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"Adams, John H"
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Longitudinal analysis of antibody responses to Plasmodium vivax sporozoite antigens following natural infection
P. vivax malaria is a major global health burden hindering social and economic development throughout many tropical and sub-tropical countries. Pre-erythrocytic (PE) vaccines emerge as an attractive approach for the control and elimination of malaria infection. Therefore, evaluating the magnitude, longevity and prevalence of naturally acquired IgG antibody responses against PE candidate antigens is useful for vaccine design.
The antigenicity of five recombinant PE antigens (PvCSP-VK210, PvSSP3, PvM2-MAEBL, PvCelTOS and PvSPECT1) was evaluated in plasma samples from individuals residing in low transmission areas in Thailand (Ranong and Chumphon Provinces). The samples were collected at the time of acute vivax malaria and 90, 270 and 360 days later. The prevalence, magnitude and longevity of total IgG and IgG subclasses were determined for each antigen using the longitudinal data. Our results showed that seropositivity of all tested PE antigens was detected during infection in at least some subjects; anti-PvCSP-VK210 and anti-PvCelTOS antibodies were the most frequent. Titers of these antibodies declined during the year of follow up, but notably seropositivity persisted. Among seropositive subjects at post-infection, high number of subjects possessed antibodies against PvCSP-VK210. Anti-PvSSP3 antibody responses had the longest half-life. IgG subclass profiling showed that the predominant subclasses were IgG1 and IgG3 (cytophilic antibodies), tending to remain detectable for at least 360 days after infection.
The present study demonstrated the magnitude and longevity of serological responses to multiple PE antigens of P. vivax after natural infection. This knowledge could contribute to the design of an effective P. vivax vaccine.
Journal Article
Robot uprisings
\"As real robots creep into our lives, so does a sense of fear--we have all wondered what horrifying scenarious might unfold if our technology were to go awry. This anthology brings to life the half-formed questions and fears we all have about the machines we live with. With contributions by Alan Dean Foster, Charles Yu, Hugh Howey, Daniel H. Wilson, Corey Doctorow, Ian McDonald, Ernie Cline, Jeff Abbott, Robin Wasserman, and Anna North, Robot Uprisings contains meticulously described, exhilarating trips to futures in which humans can only survive by being more clever and tenacious than the rebellious machines they have unwittingly created\"-- Provided by publisher.
Book
A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum
Malaria liver stages represent an ideal therapeutic target with a bottleneck in parasite load and reduced clinical symptoms; however, current in vitro pre-erythrocytic (PE) models for
Plasmodium vivax
and
P
.
falciparum
lack the efficiency necessary for rapid identification and effective evaluation of new vaccines and drugs, especially targeting late liver-stage development and hypnozoites. Herein we report the development of a 384-well plate culture system using commercially available materials, including cryopreserved primary human hepatocytes. Hepatocyte physiology is maintained for at least 30 days and supports development of
P
.
vivax
hypnozoites and complete maturation of
P
.
vivax
and
P
.
falciparum
schizonts. Our multimodal analysis in antimalarial therapeutic research identifies important PE inhibition mechanisms: immune antibodies against sporozoite surface proteins functionally inhibit liver stage development and ion homeostasis is essential for schizont and hypnozoite viability. This model can be implemented in laboratories in disease-endemic areas to accelerate vaccine and drug discovery research.
Currently available platforms to study liver stage of
Plasmodium
species have limitations. Here, the authors show that primary human hepatocyte cultures in 384-well format support hypnozoite and other liver stage development and are suitable for drug and antibody screens.
Journal Article
Intestinal injury and the gut microbiota in patients with Plasmodium falciparum malaria
The pathophysiology of severe falciparum malaria involves a complex interaction between the host, parasite, and gut microbes. In this review, we focus on understanding parasite-induced intestinal injury and changes in the human intestinal microbiota composition in patients with Plasmodium falciparum malaria. During the blood stage of P . falciparum infection, infected red blood cells adhere to the vascular endothelium, leading to widespread microcirculatory obstruction in critical tissues, including the splanchnic vasculature. This process may cause intestinal injury and gut leakage. Epidemiological studies indicate higher rates of concurrent bacteraemia in severe malaria cases. Furthermore, severe malaria patients exhibit alterations in the composition and diversity of the intestinal microbiota, although the exact contribution to pathophysiology remains unclear. Mouse studies have demonstrated that the gut microbiota composition can impact susceptibility to Plasmodium infections. In patients with severe malaria, the microbiota shows an enrichment of pathobionts, including pathogens that are known to cause concomitant bloodstream infections. Microbial metabolites have also been detected in the plasma of severe malaria patients, potentially contributing to metabolic acidosis and other clinical complications. However, establishing causal relationships requires intervention studies targeting the gut microbiota.
Journal Article
The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite
The emergence and spread of
Plasmodium falciparum
parasites resistant to front-line antimalarial artemisinin-combination therapies (ACT) threatens to erase the considerable gains against the disease of the last decade. Here, we develop a large-scale phenotypic screening pipeline and use it to carry out a large-scale forward-genetic phenotype screen in
P. falciparum
to identify genes allowing parasites to survive febrile temperatures. Screening identifies more than 200
P. falciparum
mutants with differential responses to increased temperature. These mutants are more likely to be sensitive to artemisinin derivatives as well as to heightened oxidative stress. Major processes critical for
P. falciparum
tolerance to febrile temperatures and artemisinin include highly essential, conserved pathways associated with protein-folding, heat shock and proteasome-mediated degradation, and unexpectedly, isoprenoid biosynthesis, which originated from the ancestral genome of the parasite’s algal endosymbiont-derived plastid, the apicoplast. Apicoplast-targeted genes in general are upregulated in response to heat shock, as are other
Plasmodium
genes with orthologs in plant and algal genomes.
Plasmodium falciparum
parasites appear to exploit their innate febrile-response mechanisms to mediate resistance to artemisinin. Both responses depend on endosymbiont-derived genes in the parasite’s genome, suggesting a link to the evolutionary origins of
Plasmodium
parasites in free-living ancestors.
Repeating fever is a hallmark of malaria. Here, a large-scale forward genetic screen in malaria-causing Plasmodium falciparum identifies genes associated with parasite tolerance to host fever, including apicoplast targeted isoprenoid biosynthesis—sharing features with artemisinin resistance.
Journal Article
Correction: Cross-reactive inhibitory antibody and memory B cell responses to variant strains of Duffy binding protein II at post-Plasmodium vivax infection
[This corrects the article DOI: 10.1371/journal.pone.0276335.].
Journal Article
Atypical memory B cells from natural malaria infection produced broadly neutralizing antibodies against Plasmodium vivax variants
Expansion of atypical memory B cells (aMBCs) was demonstrated in malaria-exposed individuals. To date, the generation of P . vivax -specific aMBCs and their function in protective humoral immune responses is unknown. Here, P . vivax Duffy Binding Protein II (PvDBPII) probes were generated to detect the development and durability of specific aMBCs, and to demonstrate the capacity of these cells to produce neutralizing antibodies following natural infections. PvDBPII-specific aMBCs were elicited during malaria illness, and they persisted through the recovery phase of infections. To address biology and function of P . vivax -specific aMBCs in producing protective antibodies, a single MBC was cultured, and the secreted IgG was tested for binding and inhibition activity. The aMBC-derived clones produced antibodies with variable levels of anti-PvDBPII IgG in cultures, and some produced high antibody levels comparable to classical MBC clones. Thus, we focused our attention on the function of aMBCs in producing neutralizing antibodies. Among the aMBC clones, A1F12 and B4E11 produced broadly neutralizing antibodies against a panel of PvDBPII variants. Notably, B cell receptors (BCRs) of PvDBPII-specific aMBCs expressed unique IGHV genes, with similar usage of IGHV1-3, comparable to classical MBCs. The somatic hypermutation (SHM) rate and CDR3 length of VH and Vκ in these two MBC subsets were not significantly different. Together, our findings revealed that P . vivax infections elicited the development and persistence of P . vivax -specific aMBCs. The accumulation of aMBCs during and following infections might play an important role in producing protective antibodies against malaria.
Journal Article
Oxidative stress changes the effectiveness of artemisinin in Plasmodium falciparum
Emerging resistance to the frontline antimalarial drug artemisinin represents a significant threat to worldwide malaria control and elimination. The patterns of parasite changes associated with emerging resistance represent a complex array of metabolic processes evident in various genetic mutations and altered transcription profiles. Genetic factors identified in regulating P. falciparum sensitivity to artemisinin overlap with the parasite’s responses to malarial fever, sickle trait, and other types of oxidative stresses, suggesting conserved inducible survival responses. In this study we show that intraerythrocytic stress conditions, oxidative stress and heat shock, can significantly decrease the sensitivity of the parasite to artemisinin and lumefantrine, respectively. These results indicate that an intraerythrocytic oxidative stress microenvironment and heat-shock condition can alter antimalarial drug efficacy. Evaluating efficacy of antimalarial drugs under ideal in vitro culture conditions may not accurately predict drug efficacy in all malaria patients.
Journal Article
Confronting Climate Crises Through Education
Confronting Climate Crises through Education: Reading Our Way Forward envisions the responsibility of public education to engage a citizenry more prepared to address the challenges of a changing world.Young advocates a paradigm shift that positions ecopedagogy as the central organizing principle of curriculum and assessment design.
eBook