conditions, since the killing rates of virulent P. aeruginosa and non-virulent E coli strains were indistinguishable.

Sanchez-Diener I et al. (2019) Clin Microbiol Infect "Weighting the impact of virulence on the outcome of Pseudomonas aeruginosa bloodstream infections."

Calbo E, Pena C, Almirante B, Tubau F, Navas A, Aguilar M, Granados A, Oliver A, Cabot G, Sanchez-Diener I, Rodriguez-Lopez F, Zamorano L, Ocampo-Sosa A, Bano JR, Martinez-Martinez L, Gomez-Zorrilla S

[Clin Microbiol Infect, 2019]

OBJECTIVES: We assessed the association between the lethality of Pseudomonas aeruginosa in a Caenorhabditis elegans model and outcomes of P. aeruginosa bloodstream infections. METHODS: A total of 593 P. aeruginosa bloodstream isolates recovered from a prospective Spanish multicenter study were analyzed. Clinical variables, susceptibility profiles and Type III Secretion System (TTSS) genotypes (exoU/exoS genes) were available from previous studies. A C. elegans virulence score (CEVS) was used, classifying the isolates into high (CEVS 4-5), intermediate (CEVS 3) and low-virulence (CEVS 1-2). The main outcome analyzed was 30-days mortality. RESULTS: Up to 75% (446/593) of the isolates showed a high-virulence phenotype, and 17% (101/593) a low-virulence one. No association between virulence phenotype and the main outcome variable (30-days) mortality was evidenced (29/101(28.7%) vs 127/446 (28.5%), p=1. However, an inverse association between C. elegans virulence and MDR and XDR profiles was documented (O.R=0.655 (0.571-0.751)) and O.R=0.523 (0.436-0.627), p0.001, respectively), whereas the exoU genotype was significantly more frequent among isolates showing high-virulence (10/101 (9.9%)vs 112/446 (25.1%), p0.001). Moreover, although significance was not reached, strains showing a high-virulence phenotype tended to be associated with community acquired infections (1/101 (1%) vs 25/446 (5.6%), p=0.065), whereas low-virulence phenotypes tended to be associated with a higher illness severity [such as higher median Pitt Score (2(1-4) vs 1(0-3), p=0.036) or initial multiorgan disfuction (17/101(16.8%) vs 41/446 (9.2%), p=0.024)], with some underlying conditions (such as chronic renal failure 24/101 (23.8%)vs 59/446 (13.2%), p=0.013) and with the respiratory source of infections (17/101 (16.8%) vs 45/446 (10.1%), p=0.058). CONCLUSIONS: Our results indicate that P. aeruginosa virulence phenotype in C. elegans model correlates with virulence genotype (TTSS) and resistance profile, but it is a poor prognostic marker of mortality in bloodstream infections.

Sanchez-Diener I et al. (2017) Antimicrob Agents Chemother "Interplay among resistance profiles, high-risk clones and virulence in the Caenorhabditis elegans Pseudomonas aeruginosa infection model."

Pena C, Lopez-Causape C, Cabot G, Martinez-Martinez L, Oliver A, Zamorano L, Sanchez-Diener I, Canton R, Mulet X, Arcos SC, Domenech-Sanchez A, Del Campo R, Navas A

[Antimicrob Agents Chemother, 2017]

The increasing prevalence of nosocomial infections produced by multidrug-resistant (MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa is frequently linked to widespread international strains designated as high-risk clones. In this work we attempted to decipher the interplay between resistance profiles, high-risk clones and virulence, testing a large (n=140) collection of well characterized P. aeruginosa isolates from different sources (bloodstream infections, nosocomial outbreaks, cystic fibrosis and environment) in a Caenorhabditis elegans infection model. Consistently with previous data, we documented a clear inverse correlation between antimicrobial resistance and virulence in the C. elegans model. Indeed, lowest virulence was linked to XDR profiles, which were typically linked to defined high-risk clones. However, virulence varied broadly depending on the involved high-risk clone; it was high for ST111 and ST235 but very low for ST175. The highest virulence of ST235 could be attributed to its ExoU+ Type III secretion system (TTSS) genotype, found to be linked with higher virulence in our C. elegans model. Other markers, such as motility or pigment production were not essential for virulence in the C. elegans model, but seemed to be related with the higher values of the statistical normalized data. Opposite to ST235, the ST175 high-risk clone, widespread in Spain and France, seems to be associated with a particularly low virulence in the C. elegans model. Moreover, the previously described G154R AmpR mutation, prevalent in ST175, was found to contribute to the reduced virulence, although it was not the only factor involved. Altogether, our results provide a major step forward for understanding the interplay between P. aeruginosa resistance profiles, high-risk clones and virulence.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.