Dataset Information

Up regulated Variant Surface Glycoproteins under TDP1 overexpression

ABSTRACT: Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of Variant Surface Glycoproteins (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection in terms of antibody response and disease severity remain unknown. In this study, we overexpressed a high mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed a prolonged mice survival in which nearly 90% of the mice survived a 30-day period infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control the infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reduce disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental for the parasite even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis.

INSTRUMENT(S):

ORGANISM(S): Trypanosoma Brucei

TISSUE(S): Cell Culture

DISEASE(S): Trypanosomiasis

SUBMITTER: Douglas Lamont

LAB HEAD: Francisco Aresta Branco

PROVIDER: PXD014803 | Pride | 2019-09-13

REPOSITORIES: Pride

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Publications

African trypanosomes expressing multiple VSGs are rapidly eliminated by the host immune system.

Aresta-Branco Francisco F Sanches-Vaz Margarida M Bento Fabio F Rodrigues João A JA Figueiredo Luisa M LM

Proceedings of the National Academy of Sciences of the United States of America 20190925 41

<i>Trypanosoma brucei</i> parasites successfully evade the host immune system by periodically switching the dense coat of variant surface glycoprotein (VSG) at the cell surface. Each parasite expresses <i>VSGs</i> in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection, in terms of antibody response and disease severity, remain unknown. In this study, we overexpressed a high-mobility group box protein, TDP1, which was sufficient to open ...[more]

PMID: 31554700

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Project description:Microarray studies using synchronized Plasmodium falciparum parasites have revealed a ‘continuous cascade’ of gene expression. Reports vary regarding the stability in these transcriptional patterns in the presence of external stressors. Using Plasmodium yoelii 17X parasites replicating in vivo, we have examined differential gene expression in parasites isolated from individual mice, from independent infections, during ascending and peak parasitemia and in the presence and absence of host antibody responses. Across experimental conditions, transcription was surprisingly stable. Differential gene expression was greatest when comparing differences due to parasite load and/or host cell availability; however, even these changes were modest. Of genes that were differentially expressed, many are of unknown function. There was little to no differential expression of members of the yir and pyst-a multigene families, although a relatively large number of these were expressed during blood-stage infection regardless of experimental condition. Taken together, these results indicate that 1) P. yoelii gene expression remains stable in the presence of a changing host environment and 2) concurrent expression of a large number of the yir and pyst-a genes may function to divert host immune responses away from invariant protective antigens. 1. P. yoelii 17X gene expression profiles were determined in blood-stage parasites isolated from infected Balb/c mice (male, 8-12 weeks old) as follows: a. Mouse 1 (M1), Mouse 2 (M2), Mouse 3 (M3), Donor (D) mouse – three mice simultaneously infected with P. yoelii 17X iRBCs from a single donor mouse. Parasite RNA was isolated early during infection when parasitemia was ascending as follows: M1 - day 11 at 13.0% parasitemia; M2 - day 10 at 11.1% parasitemia; M3 - day 10 at 18.6% parasitemia; D – day 11 at 18.7% parasitemia. b. Infection #1 (I1), infection #2 (I2), infection #3 (I3), infection #4 (I4) – four groups of mice infected on four separate occasions using P. yoelii 17X iRBCs obtained from four separate donor mice. In each case, P. yoelii 17X RNA was isolated from iRBCs obtained on days 10-11 of infection when parasitemia was ascending and was ~15%. c. Day 10 (D10), Day 14 (D14) – P. yoelii 17X RNA isolated from iRBCs during infection #2 on day 10 (14% parasitemia, 14.4% reticulocytes) and on day 14 of infection #2 (43.5% parasitemia, 57.9% reticulocytes). d. WT and JHD - P. yoelii 17X RNA isolated from iRBCs during infection #4 from immunologically intact, wild-type Balb/c mice and B cell deficient, JHD mice on a Balb/c background (ascending infection, 15% parasitemia). e. QA and RMP - P. yoelii 17X RNA isolated from iRBCs during infection #1 from mice previously immunized with a preparation of membrane proteins isolated from P. yoelii 17X infected reticulocytes (PyRMP) (day 12, 13.3% parasitemia and Quil A immunized (QA) control mice (day 10, 15.6% parasitemia) 2. On each array, gene expression in P. yoelii 17X blood-stage parasites was evaluated relative to a standard comparator of purified P. yoelii 17XL total RNA (pooled RNA from 45 mice, mean parasitemia ~35%). Each sample was analyzed on three replicate arrays, one of which was a standard dye-flip. One exception was the infection #3 sample which was analyzed on only on two arrays. On each array, oligonucleotides were spotted in duplicate. 3. Through the use of the standard reference RNA, the following 15 pairwise comparisons across samples were made: (M1 vs M2); (M2 vs M3); (M1 vs M3); (D vs M1); (D vs M2); (D vs M3); (I1 vs I2); (I1 vs I3); (I1 vs I4); (I2 vs I3); (I2 vs I4); (I3 vs I4); (D10 vs D14); (WT vs JHD); (QA vs RMP)

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