Imperial College London

DrKatrinaLythgoe

Faculty of MedicineSchool of Public Health

Honorary Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3820k.lythgoe CV

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

24 results found

Pike VL, Lythgoe KA, King KC, 2019, On the diverse and opposing effects of nutrition on pathogen virulence., Proc Biol Sci, Vol: 286

Climate change and anthropogenic activity are currently driving large changes in nutritional availability across ecosystems, with consequences for infectious disease. An increase in host nutrition could lead to more resources for hosts to expend on the immune system or for pathogens to exploit. In this paper, we report a meta-analysis of studies on host-pathogen systems across the tree of life, to examine the impact of host nutritional quality and quantity on pathogen virulence. We did not find broad support across studies for a one-way effect of nutrient availability on pathogen virulence. We thus discuss a hypothesis that there is a balance between the effect of host nutrition on the immune system and on pathogen resources, with the pivot point of the balance differing for vertebrate and invertebrate hosts. Our results suggest that variation in nutrition, caused by natural or anthropogenic factors, can have diverse effects on infectious disease outcomes across species.

Journal article

Raghwani J, Wu C-H, Ho CKY, De Jong M, Molenkamp R, Schinkel J, Pybus OG, Lythgoe KAet al., 2019, High-Resolution Evolutionary Analysis of Within-Host Hepatitis C Virus Infection., J Infect Dis, Vol: 219, Pages: 1722-1729

BACKGROUND: Despite recent breakthroughs in treatment of hepatitis C virus (HCV) infection, we have limited understanding of how virus diversity generated within individuals impacts the evolution and spread of HCV variants at the population scale. Addressing this gap is important for identifying the main sources of disease transmission and evaluating the risk of drug-resistance mutations emerging and disseminating in a population. METHODS: We have undertaken a high-resolution analysis of HCV within-host evolution from 4 individuals coinfected with human immunodeficiency virus 1 (HIV-1). We used long-read, deep-sequenced data of full-length HCV envelope glycoprotein, longitudinally sampled from acute to chronic HCV infection to investigate the underlying viral population and evolutionary dynamics. RESULTS: We found statistical support for population structure maintaining the within-host HCV genetic diversity in 3 out of 4 individuals. We also report the first population genetic estimate of the within-host recombination rate for HCV (0.28 × 10-7 recombination/site/year), which is considerably lower than that estimated for HIV-1 and the overall nucleotide substitution rate estimated during HCV infection. CONCLUSIONS: Our findings indicate that population structure and strong genetic linkage shapes within-host HCV evolutionary dynamics. These results will guide the future investigation of potential HCV drug resistance adaptation during infection, and at the population scale.

Journal article

Thompson RN, Wymant C, Spriggs RA, Raghwani J, Fraser C, Lythgoe KAet al., 2019, Link between the numbers of particles and variants founding new HIV-1 infections depends on the timing of transmission, Virus Evolution, Vol: 5, ISSN: 2057-1577

Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral population within the donor at the time of transmission is also important. To support this argument, we developed a probabilistic model describing HIV-1 transmission in an untreated population, and parameterised the model using both within-host next generation sequencing data and population-level epidemiological data on heterosexual transmission. The most basic HIV-1 transmission models cannot explain simultaneously the low probability of transmission and the non-negligible proportion of infections founded by multiple variants. In our model, transmission can only occur when environmental conditions are appropriate (e.g. abrasions are present in the genital tract of the potential recipient), allowing these observations to be reconciled. As well as reproducing features of transmission in real populations, our model demonstrates that, contrary to expectation, there is not a simple link between the number of viral variants and the number of viral particles founding each new infection. These quantities depend on the timing of transmission, and infections can be founded with small numbers of variants yet large numbers of particles. Including selection, or a bias towards early transmission (e.g. due to treatment), acts to enhance this conclusion. In addition, we find that infections initiated by multiple variants are most likely to have derived from donors with intermediate set-point viral loads, and not from individuals with high set-point viral loads as might be expected. We therefore emphasise the importance of considering viral diversity in donors, and the timings of transmissions, when trying to discern the complex factors governing

Journal article

Abdullah N, Kelly JT, Graham SC, Birch J, Goncalves-Carneiro D, Mitchell T, Thompson RN, Lythgoe KA, Logan N, Hosie MJ, Bavro VN, Willett BJ, Heaton MP, Bailey Det al., 2018, Structure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic Potential, JOURNAL OF VIROLOGY, Vol: 92, ISSN: 0022-538X

Journal article

Thompson R, Wymant C, Spriggs R, Raghwani J, Fraser C, Lythgoe Ket al., 2018, Link between the numbers of particles and variants founding new HIV-1 infections depends on the timing of transmission

<jats:p>Understanding which HIV-1 variants are most likely to be transmitted is important for vaccine design and predicting virus evolution. Since most infections are founded by single variants, it has been suggested that selection at transmission has a key role in governing which variants are transmitted. We show that the composition of the viral population within the donor at the time of transmission is also important. To support this argument, we developed a probabilistic model describing HIV-1 transmission in an untreated population, and parameterised the model using both within-host next generation sequencing data and population-level epidemiological data on heterosexual transmission. The most basic HIV-1 transmission models cannot explain simultaneously the low probability of transmission and the non-negligible proportion of infections founded by multiple variants. In our model, transmission can only occur when environmental conditions are appropriate (e.g. abrasions are present in the genital tract of the potential recipient), allowing these observations to be reconciled. As well as reproducing features of transmission in real populations, our model demonstrates that, contrary to expectation, there is not a simple link between the number of viral variants and the number of viral particles founding each new infection. These quantities depend on the timing of transmission, and infections can be founded with small numbers of variants yet large numbers of particles. Including selection, or a bias towards early transmission (e.g. due to treatment) acts to enhance this conclusion. In addition, we find that infections initiated by multiple variants are most likely to have derived from donors with intermediate set-point viral loads, and not from individuals with high set-point viral loads as might be expected. We therefore emphasise the importance of considering viral diversity in donors, and the timings of transmissions, when trying to discern the complex fact

Journal article

Raghwani J, Wu C-H, Ho CKY, de Jong M, Molenkamp R, Schinkel J, Pybus OG, Lythgoe KAet al., 2018, High resolution evolutionary analysis of within-host hepatitis C virus infection

<jats:p>Despite the breakthroughs in the treatment of HCV infection in recent years, we have a limited understanding of how virus diversity generated within individuals impacts the evolution and spread of HCV variants at the population scale. Addressing this gap will be important for building models for molecular epidemiology, which can identify main sources of disease transmission and evaluate the risks of drug-resistance mutations emerging and disseminating in a population. Here, we have undertaken a high-resolution analysis of HCV within-host evolution from four individuals co-infected with HIV. Specifically, we used long-read, deep-sequenced data of the full-length HCV envelope glycoprotein, longitudinally sampled from acute to chronic HCV infection to investigate the underlying viral evolutionary dynamics. In three individuals we found strong statistical support for population structure maintaining within-host HCV genetic diversity. Furthermore, we found significant variation in rates of molecular evolution among different regions of the HCV envelope region, both within and between individuals. Lastly, we report the first estimate of the within-host population genetic rate of recombination for HCV (0.28 x 10-7 recombinations per site per day; interquartile range: 0.13-1.05 x 10-7), which is two orders of magnitude lower than that estimated for HIV-1, and four orders of magnitude lower than the nucleotide substitution rate of the HCV envelope gene. Together, these observations indicate that population structure and strong genetic linkage shapes within-host HCV evolutionary dynamics. These results will guide the future investigation of potential HCV drug resistance adaptation during infection, and at the population scale.</jats:p>

Journal article

Lumley SF, McNaughton AL, Klenerman P, Lythgoe KA, Matthews PCet al., 2018, Hepatitis B virus Adaptation to the CD8+T Cell Response: Consequences for Host and Pathogen, FRONTIERS IN IMMUNOLOGY, Vol: 9, ISSN: 1664-3224

Journal article

Raghwani J, Redd AD, Longosz AF, Wu C-H, Serwadda D, Martens C, Kagaayi J, Sewankambo N, Porcella SF, Grabowski MK, Quinn TC, Eller MA, Eller LA, Wabwire-Mangen F, Robb ML, Fraser C, Lythgoe KAet al., 2018, Evolution of HIV-1 within untreated individuals and at the population scale in Uganda, PLOS PATHOGENS, Vol: 14, ISSN: 1553-7366

Journal article

Lythgoe KA, Gardner A, Pybus OG, Grove Jet al., 2017, Short-sighted virus evolution and a germline hypothesis for chronic viral infections., Trends in Microbiology, Vol: 25, Pages: 336-348, ISSN: 0966-842X

With extremely short generation times and high mutability, many viruses can rapidly evolve and adapt to changing environments. This ability is generally beneficial to viruses as it allows them to evade host immune responses, evolve new behaviours, and exploit ecological niches. However, natural selection typically generates adaptation in response to the immediate selection pressures that a virus experiences in its current host. Consequently, we argue that some viruses, particularly those characterised by long durations of infection and ongoing replication, may be susceptible to short-sighted evolution, whereby a virus' adaptation to its current host will be detrimental to its onward transmission within the host population. Here we outline the concept of short-sighted viral evolution and provide examples of how it may negatively impact viral transmission among hosts. We also propose that viruses that are vulnerable to short-sighted evolution may exhibit strategies that minimise its effects. We speculate on the various mechanisms by which this may be achieved, including viral life history strategies that result in low rates of within-host evolution, or the establishment of a 'germline' lineage of viruses that avoids short-sighted evolution. These concepts provide a new perspective on the way in which some viruses have been able to establish and maintain global pandemics.

Journal article

Doekes HM, Fraser C, Lythgoe KA, 2017, Effect of the latent reservoir on the evolution of HIV at the within- and between-host Levels, PLoS Computational Biology, Vol: 13, Pages: 1-27, ISSN: 1553-734X

The existence of long-lived reservoirs of latently infected CD4+ T cells is the major barrier to curing HIV, and has been extensively studied in this light. However, the effect of these reservoirs on the evolutionary dynamics of the virus has received little attention. Here, we present a within-host quasispecies model that incorporates a long-lived reservoir, which we then nest into an epidemiological model of HIV dynamics. For biologically plausible parameter values, we find that the presence of a latent reservoir can severely delay evolutionary dynamics within a single host, with longer delays associated with larger relative reservoir sizes and/or homeostatic proliferation of cells within the reservoir. These delays can fundamentally change the dynamics of the virus at the epidemiological scale. In particular, the delay in within-host evolutionary dynamics can be sufficient for the virus to evolve intermediate viral loads consistent with maximising transmission, as is observed, and not the very high viral loads that previous models have predicted, an effect that can be further enhanced if viruses similar to those that initiate infection are preferentially transmitted. These results depend strongly on within-host characteristics such as the relative reservoir size, with the evolution of intermediate viral loads observed only when the within-host dynamics are sufficiently delayed. In conclusion, we argue that the latent reservoir has important, and hitherto under-appreciated, roles in both within- and between-host viral evolution.

Journal article

Blanquart F, Grabowski MK, Herbeck J, Nalugoda F, Serwadda D, Eller MA, Robb ML, Gray R, Kigozi G, Laeyendecker O, Lythgoe KA, Nakigozi G, Quinn TC, Reynolds SJ, Wawer MJ, Fraser Cet al., 2016, A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda, eLife, Vol: 5, ISSN: 2050-084X

Evolutionary theory hypothesizes that intermediate virulence maximizes pathogenfitness as a result of a trade-off between virulence and transmission, but empirical evidenceremains scarce. We bridge this gap using data from a large and long-standing HIV-1 prospectivecohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data toderive evolutionary predictions based on analysis and detailed individual-based simulations. Werobustly predict stabilising selection towards a low level of virulence, and rapid attenuation of thevirus. Accordingly, set-point viral load, the most common measure of virulence, has declined in thelast 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with bothsubtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads shouldhave resulted in a 20% reduction in incidence, and a three years extension of untreatedasymptomatic infection, increasing opportunities for timely treatment of infected individuals.

Journal article

Lythgoe KA, Blanquart F, Pellis L, Fraser Cet al., 2016, Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics, PLOS Biology, Vol: 14, ISSN: 1545-7885

The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body's viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation.

Journal article

Fraser C, Lythgoe K, Leventhal GE, Shirreff G, Hollingsworth TD, Alizon S, Bonhoeffer Set al., 2014, Virulence and Pathogenesis of HIV-1 Infection: An Evolutionary Perspective, SCIENCE, Vol: 343, Pages: 1328-+, ISSN: 0036-8075

Journal article

van de Vijver DA, Nichols BE, Abbas UL, Boucher CA, Cambiano V, Eaton JW, Glaubius R, Lythgoe K, Mellors J, Phillips A, Sigaloff KC, Hallett TBet al., 2013, Pre-exposure prophylaxis (PrEP) will have a limited impact on the prevalence of HIV-1 drug resistance in sub-Saharan Africa: comparison of mathematical models, AIDS, Vol: 27, Pages: 2943-2951, ISSN: 0269-9370

BACKGROUND: Preexposure prophylaxis (PrEP) with tenofovir and emtricitabine can prevent new HIV-1 infections, but there is a concern that use of PrEP could increase HIV drug resistance resulting in loss of treatment options. We compared standardized outcomes from three independent mathematical models simulating the impact of PrEP on HIV transmission and drug resistance in sub-Saharan African countries.METHODS: All models assume that people using PrEP receive an HIV test every 3-6 months. The models vary in structure and parameter choices for PrEP coverage, effectiveness of PrEP (at different adherence levels) and the rate with which HIV drug resistance emerges and is transmitted.RESULTS: The models predict that the use of PrEP in conjunction with antiretroviral therapy will result in a lower prevalence of HIV than when only antiretroviral therapy is used. With or without PrEP, all models suggest that HIV drug resistance will increase over the next 20 years due to antiretroviral therapy. PrEP will increase the absolute prevalence of drug resistance in the total population by less than 0.5% and amongst infected individuals by at most 7%. Twenty years after the introduction of PrEP, the majority of drug-resistant infections is due to antiretroviral therapy (50-63% across models), whereas 40-50% will be due to transmission of drug resistance, and less than 4% to the use of PrEP.CONCLUSION: HIV drug resistance resulting from antiretroviral therapy is predicted to far exceed that resulting from PrEP. Concern over drug resistance should not be a reason to limit the use of PrEP.

Journal article

van de Vijver DAMC, Nichols BE, Abbas UL, Boucher CAB, Cambiano V, Eaton JW, Glaubius R, Lythgoe K, Mellors J, Phillips A, Sigaloff KC, Hallett TBet al., 2013, Preexposure prophylaxis will have a limited impact on HIV-1 drug resistance in sub-Saharan Africa: a comparison of mathematical models, AIDS, Vol: 27, Pages: 2943-2951, ISSN: 0269-9370

Journal article

Lythgoe KA, Pellis L, Fraser C, 2013, IS HIV SHORT-SIGHTED? INSIGHTS FROM A MULTISTRAIN NESTED MODEL, EVOLUTION, Vol: 67, Pages: 2769-2782, ISSN: 0014-3820

Journal article

Lythgoe KA, Fraser C, 2012, New insights into the evolutionary rate of HIV-1 at the within-host and epidemiological levels, PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 279, Pages: 3367-3375, ISSN: 0962-8452

Journal article

Lythgoe KA, Morrison LJ, Read AF, Barry JDet al., 2007, Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 104, Pages: 8095-8100, ISSN: 0027-8424

Journal article

Barry JD, Marcello L, Morrison LJ, Read AF, Lythgoe K, Jones N, Carrington M, Blandin G, Bohme U, Caler E, Hertz-Fowler C, Renauld H, El-Sayed N, Berriman Met al., 2005, What the genome sequence is revealing about trypanosome antigenic variation, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 33, Pages: 986-989, ISSN: 0300-5127

Journal article

Lythgoe KA, Chao L, 2003, Mechanisms of coexistence of a bacteria and a bacteriophage in a spatially homogeneous environment, ECOLOGY LETTERS, Vol: 6, Pages: 326-334, ISSN: 1461-023X

Journal article

Lythgoe KA, 2002, Effects of acquired immunity and mating strategy on the genetic structure of parasite populations, AMERICAN NATURALIST, Vol: 159, Pages: 519-529, ISSN: 0003-0147

Journal article

Lythgoe KA, 2000, The coevolution of parasites with host-acquired immunity and the evolution of sex, EVOLUTION, Vol: 54, Pages: 1142-1156, ISSN: 0014-3820

Journal article

Lythgoe KA, Read AF, 1998, Catching the Red Queen? The advice of the rose, TRENDS IN ECOLOGY & EVOLUTION, Vol: 13, Pages: 473-474, ISSN: 0169-5347

Journal article

Lythgoe KA, 1997, Consequences of gene flow in spatially structured populations, GENETICS RESEARCH, Vol: 69, Pages: 49-60, ISSN: 0016-6723

Journal article

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