About
103
Publications
8,914
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
4,815
Citations
Citations since 2017
Publications
Publications (103)
Background
Assessing the status of malaria transmission in endemic areas becomes increasingly challenging as countries approach elimination. Serology can provide robust estimates of malaria transmission intensities, and multiplex serological assays allow for simultaneous assessment of markers of recent and historical malaria exposure.
Methods
Here...
Recognition of pathogen-associated molecular patterns (PAMPs) through Toll-like receptors (TLRs) plays a pivotal role in first-line pathogen defence. TLRs are likely also triggered during a Plasmodium infection in vivo by parasite-derived components. However, the contribution of innate responses to liver infection and to the subsequent clinical out...
Objective:
This study provides 2016 data on the prevalence of key single nucleotide polymorphisms (SNPs) associated with antimalarial drug resistance in Palawan, Philippines. Findings were combined with historical data to model temporal changes in the prevalence of these SNPs in Plasmodium isolates.
Methods:
Plasmodium isolates were genotyped usin...
Sporozoite antigens are the basis of a number of malaria vaccines being tested, but the contribution of antigens expressed during subsequent liver stage development to pre‐erythrocytic stage immunity is poorly understood. We previously showed that, following immunisation with radiation attenuated sporozoites (RAS), a model epitope embedded in a spo...
Despite many decades of research to develop a malaria vaccine, only one vaccine candidate has been explored in pivotal phase III clinical trials. This candidate subunit vaccine consists of a portion of a single Plasmodium antigen, circumsporozoite protein (CSP). This antigen was initially identified in the murine malaria model and shown to contain...
Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8+ T cells, either a...
Background:
The immune mechanisms that determine whether a Plasmodium falciparum infection would be symptomatic or asymptomatic are not fully understood. Several studies have been carried out to characterize the associations between disease outcomes and leucocyte numbers. However, the majority of these studies have been conducted in adults with ac...
Potent protection against malaria can be induced by attenuated live-immunization with Plasmodium falciparum (Pf) sporozoites (SPZ). However, a better understanding of the critical processes involved in the establishment of protective immunity is needed. We explored the safety and vaccine efficacy of early chemo-attenuation of PfSPZ under atovaquone...
Vaccine discovery and development critically depends on predictive assays, which prioritise protective antigens. Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation, including phase I/II trials. Here, we tested this assumption in an infection and vaccination model for malaria pre...
The circumsporozoite protein (CSP) builds up the surface coat of sporozoites and is the leading malaria pre-erythrocytic-stage vaccine candidate. CSP has been shown to induce robust CD8+ T cell responses that are capable of eliminating developing parasites in hepatocytes resulting in protective immunity. In this study, we characterised the importan...
The immune state of wild animals is largely unknown. Knowing this and what affects it is important in understanding how infection and disease affects wild animals. The immune state of wild animals is also important in understanding the biology of their pathogens, which is directly relevant to explaining pathogen spillover among species, including t...
Full structural equation modelling (SEM) causal diagram, where the latent variable immune state can be adaptive cellular, innate cellular, or adaptive humoral immune state with season (measured as day length), body condition (measured as the scaled mass index), age in weeks, and infection with 7 microbial infections.
(TIFF)
Infection data for all 12 sample sites, (A) for each mouse, where column A is the mouse ID number; column B is the site designation as in Fig 1; columns C–I, inclusive, are serological evidence of microbial infection on a 0 to 4 scale, where 0 is the absence of a response, and 1, 2, 3, and 4 are all seropositive results in increasing degrees of pos...
(A) PCA analysis of cellular and humoral immune measures showing the first 3 principal components, where PC1 is the scaled number of 7 cell types (CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells, neutrophils, dendritic cells (DCs), and macrophages, all scaled as for scaled mass index [SMI]), PC2 is the serum concentration of immunogl...
Wild mouse multilocus genotypes showing the 1,168 locus genotypes of mice, where column A is the locus name, column B is the chromosome the locus is on, and column C is the position of the locus on the chromosome. Row 1 shows the source of the mice as S1 Table, and row 2 is the individual number of the wild mouse. The number of genotyped mice at ea...
For sample site HW, correlations (2-tailed) among measures of infection, condition, and immune responses, with males above the diagonal and females below the diagonal. Cells are colour coded as red for p < 0.01 and green for 0.01 < p < 0.05. Daylight is a measure of the Season when mice were caught, specifically the number of minutes of daylight be...
Physical characteristics of all mice, where column A is the mouse ID number; column B is the date the mouse was captured; and column C the date it was killed, with the days in captivity shown in column D; column E is the site where it was caught, where 1 is BM, 2 is HW, 3 is LU, 4 is WF, 7 is GL, 8 is WT, 9 is PF, 10 is ST, 11 is JB, 12 is PH, 13 i...
Class 4 structural equation models, where latent variables are shown as circles and observed variables are shown as boxes. Individual numbered models refer to S5 Table.
(PDF)
Fst values shown among all sample sites. The local population genetic structure is not driven by geographical distance (S1 Table). Mantel test for correlation between immunological distance and distance and log(distance + 1), respectively: r = 0.192, p = 0.264, and r = 0.082, p = 0.339.
(DOCX)
The estimated standardised covariances (Estimate), their standard error (SE), and 2-tailed p-values (with p < 0.05 shown in bold) for structural equation models of adaptive cellular, innate cellular, and adaptive humoral immune state for female and male mice from all sites, as shown in S6 Fig. Marginally nonsignificant results are marked with *.
(D...
The estimated standardised covariances (Estimate), their standard error (SE), and 2-tailed p-values (with p < 0.05 shown in bold) for structural equation models of adaptive cellular, innate cellular, and adaptive humoral immune state for female and male mice from site HW, as shown in Fig 5. Marginally nonsignificant results are marked with *.
(DOCX...
Extended methods for structural equation modelling.
(DOCX)
STRUCTURE analysis of mice for 1–12 clusters, K, (A) for all mice and (B) for a random selection of 6 mice from each sample site. In both, there were 15 iterations, and representative figures are shown. The sample site codes for the mice are: 1 = BM, 2 = GL, 3 = HW, 4 = JB, 5 = LU, 6 = PF, 7 = PH, 8 = SK, 9 = SP, 10 = ST, 11 = WF, 12 = WT. The colo...
(A) Mouse sample sites and (B) the intersite distances in km.
(DOCX)
Immunological distance shown both within and among sample sites, shown as the mean ± 1 SE. There is no correlation between the within-site immunological distance and the number of mice at that site (r = −0.043, p = 0.89, n = 12).
(DOCX)
A summary of selected class 1–3 structural equation models showing the latent variables and observed variables used. L is a latent variable, and O is an observed variable. 1Previous Infection is the number of microbial infections and so an observed variable. Relevant structural equation modelling (SEM) diagrams are shown in S3 Fig.
(DOCX)
A summary of the class 4 structural equation models presented in the sequence in which they were tested, with intervening rows showing the model modifications that preceded each new model. In all models, Age was an observed variable of either eye lens mass (Lens mass) or Age in weeks calculated from eye lens mass as described in the main text; Size...
For (A) all 12 sample sites combined, and sample sites (B) GL, (C) PH, and (D) SK, correlations (2-tailed) among measures of infection, condition, and immune measures, with males above the diagonal and females below the diagonal. In all, cells are colour coded as red for p < 0.01 and green for 0.01 < p < 0.05. Daylight is a measure of the Season wh...
The age distribution of mice from all sites. The median age is 7.4 weeks, the mean (±SD) is 10 (±8), and 75% of mice are ≤ 12 weeks old; n = 460 mice. Mice at the different sample sites differ by age (H = 35.882, p < 0.001), which post hoc tests show is due to site BM having older mice than sites HW (p = 0.017) and PF (p = 0.047).
(TIFF)
Class 1–3 structural equation models, where latent variables are shown as circles and observed variables are shown as boxes. Individual numbered models refer to S4 Table.
(PDF)
The principal drivers of immune state in wild mice. How (A) adaptive cellular, (B) innate cellular, and (C) adaptive humoral immune state is affected by Season (measured as day length), Body Condition (measured as the scaled mass index), Age in weeks, and Infection with 7 microbial infections, where blue arrows show positive effects, red blunt-ende...
The laboratory mouse is the workhorse of immunology, used as a model of mammalian immune function, but how well immune responses of laboratory mice reflect those of free-living animals is unknown. Here we comprehensively characterize serological, cellular and functional immune parameters of wild mice and compare them with laboratory mice, finding t...
Supplementary Figure and Supplementary Tables
Correlation matrix of wild mouse morphometrics, infection status and immune measures. For each measure the Pearson correlation (two-tailed) value r, the P value and the relevant sample size are shown. Cells are colour coded such that > 0.01 P < 0.05 is green and P < 0.01 is red. The results for male mice are above the black diagonal, female mice be...
Preliminary characterisation of cytokines and chemokines. For wild and laboratory mice where column A is the mouse ID shown as Wild Mouse (WM) or Lab Mouse Control (LMC), Column B shows the site from where the wild mouse was caught (Supplementary Table 1), or that mice were laboratory mice. Column D shows what was used to stimulate the cells as ant...
Complete data set of immune measures of wild and laboratory mice. (a) immunoglobulins, serum proteins and morphometrics (b1-3) splenocyte populations analysed by flow cytometry and (c) cytokine responses of in vitro stimulated splenocytes. In all column A is the mouse ID shown as Wild Mouse (WM) or Lab Mouse Control (LMC). In (a) Column B shows the...
Wild mouse multilocus genotypes. (a) shows the 1168 locus genotypes of mice where column A is the locus name, column B the chromosome the locus is on, column C the position of the locus on the chromosome. Row 1 shows the source of the mice either as wild mice from HW or laboratory mouse strains shown as L, and row 2 is the individual number of the...
The resolution of malaria infection is dependent on a balance between pro-inflammatory and regulatory immune responses. Whilst early effector T cell responses are required for limiting parasitaemia, these responses need to be switched off by regulatory mechanisms in a timely manner to avoid immune-mediated tissue damage. Interleukin-10 (IL-10) rece...
Malaria transmission occurs by mosquito bite. Thereafter, Plasmodium sporozoites specifically invade the liver, where they develop into thousands of merozoites that initiate blood stage infection and clinical malaria. The pre-erythrocytic phase of a Plasmodium infection is the target of experimental whole parasite vaccines against malaria. Repeated...
CD8(+) T cells mediate immunity against Plasmodium liver stages. However, the paucity of parasite-specific epitopes of CD8(+) T cells has limited our current understanding of the mechanisms influencing the generation, maintenance and efficiency of these responses. To identify antigenic epitopes in a stringent murine malaria immunisation model, we p...
The role of T-cells in immunity against Mycobacterium tuberculosis (M. tuberculosis) infection has been extensively studied, however, that of B-cells still remains comparatively unexplored. In this study, we determined the presence and frequencies of mycobacteria-specific memory B-cells (MBCs) in peripheral blood from clinically healthy, Bacillus C...
It is well established that IFN-γ is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the temporal and tissue-specific cellular sources of IFN-γ during P. berghei ANKA infection have not been investigated, and it is not known whether IFN-γ production by a single c...
RTS,S/AS01, a vaccine targeting pre-erythrocytic stages of Plasmodium falciparum, is undergoing clinical trials. We report an analysis of cellular immune response to component Ags of RTS,S-hepatitis B surface Ag (HBs) and P. falciparum circumsporozoite (CS) protein-among Tanzanian children in a phase IIb RTS,S/AS01(E) trial. RTS,S/AS01 (E) vaccinee...
The balance between pro-inflammatory and regulatory immune responses in determining optimal T cell activation is vital for the successful resolution of microbial infections. This balance is maintained in part by the negative regulators of T cell activation, CTLA-4 and PD-1/PD-L, which dampen effector responses during chronic infections. However, th...
The outcome of infection depends on multiple layers of immune regulation, with innate immunity playing a decisive role in
shaping protection or pathogenic sequelae of acquired immunity. The contribution of pattern recognition receptors and adaptor
molecules in immunity to malaria remains poorly understood. Here, we interrogate the role of the caspa...
Baseline characteristics of the study cohort.
(DOC)
Malaria caused by Plasmodium falciparum remains a major cause of death in sub-Saharan Africa. Immunity against symptoms of malaria requires repeated exposure, suggesting either that the parasite is poorly immunogenic or that the development of effective immune responses to malaria may be impaired.
We carried out two age-stratified cross-sectional s...
IFN-γ and T cells are both required for the development of experimental cerebral malaria during Plasmodium berghei ANKA infection. Surprisingly, however, the role of IFN-γ in shaping the effector CD4(+) and CD8(+) T cell response during this infection has not been examined in detail. To address this, we have compared the effector T cell responses i...
Malaria infection is initiated by sporozoite invasion of hepatocytes and asexual reproduction of liver stages, processes that
are regarded to be “clinically and diagnostically silent.” Merozoites, which egress from hepatocytes, infect erythrocytes
in periodic cycles and induce disease. How the host innate immune system contributes to disease outcom...
Malaria is a vector-borne infectious disease caused by unicellular parasites of the genus Plasmodium. These obligate intracellular parasites have the unique capacity to infect and replicate within erythrocytes, which are terminally differentiated host cells that lack antigen presentation pathways. Prior to the cyclic erythrocytic infections that ca...
The mean ± SD of the percentages of CD45RO+ CD4+ T cells that divided (i.e. were CFSElow) after in vitro restimulation with PfSE, PPD or PHA.
(0.13 MB PPT)
Author Summary
Despite some recent successes in reducing the burden of malaria in several African countries, malaria still causes up to 500 million cases of acute illness every year, killing over a million people. The widespread availability of a safe and effective vaccine would greatly increase our chances of controlling this disease and possibly,...
: The outcome of infection depends on multiple layers of immune regulation with innate immunity playing a decisive role in shaping protection or pathogenic sequelae of acquired immunity. The contribution of pattern recognition receptors and adaptor molecules in immunity to malaria remains poorly understood. Here we interrogate the role of the caspa...
Eukaryotic pathogens typically follow a complex life cycle, including host switch and morphologically distinct forms. Parasite stage conversion offers exceptional opportunities for whole organism vaccine development. In case of Plasmodium, the causative agent of malaria, disease is exclusively caused by asexual blood stages that invade and replicat...
The immune function of wild animals has been rather little studied. Wild animals' immune function may differ from that of laboratory bred animals because of their different environments. This idea follows from the concept of resource partitioning in which animals distribute scarce resources to all aspects of life, including to costly immune respons...
Successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. The pathways that maintain this immunological balance during malaria infection remain poorly defined. In this study, we demonstrate t...
Malaria remains the most prevalent vector-borne infectious disease and has the highest rates of fatality. Current antimalarial drug strategies cure malaria or prevent infections but lack a sustained public health impact because they fail to expedite the acquisition of protective immunity. We show that antibiotic administration during transmission o...
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they...
Author Summary
It is widely perceived that immunity to malaria is short-lived, rendering people susceptible to repeated malaria infections. However, there have been very few studies on “memory” responses, how the human immune system recognizes previously encountered malaria parasites. In particular, very little is known about the durability of mala...
Distinct kinetics of CD40 upregulation and TNF production by macrophages following stimulation with LPS and PbA-induced MPs. Macrophages were stimulated for 6hrs, 12hrs, 24hrs or 48hrs with LPS (200ng/ml) or MPs prepared from the plasma of mice infected with P. berghei ANKA (day 7: PbA MP). (A) Mean fluorescence intensity of CD40 expression by macr...
There is considerable debate as to the nature of the primary parasite-derived moieties that activate innate pro-inflammatory responses during malaria infection. Microparticles (MPs), which are produced by numerous cell types following vesiculation of the cellular membrane as a consequence of cell death or immune-activation, exert strong pro-inflamm...
Cerebral malaria is a life-threatening complication of malaria infection. The pathogenesis of cerebral malaria is poorly defined and progress in understanding the condition is severely hampered by the inability to study in detail, ante-mortem, the parasitological and immunological events within the brain that lead to the onset of clinical symptoms....
Author Summary
Much of the pathology of malaria infection is due to an excessive inflammatory response to the parasite. The regulatory cytokine IL-10 is known to control inflammation during malaria infections and thus protect against immunopathology, but, in so doing, it reduces the effectiveness of other immune mechanisms which remove the parasite...
Anti-CD25 antibody administration does not affect the outcome of low dose PyL infection.
C57BL/6 mice were treated with either a single dose of 0.75 mg 7D4, or with 0.25 mg 7D4 combined with 0.75 mg PC61, 3 days prior to infection with 103 PyL parasites. The course of PyL in anti-CD25 antibody-treated mice and control mice was then followed by moni...
Anti-CD25 antibody administration does not affect the outcome of PyNL infection.
C57BL/6 mice were treated with either a single dose of 1 mg PC61 7 days prior to infection with PyNL (Expt 1) or with a single dose of 0.75 mg 7D4 or 0.25 mg 7D4 combined with 0.75 mg PC61 on the day of PyNL infection (Expt 2). The course of PyNL in anti-CD25 antibody-...
Anti-CD25 antibody administration does not affect the outcome of PyL infection in BALB/c mice.
BALB/c mice were treated with either a single dose of 0.75 mg 7D4, or with 0.25 mg 7D4 combined with 0.75 mg PC61, 3 days prior to infection with 104 PyL pRBC or with 3 repeated injections of 0.5 mg 7D4 on days −3, −1 and +5 relative to PyL infection. The...
The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology. IL-10 and TGF-beta are know...
Immunity to Plasmodium liver stages in individuals in malaria-endemic areas is inextricably linked to concomitant blood-stage parasitemia. Although
Plasmodium sporozoite infection induces measurable CD8+ T cell responses, the development of memory T cells during active erythrocytic infection remains uncharacterized. Using transgenic
T cells, we ass...
In most models of blood-stage malaria infection, proinflammatory immune responses are required for control of infection and
elimination of parasites. We hypothesized therefore that the fulminant infections caused in mice by the lethal strain of Plasmodium yoelii (17XL) might be due to failure to activate a sufficient inflammatory response. Here we...
Malaria, a vector-borne disease caused by Plasmodium parasites, remains a major cause of morbidity and mortality in the developing world. To attain a substantial and steady decline in disease and deaths, a safe and efficacious vaccine is an indispensable tool. However, fundamental to the discovery, design and development of a malaria vaccine is a c...
Data from a variety of experimental models suggest that natural killer (NK) cells require signals from accessory cells in order to respond optimally to pathogens, but the precise identity of the cells able to provide such signals depends upon the nature of the infectious organism. Here we show that the ability of human NK cells to produce interfero...