Adaptive immunity selects against malaria infection blocking mutations

The mutation responsible for Duffy negativity, which impedes Plasmodium vivax infection, has reached high frequencies in certain human populations. Conversely, mutations capable of blocking the more lethal P. falciparum have not succeeded in malarious zones. Here we present an evolutionary-epidemiological model of malaria which demonstrates that if adaptive immunity against the most virulent effects of malaria is gained rapidly by the host, mutations which prevent infection per se are unlikely to succeed. Our results (i) explain the rarity of strain-transcending P. falciparum infection blocking adaptations in humans; (ii) make the surprising prediction that mutations which block P. falciparum infection are most likely to be found in populations experiencing low or infrequent malaria transmission, and (iii) predict that immunity against some of the virulent effects of P. vivax malaria may be built up over the course of many infections

Recherche des serotypes d’Escherichia coli de la gastro-entérite infantile dans le lait, les produits laitiers et les ovoproduits

Viale Rigo S., Gandon Y. Recherche des sérotypes d’Escherichia coli de la gastro-entérité infantile dans le lait, les produits laitiers et les ovoproduits. In: Bulletin de l'Académie Vétérinaire de France tome 114 n°6, 1961. pp. 223-225

Utility of enhanced CT for patients with suspected uncomplicated renal colic and no acute findings on non-enhanced CT

AIM: To evaluate the utility of contrast-enhanced computed tomography (CECT) for patients with suspected uncomplicated renal colic (URC) and no abnormalities on non-enhanced computed tomography (NECT). MATERIALS AND METHODS: The hospital institutional review board and ethics committee approved this retrospective study with a waiver of informed consent. Between January 2016 and April 2017, all consecutive adult patients who consulted at the adult Emergency Department (ED) with suspected URC and who had undergone both NECT and CECT were included retrospectively. The primary endpoint was prevalence of CECT-only diagnosis without acute findings on NECT. The risk factors for an acute finding were identified by logistic regression analysis. RESULTS: Among 126 patients with suspected URC, 12 were excluded. Among the 76 patients with no acute findings on NECT, CECT led to find acute lesions in 14/76 (18%) cases, but only 2/76 (3%) resulted in a change of management. Predictive factors of abnormal finding on CECT were: low renal clearance and high leukocyte count with OR 0.96 (95% confidence interval [CI]: 0.93-0.99), p=0.0189 and OR 5.79 (95% CI: 1.55-21.64), p=0.0091, respectively. CONCLUSIONS: In most cases, NECT is sufficient for screening patients with suspected URC. If leucocytosis and low renal function are present, stronger consideration may be given to CECT

Variability in the durability of CRISPR-Cas immunity

This is the author accepted manuscript. The final version is available from Royal Society via the DOI in this record.The durability of host resistance is challenged by the ability of pathogens to escape the defence of their hosts. Understanding the variability in the durability of host resistance is of paramount importance for designing more effective control strategies against infectious diseases. Here, we study the durability of various clustered regularly interspaced short palindromic repeats-Cas (CRISPR-Cas) alleles of the bacteria Streptococcus thermophilus against lytic phages. We found substantial variability in durability among different resistant bacteria. Since the escape of the phage is driven by a mutation in the phage sequence targeted by CRISPR-Cas, we explored the fitness costs associated with these escape mutations. We found that, on average, escape mutations decrease the fitness of the phage. Yet, the magnitude of this fitness cost does not predict the durability of CRISPR-Cas immunity. We contend that this variability in the durability of resistance may be because of variations in phage mutation rate or in the proportion of lethal mutations across the phage genome. These results have important implications on the coevolutionary dynamics between bacteria and phages and for the optimal deployment of resistance strategies against pathogens and pests. Understanding the durability of CRISPR-Cas immunity may also help develop more effective gene-drive strategies based on CRISPR-Cas9 technology. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.Natural Environment Research Council (NERC)Biotechnology & Biological Sciences Research Council (BBSRC)European CommissionEuropean Molecular Biology Organization (EMBO)Leverhulme TrustNatural Sciences and Engineering Research Council of Canad

Evolutionary emergence of infectious diseases in heterogeneous host populations

This is the final version. Available from Public Library of Science via the DOI in this record.The emergence and re-emergence of pathogens remains a major public health concern. Unfortunately, when and where pathogens will (re-)emerge is notoriously difficult to predict, as the erratic nature of those events is reinforced by the stochastic nature of pathogen evolution during the early phase of an epidemic. For instance, mutations allowing pathogens to escape host resistance may boost pathogen spread and promote emergence. Yet, the ecological factors that govern such evolutionary emergence remain elusive because of the lack of ecological realism of current theoretical frameworks and the difficulty of experimentally testing their predictions. Here, we develop a theoretical model to explore the effects of the heterogeneity of the host population on the probability of pathogen emergence, with or without pathogen evolution. We show that evolutionary emergence and the spread of escape mutations in the pathogen population is more likely to occur when the host population contains an intermediate proportion of resistant hosts. We also show that the probability of pathogen emergence rapidly declines with the diversity of resistance in the host population. Experimental tests using lytic bacteriophages infecting their bacterial hosts containing Clustered Regularly Interspaced Short Palindromic Repeat and CRISPR-associated (CRISPR-Cas) immune defenses confirm these theoretical predictions. These results suggest effective strategies for cross-species spillover and for the management of emerging infectious diseases.Natural Environment Research Council (NERC)Wellcome TrustBiotechnology & Biological Sciences Research Council (BBSRC)European CommissionMarie Curie ActionsNatural Sciences and Engineering Research Council of CanadaLeverhulme Trus

Anti-CRISPR Phages Cooperate to Overcome CRISPR-Cas Immunity

This is the final version of the article. Available from Elsevier via the DOI in this record.Some phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here, we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As a consequence, Acr-phages often need to cooperate in order to overcome CRISPR resistance, with a first phage blocking the host CRISPR-Cas immune system to allow a second Acr-phage to successfully replicate. This cooperation leads to epidemiological tipping points in which the initial density of Acr-phage tips the balance from phage extinction to a phage epidemic. Furthermore, both higher levels of CRISPR-Cas immunity and weaker Acr activities shift the tipping points toward higher initial phage densities. Collectively, these data help elucidate how interactions between phage-encoded immune suppressors and the CRISPR systems they target shape bacteria-phage population dynamics.M.L. was supported by funding from the Wellcome Trust (https://wellcome.ac.uk) (109776/Z/15/Z), which was awarded to E.R.W. E.R.W. further acknowledges the Natural Environment Research Council (https://nerc.ukri.org) (NE/M018350/1), the BBSRC (BB/N017412/1), and the European Research Council (https://erc.europa.eu) (ERC-STG-2016-714478 - EVOIMMECH) for funding. S.v.H. acknowledges funding from the People Programme (Marie Curie Actions; https://ec.europa.eu/research/mariecurieactions/) of the European Union’s Horizon 2020 (REA grant agreement no. 660039) and from the BBSRC (BB/R010781/1). S.G. acknowledges funding (Visiting Professorship) from the Leverhulme Trust. A.B. acknowledges funding from the Royal Society. The authors thank Olivier Fradet for experimental contributions and Adair Borges and Joe Bondy-Denomy (UCSF) for providing DMS3mvir-AcrIF4 and phage JBD26

Exploitation of the cooperative behaviors of anti-CRISPR phages

This is the final version. Available on open access from Elsevier via the DOI in this recordBacteriophages encoding anti-CRISPR proteins (Acrs) must cooperate to overcome phage resistance mediated by the bacterial immune system CRISPR-Cas, where the first phage blocks CRISPR-Cas immunity in order to allow a second Acr phage to successfully replicate. However, in nature, bacteria are frequently not pre-immunized, and phage populations are often not clonal, exhibiting variations in Acr presence and strength. We explored how interactions between Acr phages and initially sensitive bacteria evolve, both in the presence and absence of competing phages lacking Acrs. We find that Acr phages benefit "Acr-negative" phages by limiting the evolution of CRISPR-based resistance and helping Acr-negative phages to replicate on resistant host sub-populations. These benefits depend on the strength of CRISPR-Cas inhibitors and result in strong Acrs providing smaller fitness advantages than weaker ones when Acr phages compete with Acr-negative phages. These results indicate that different Acr types shape the evolutionary dynamics and social interactions of phage populations in natural communities.European Commissio

The ecology and evolution of microbial CRISPR-Cas adaptive immune systems

This is the author accepted manuscript. The final version is available from the Royal Society via the DOI in this record Data accessibility: This article has no additional data.Cystic Fibrosis Foundatio

doi:10.1016/j.vaccine.2008.04.012

a b s t r a c t One theory of why some pathogens are virulent (i.e., they damage their host) is that they need to extract resources from their host in order to compete for transmission to new hosts, and this resource extraction can damage the host. Here we describe our studies in malaria that test and support this idea. We go on to show that host immunity can exacerbate selection for virulence and therefore that vaccines that reduce pathogen replication may select for more virulent pathogens, eroding the benefits of vaccination and putting the unvaccinated at greater risk. We suggest that in disease contexts where wild-type parasites can be transmitted through vaccinated hosts, evolutionary outcomes need to be considered. © 2008 Elsevier Ltd. All rights reserved. An evolutionary hypothesis for pathogen virulence Why are pathogens virulent? 1 Why would they run the risk of killing their host when, in doing so, they lose their ongoing source of transmission to new hosts? Some evolutionary biologists believe that the answer to this question will make it possible to design vaccines and other control measures that, in the event of eradication being impossible, drive the pathogen towards lower virulence One answer to this question is that virulence is a mistake by the pathogen-an ultimately maladaptative outcome that occasionally happens when a pathogen accidentally ends up in an abnormal host environment, or when a virulent mutant has a transient competitive advantage within a host ('short-sighted, or dead-end evolution') E-mail address: [email protected] (M.J. Mackinnon). 1 Throughout this paper, we strictly define virulence as the fitness cost that the parasite causes the host. This may be through mortality, or morbidity-related reduction in fertility or fecundity. We sometimes use morbidity as a surrogate measure of virulence. Of all the explanations for virulence, the trade-off hypothesis has received most attention and a large body of theory has been derived from it. Yet it is poorly supported by data. Here we describe our studies in malaria parasites, the causative agents of a disease of global importance, in which we have comprehensively explored the trade-off hypothesis. We begin by summarising our experimental tests in a laboratory mouse-malaria system of the assumptions underlying the trade-off theory. We then ask whether the rodent data are relevant to malaria parasites in their human setting. Next, we use the trade-off theory to predict what the impact might be on the evolution of the pathogen's virulence if malaria vaccines went into widespread use. Finally, we summarise an experimental evolution study to test our prediction that enhanced immunity would select for more virulent parasites. Together, this work has led us to a deeper understanding of why malaria still kills its host despite millenia of coevolution, and what might happen when disease control campaigns change the level of population immunity, e.g., enhance it using vaccines, or reduce it using bednets and vector control. The trade-off hypothesis and its assumptions Under the trade-off hypothesis, it is assumed that there are both fitness benefits and costs associated with virulence. The cost is assumed to be host death because, for most pathogens, transmission stops when the host dies. The benefits associated with virulence are assumed to be production of more transmission forms per unit time, and/or increased persistence in a live host. However, the benefits of higher transmissibility and persistence only accrue 0264-410X/$ -see front matte