Dr Mario Recker
Associate Professor in Applied Mathematics
Telephone: 01326 259329Royal Society University Research Fellow
Many pathogens utilise antigenic diversity as a means to avoid detection and clearance by the host’s immune system, which enables them to remain within the host for prolonged periods of time and/or allows the pathogen to establish infections in previously exposed individuals. My research focuses on the multifaceted epidemiology of antigenically diverse pathogens, such as Plasmodium falciparum, dengue or Influenza, which often comprises oscillatory population dynamics across time and space. With the help of mathematical models and in close collaboration with field and laboratory scientists I investigate the evolutionary epidemiology of these pathogens, focusing on host-pathogen interactions at multiple ecological scales that link within-host processes of gene expression and immune selection to between-host epidemiological patterns of infection and disease.
The causative agent of severe malaria in humans, Plasmodium falciparum, employs a sophisticated immune evasion startegy, called antigenic variation, to circumvent the host's immune pressure and maintain long lasting infections. Central to this process is the var multi-gene family, which encode the cell-surface antigens PfEMP1. Mutually exclusive switching between ~60 members of these highly polymorphic genes ensures that only a small fraction of the whole antigenic reperoire is exposed to the immune system at a time. PfEMP1 are also involved in malaria virulence. They mediate the attachement of parasitised red blood cells to host tissues, which can then lead to parasite sequestration and obstruction of blood flow in vital organs, such as the brain or placenta. Different PfEMP1 variants adhere to different host tissues, and antigenic switches between var genes can therefore also lead to a phenotypic change during the course of an infection. The involvement of var genes and var gene switching is therefore central for our understanding of the infection dynamics, pathology and epidemiology of P. falciparum malaria.
I am particularly interested in the underlying patterns of var gene switching, and how these relate to observed gene expression pattern in individuals growing up in malaria endemic regions. E.g. we have shown that antigenic switching is a highly non-random process in which different genes have different, hard-wired switch characteristics in terms of the rates at which they are activated or silenced [1,2]. Furthermore, we could show the resulting switch hierarchy is inherently linked to gene recombination and therefore the generation of further antigenic diversity in these parasites. My work currently focuses on developing multi-scale, mathematical frameworks that integrate molecular genetic processes with the dynamics of within-host infections and between-host epidemiologies.
In less than six decades dengue has emerged from South East Asia to become the most widespread arbovirus affecting human populations. A recent dramatic increase in epidemic dengue fever has mainly been attributed to factors such as vector expansion and ongoing ecological, climate and socio-demographic changes. The lack of antivirals or vaccines and the current failure to control the pathogen in endemic regions and to prevent globalized distribution of the vector-species and viral variants underlines the urgency for reassessment of previous research methods, hypothesis and empirical observations.
Previous modelling approaches have mostly focused on the impact of immunological competition between dengue’s four serotypes (DENV1-4), which can generate a frequency-dependent mechanism that partially explains dengue's temporal epidemiological patterns. We have developed a spatially explicit, individual-based model to investigate the effects of demographic and ecological stochasticities. Our model demostrated that amplification of natural stochastic differences in disease transmission can give rise to persistent oscillations comprising semi-regular epidemic outbreaks and sequential serotype dominance that are characteristic of dengue's epidemiolgical dynamics. Work is currently under way to address such questions as if and how host ecological and demographic heterogeneities are shaping the viral evolution of dengue, and how different population structures (small-world, lattice, scale-free, etc) can affect the spatial epidemiology of dengue, including persistence and synchrony?
Flasche S, Jit M, Rodríguez-Barraquer I, Coudeville L, Recker M*, et al. (2016). The long term safety, public health impact, and cost effectiveness of routine vaccination with a recombinant, live-attenuated dengue vaccine (Dengvaxia): a model comparison study. PLoS Medicine, 13(11):e1002181
Laabei M, Uhlemann AC, Lowy FD, Austin ED, Yokoyama M, Ouadi K, Feil E, Thorpe HA, Williams B, Perkins M, Peacock SJ, Clarke SR, Dordel J, Holden M, Votintseva AA, Bowden R, Crook DW, Young BC, Wilson DJ, Recker M*, Massey RC (2015) Evolutionary Trade-Offs Underlie the Multi-faceted Virulence of Staphylococcus aureus. PLoS Biol, 13(9):e1002229
Laabei M*, Recker M*, Rudkin J, Sloan T, Williams P, Lewis K, Scowen L, Peacock S, van den Elsen J, Priest N, Feil E, Josefsson E, & Massey RC (2014). Predicting the virulence of MRSA from its genome sequence. Genome Res, 24: 839-849
Lourenço J, & Recker M (2013). Natural, persistent oscillations in a spatial multi-strain disease system with application to dengue. PLoS Comp Biol, 9(10): e1003308
Noble R, Christodoulou Z, Kyes S, Pinches R , Newbold CI, & Recker M (2013). The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria. eLife 2013;2:e01074
Buckee CO, & Recker M (2012). Evolution of the multi-domain structures of virulence genes in the human malaria parasite Plasmodium falciparum. PLoS Comp Biol, 8(4): e1002451
Recker M, Buckee CO, Serazin A, Kyes S, Pinches R, Christodoulou Z, Springer AL, Gupta S, Newbold CI (2011). Antigenic variation in Plasmodium falciparum malaria involves a highly structured switching pattern. PLoS Pathog, 7(3):e1001306
Recker M*, Pybus OG*, Nee S, & Gupta S (2007). The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types. Proc Natl Acad Sci U S A, 104(18):7711-6
Recker M, Nee S, Bull PC, Kinyanjui S, Marsh K, Newbold C, & Gupta S (2004). Transient cross-reactive immune responses can orchestrate antigenic variation in malaria. Nature, 429(6991):555-8