Mosquito Passage Dramatically Changes var Gene Expression in Controlled Human Plasmodium falciparum Infections

Bachmann, Anna; Petter, Michaela; Krumkamp, Ralf; Esen, Meral; Held, Jana; Scholz, Jochen; Li, Tao; Sim, B. Kim Lee; Hoffman, Stephen L.; Kremsner, Peter G.; Mordmüller, Benjamin; Duffy, Michael; Tannich, Egbert

doi:10.1371/journal.ppat.1005538

Cited by 56 publications

(93 citation statements)

References 47 publications

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“…One possible explanation stems from P. chabaudi models, in which passage through mosquito resets virulence gene expression [40], assuming that the var gene expressed in our samples represents the first to be expressed post-mosquito transmission. Our data also partially corroborate a recent study from infections in non-immune human volunteers in which there was a striking conservation in the var genes expressed post-mosquito infection from a single-strain source of sporozoites [41].…”

Section: Discussionsupporting

confidence: 89%

Plasmodium falciparum population genetic complexity influences transcriptional profile and immune recognition of highly related genotypic clusters

Larremore

Miura

et al. 2020

Preprint

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As transmission intensity has declined in Senegal, so has the genetic complexity of circulating Plasmodium falciparum parasites, resulting in specific genotypes emerging and persisting over years. We address whether changes in parasite genetic signatures can alter the immune repertoire to variant surface antigens, and whether such responses can influence the expansion or contraction of specific parasite genotypes in the population. We characterize parasites within genotypic clusters, defined as identical by a 24-SNP molecular barcode and a haplotype identifier for other highly polymorphic loci; we measure expression of variant surface antigens (VSA) such as PfEMP-1 by transcript expression typing and expressed var DBL1α sequencing in ex vivo and short-term adapted RNA samples; and we measure IgG responses against VSAs from short-term adapted parasites. We find that parasites within genotypic clusters are genetically identical at other highly polymorphic loci. These parasites express similar Ups var classes and largely the same dominant var DBL1α sequences ex vivo. These parasites are recognized similarly by anti-VSA antibodies after short-term adaptation to culture; however, antibody responses do not correlate with genotype frequencies over time. Both genotype-specific and multiple genotype-reactive surface IgG responses are observed in this population. Parasites with identical genomes are extremely similar in their expression and host antibody recognition of VSAs. Monitoring changes in population-level parasite genomics and transmission dynamics is critical, as fluctuations will influence the breadth of resulting host immune responses to circulating parasite genotypes. These findings suggest shared immune recognition of genetically similar parasites, which has implications for both our understanding of immunity and vaccine development strategies in malaria elimination settings.

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Section: Discussionsupporting

confidence: 89%

Plasmodium falciparum population genetic complexity influences transcriptional profile and immune recognition of highly related genotypic clusters

Larremore

Miura

et al. 2020

Preprint

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“…An analogous approach has been previously used to study the expression of var genes in the context of a human infection, which revealed a reset of the expression patterns of this gene family during transmission stages [38][39][40]. Here we show that the expression of clag3 genes is also reset.…”

Section: Discussionsupporting

confidence: 51%

Expression of the Plasmodium falciparum Clonally Variant clag3 Genes in Human Infections

Mira-Martínez

Schuppen

Amambua-Ngwa

et al. 2017

The Journal of Infectious Diseases

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Background. Many genes of the malaria parasite Plasmodium falciparum show clonally variant expression regulated at the epigenetic level. These genes participate in fundamental host-parasite interactions and contribute to adaptive processes. However, little is known about their expression patterns during human infections. A peculiar case of clonally variant genes are the 2 nearly identical clag3 genes, clag3.1 and clag3.2, which mediate nutrient uptake and are linked to resistance to some toxic compounds.Methods. We developed a procedure to characterize the expression of clag3 genes in naturally infected patients and in experimentally infected human volunteers.Results. We provide the first description of clag3 expression during human infections, which revealed mutually exclusive expression and identified the gene predominantly expressed. Adaptation to culture conditions or selection with a toxic compound resulted in isolate-dependent changes in clag3 expression. We also found that clag3 expression patterns were reset during transmission stages.Conclusions. Different environment conditions select for parasites with different clag3 expression patterns, implying functional differences between the proteins encoded. The epigenetic memory is likely erased before parasites start infection of a new human host. Altogether, our findings support the idea that clonally variant genes facilitate the adaptation of parasite populations to changing conditions through bet-hedging strategies.

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“…In addition, an important unresolved question in the field is whether the regulation of var genes during sporogonic development of P. falciparum affects malaria virulence. A recent study examined the dynamics of var gene expression in patients infected with mosquito-passaged P. falciparum parasites via quantitative real-time PCR and reported changes in var gene expression between a parental parasite culture line, and the parasites isolated from the infected volunteers57. The authors suggest that this may be the result of epigenetic reprogramming in the mosquito prior to infection of the human, but no data is presented supporting this suggestion.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of Plasmodium falciparum clonally variant gene expression during development in Anopheles gambiae

Gómez-Díaz¹,

Yerbanga²,

Lefèvre³

et al. 2017

Sci Rep

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P. falciparum phenotypic plasticity is linked to the variant expression of clonal multigene families such as the var genes. We have examined changes in transcription and histone modifications that occur during sporogonic development of P. falciparum in the mosquito host. All var genes are silenced or transcribed at low levels in blood stages (gametocyte/ring) of the parasite in the human host. After infection of mosquitoes, a single var gene is selected for expression in the oocyst, and transcription of this gene increases dramatically in the sporozoite. The same PF3D7_1255200 var gene was activated in 4 different experimental infections. Transcription of this var gene during parasite development in the mosquito correlates with the presence of low levels of H3K9me3 at the binding site for the PF3D7_1466400 AP2 transcription factor. This chromatin state in the sporozoite also correlates with the expression of an antisense long non-coding RNA (lncRNA) that has previously been shown to promote var gene transcription during the intraerythrocytic cycle in vitro. Expression of both the sense protein-coding transcript and the antisense lncRNA increase dramatically in sporozoites. The findings suggest a complex process for the activation of a single particular var gene that involves AP2 transcription factors and lncRNAs.

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Mosquito Passage Dramatically Changes var Gene Expression in Controlled Human Plasmodium falciparum Infections

Cited by 56 publications

References 47 publications

Plasmodium falciparum population genetic complexity influences transcriptional profile and immune recognition of highly related genotypic clusters

Plasmodium falciparum population genetic complexity influences transcriptional profile and immune recognition of highly related genotypic clusters

Expression of the Plasmodium falciparum Clonally Variant clag3 Genes in Human Infections

Epigenetic regulation of Plasmodium falciparum clonally variant gene expression during development in Anopheles gambiae

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