A coordinated transcriptional switching network mediates antigenic variation of human malaria parasites
- Weill Cornell Medicine, United States
Abstract
Malaria parasites avoid immune clearance through their ability to systematically alter antigens exposed on the surface of infected red blood cells. This is accomplished by tightly regulated transcriptional control of individual members of a large, multicopy gene family called var and is the key to both the virulence and chronic nature of malaria infections. Expression of var genes is mutually exclusive and controlled epigenetically, however how large populations of parasites coordinate var gene switching to avoid premature exposure of the antigenic repertoire is unknown. Here we provide evidence for a transcriptional network anchored by a universally conserved gene called var2csa that coordinates the switching process. We describe a structured switching bias that shifts overtime and could shape the pattern of var expression over the course of a lengthy infection. Our results provide an explanation for a previously mysterious aspect of malaria infections and shed light on how parasites possessing a relatively small repertoire of variant antigen encoding genes can coordinate switching events to limit antigen exposure, thereby maintaining chronic infections.
Data availability
Whole genome sequence and transcriptome data are available at the BioProject database of the NCBI. The genome sequencing data can be accessed at this link: http://www.ncbi.nlm.nih.gov/bioproject/515738. The RNAseq data can be accessed at this link: https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA802886.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (AI 52390)
- Kirk W Deitsch
National Institute of Allergy and Infectious Diseases (AI99327)
- Kirk W Deitsch
National Institutes of Health (T32GM008539)
- Joseph E Visone
Swiss National Science Foundation (P2BEP3_191777)
- Francesca Florini
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A coordinated transcriptional switching network mediates antigenic variation of human malaria parasites
eLife 11:e83840.
https://doi.org/10.7554/eLife.83840
Further reading
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- Microbiology and Infectious Disease
Pathogenic and nonpathogenic mycobacteria secrete extracellular vesicles (EVs) under various conditions. EVs produced by Mycobacterium tuberculosis (Mtb) have raised significant interest for their potential in cell communication, nutrient acquisition, and immune evasion. However, the relevance of vesicle secretion during tuberculosis infection remains unknown due to the limited understanding of mycobacterial vesicle biogenesis. We have previously shown that a transposon mutant in the LCP-related gene virR (virRmut) manifested a strong attenuated phenotype during experimental macrophage and murine infections, concomitant to enhanced vesicle release. In this study, we aimed to understand the role of VirR in the vesicle production process in Mtb. We employ genetic, transcriptional, proteomics, ultrastructural, and biochemical methods to investigate the underlying processes explaining the enhanced vesiculogenesis phenomenon observed in the virRmut. Our results establish that VirR is critical to sustain proper cell permeability via regulation of cell envelope remodeling possibly through the interaction with similar cell envelope proteins, which control the link between peptidoglycan and arabinogalactan. These findings advance our understanding of mycobacterial extracellular vesicle biogenesis and suggest that these set of proteins could be attractive targets for therapeutic intervention.
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- Epidemiology and Global Health
- Microbiology and Infectious Disease
Background:
In many settings, a large fraction of the population has both been vaccinated against and infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, quantifying the protection provided by post-infection vaccination has become critical for policy. We aimed to estimate the protective effect against SARS-CoV-2 reinfection of an additional vaccine dose after an initial Omicron variant infection.
Methods:
We report a retrospective, population-based cohort study performed in Shanghai, China, using electronic databases with information on SARS-CoV-2 infections and vaccination history. We compared reinfection incidence by post-infection vaccination status in individuals initially infected during the April–May 2022 Omicron variant surge in Shanghai and who had been vaccinated before that period. Cox models were fit to estimate adjusted hazard ratios (aHRs).
Results:
275,896 individuals were diagnosed with real-time polymerase chain reaction-confirmed SARS-CoV-2 infection in April–May 2022; 199,312/275,896 were included in analyses on the effect of a post-infection vaccine dose. Post-infection vaccination provided protection against reinfection (aHR 0.82; 95% confidence interval 0.79–0.85). For patients who had received one, two, or three vaccine doses before their first infection, hazard ratios for the post-infection vaccination effect were 0.84 (0.76–0.93), 0.87 (0.83–0.90), and 0.96 (0.74–1.23), respectively. Post-infection vaccination within 30 and 90 days before the second Omicron wave provided different degrees of protection (in aHR): 0.51 (0.44–0.58) and 0.67 (0.61–0.74), respectively. Moreover, for all vaccine types, but to different extents, a post-infection dose given to individuals who were fully vaccinated before first infection was protective.
Conclusions:
In previously vaccinated and infected individuals, an additional vaccine dose provided protection against Omicron variant reinfection. These observations will inform future policy decisions on COVID-19 vaccination in China and other countries.
Funding:
This study was funded the Key Discipline Program of Pudong New Area Health System (PWZxk2022-25), the Development and Application of Intelligent Epidemic Surveillance and AI Analysis System (21002411400), the Shanghai Public Health System Construction (GWVI-11.2-XD08), the Shanghai Health Commission Key Disciplines (GWVI-11.1-02), the Shanghai Health Commission Clinical Research Program (20214Y0020), the Shanghai Natural Science Foundation (22ZR1414600), and the Shanghai Young Health Talents Program (2022YQ076).
