Recent advances in the molecular epidemiology of clinical malaria

This is the final version of the article. Available from the publisher via the DOI in this record.Human malaria is a complex disease that can show a wide array of clinical outcomes, from asymptomatic carriage and chronic infection to acute disease presenting various life-threatening pathologies. The specific outcome of an infection is believed to be determined by a multifactorial interplay between the host and the parasite but with a general trend toward disease attenuation with increasing prior exposure. Therefore, the main burden of malaria in a population can be understood as a function of transmission intensity, which itself is intricately linked to the prevalence of infected hosts and mosquito vectors, the distribution of infection outcomes, and the parasite population diversity. Predicting the long-term impact of malaria intervention measures therefore requires an in-depth understanding of how the parasite causes disease, how this relates to previous exposures, and how different infection pathologies contribute to parasite transmission. Here, we provide a brief overview of recent advances in the molecular epidemiology of clinical malaria and how these might prove to be influential in our fight against this important disease.MR is supported by the Medical Research Council (grant MR/M003906/1)

Estimating internationally imported cases during the early COVID-19 pandemic

Early in the COVID-19 pandemic, predictions of international outbreaks were largely based on imported cases from Wuhan, China, potentially missing imports from other cities. We provide a method, combining daily COVID-19 prevalence and flight passenger volume, to estimate importations from 18 Chinese cities to 43 international destinations, including 26 in Africa. Global case importations from China in early January came primarily from Wuhan, but the inferred source shifted to other cities in mid-February, especially for importations to African destinations. We estimate that 10.4 (6.2 - 27.1) COVID-19 cases were imported to these African destinations, which exhibited marked variation in their magnitude and main sources of importation. We estimate that 90% of imported cases arrived between 17 January and 7 February, prior to the first case detections. Our results highlight the dynamic role of source locations, which can help focus surveillance and response efforts

Analysis of symmetries in models of multi-strain infections

In mathematical studies of the dynamics of multi-strain diseases caused by antigenically diverse pathogens, there is a substantial interest in analytical insights. Using the example of a generic model of multi-strain diseases with cross-immunity between strains, we show that a significant understanding of the stability of steady states and possible dynamical behaviours can be achieved when the symmetry of interactions between strains is taken into account. Techniques of equivariant bifurcation theory allow one to identify the type of possible symmetry-breaking Hopf bifurcation, as well as to classify different periodic solutions in terms of their spatial and temporal symmetries. The approach is also illustrated on other models of multi-strain diseases, where the same methodology provides a systematic understanding of bifurcation scenarios and periodic behaviours. The results of the analysis are quite generic, and have wider implications for understanding the dynamics of a large class of models of multi-strain diseases

The effects of symmetry on the dynamics of antigenic variation

In the studies of dynamics of pathogens and their interactions with a host immune system, an important role is played by the structure of antigenic variants associated with a pathogen. Using the example of a model of antigenic variation in malaria, we show how many of the observed dynamical regimes can be explained in terms of the symmetry of interactions between different antigenic variants. The results of this analysis are quite generic, and have wider implications for understanding the dynamics of immune escape of other parasites, as well as for the dynamics of multi-strain diseases.Comment: 21 pages, 4 figures; J. Math. Biol. (2012), Online Firs

The elusive meningococcal meningitis serogroup: a systematic review of serogroup B epidemiology

<p>Abstract</p> <p>Background</p> <p>Invasive meningococcal disease (IMD), is a widely distributed, complex human disease affecting all age categories. The causative agent, <it>Neisseria meningitidis</it>, is spread through aerosol respiratory droplets. 13 different serogroups have been identified, each with varying epidemiological features including prevalence, virulence, immunogenicity, geographical and temporal distribution. Although preventative measures are available for several of the serogroups, meningococcal disease caused by serogroup B is of particular interest due to the challenge it presents concerning vaccine development.</p> <p>Methods</p> <p>A systematic review of peer reviewed studies and reports, the collection of data from national and international health resources, along with the analysis of the Multi Locus Sequence Typing database was carried out aimed at collecting information concerning serogroup B IMD and the epidemiology attached to it.</p> <p>Results</p> <p>A continuous output of related and novel STs occurring worldwide in terms of the hypervirulent clonal complexes was observed both in published studies and the MLST database in this case using the eburst software, which highlights the genetically diverse nature of serogroup B strains.</p> <p>Conclusions</p> <p>With the recent dominance of serogroup B IMD seen in many countries, along with the presence of antibiotic resistance, vaccine development needs to target areas of the bacterium which tackle this widespread and heterogeneous aspect of meningococcal meningitis disease.</p

Serological Evidence of Discrete Spatial Clusters of Plasmodium falciparum Parasites

BACKGROUND: Malaria transmission may be considered to be homogenous with well-mixed parasite populations (as in the classic Ross/Macdonald models). Marked fine-scale heterogeneity of transmission has been observed in the field (i.e., over a few kilometres), but there are relatively few data on the degree of mixing. Since the Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) is highly polymorphic, the host's serological responses may be used to infer exposure to parasite sub-populations. METHODS AND FINDINGS: We measured the antibody responses to 46 individual PfEMP1 domains at four time points among 450 children in Kenya, and identified distinct spatial clusters of antibody responses to individual domains. 35 domains showed strongly significant sero-clusters at p = 0.001. Individuals within the high transmission hotspot showed the greatest diversity of anti-PfEMP1 responses. Individuals outside the hotspot had a less diverse range of responses, even if as individuals they were at relatively intense exposure. CONCLUSIONS: We infer that antigenically distinct sub-populations of parasites exist on a fine spatial scale in a study area of rural Kenya. Further studies should examine antigenic variation over longer periods of time and in different study areas

Structural Alterations in a Component of Cytochrome c Oxidase and Molecular Evolution of Pathogenic Neisseria in Humans

Three closely related bacterial species within the genus Neisseria are of importance to human disease and health. Neisseria meningitidis is a major cause of meningitis, while Neisseria gonorrhoeae is the agent of the sexually transmitted disease gonorrhea and Neisseria lactamica is a common, harmless commensal of children. Comparative genomics have yet to yield clear insights into which factors dictate the unique host-parasite relationships exhibited by each since, as a group, they display remarkable conservation at the levels of nucleotide sequence, gene content and synteny. Here, we discovered two rare alterations in the gene encoding the CcoP protein component of cytochrome cbb3 oxidase that are phylogenetically informative. One is a single nucleotide polymorphism resulting in CcoP truncation that acts as a molecular signature for the species N. meningitidis. We go on to show that the ancestral ccoP gene arose by a unique gene duplication and fusion event and is specifically and completely distributed within species of the genus Neisseria. Surprisingly, we found that strains engineered to express either of the two CcoP forms conditionally differed in their capacity to support nitrite-dependent, microaerobic growth mediated by NirK, a nitrite reductase. Thus, we propose that changes in CcoP domain architecture and ensuing alterations in function are key traits in successive, adaptive radiations within these metapopulations. These findings provide a dramatic example of how rare changes in core metabolic proteins can be connected to significant macroevolutionary shifts. They also show how evolutionary change at the molecular level can be linked to metabolic innovation and its reversal as well as demonstrating how genotype can be used to infer alterations of the fitness landscape within a single host

Virulence Evolution of the Human Pathogen Neisseria meningitidis by Recombination in the Core and Accessory Genome

Joseph B, Schwarz RF, Linke B, et al. Virulence Evolution of the Human Pathogen Neisseria meningitidis by Recombination in the Core and Accessory Genome. PLoS ONE. 2011;6(4): e18441.Background: Neisseria meningitidis is a naturally transformable, facultative pathogen colonizing the human nasopharynx. Here, we analyze on a genome-wide level the impact of recombination on gene-complement diversity and virulence evolution in N. meningitidis. We combined comparative genome hybridization using microarrays (mCGH) and multilocus sequence typing (MLST) of 29 meningococcal isolates with computational comparison of a subset of seven meningococcal genome sequences. Principal Findings: We found that lateral gene transfer of minimal mobile elements as well as prophages are major forces shaping meningococcal population structure. Extensive gene content comparison revealed novel associations of virulence with genetic elements besides the recently discovered meningococcal disease associated (MDA) island. In particular, we identified an association of virulence with a recently described canonical genomic island termed IHT-E and a differential distribution of genes encoding RTX toxin-and two-partner secretion systems among hyperinvasive and non-hyperinvasive lineages. By computationally screening also the core genome for signs of recombination, we provided evidence that about 40% of the meningococcal core genes are affected by recombination primarily within metabolic genes as well as genes involved in DNA replication and repair. By comparison with the results of previous mCGH studies, our data indicated that genetic structuring as revealed by mCGH is stable over time and highly similar for isolates from different geographic origins. Conclusions: Recombination comprising lateral transfer of entire genes as well as homologous intragenic recombination has a profound impact on meningococcal population structure and genome composition. Our data support the hypothesis that meningococcal virulence is polygenic in nature and that differences in metabolism might contribute to virulence