Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

Lythgoe, Katrina A.; Morrison, Liam J.; Read, Andrew F.; Barry, J. David

doi:10.1073/pnas.0606206104

Cited by 66 publications

(90 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous efforts to generate dynamical models of antigenic variation have taken a range of approaches that are complementary to our work. Some models have not considered cross-reactive immunity and instead focused on other aspects of infection dynamics such as the ordered appearance of variants, differentiation of parasites during the course of infections and linking the within and between host dynamics of the pathogen [16][17][18]22,[25][26][27]. Other models have explicitly incorporated crossreactive immunity and the breadth of immune responses but have focused on diseases such as HIV that directly subvert the immune system leading to qualitatively different dynamics [20,21,41].…”

Section: Discussionmentioning

confidence: 99%

How do antigenically varying pathogens avoid cross-reactive responses to invariant antigens?

et al. 2012

View full text Add to dashboard Cite

Pathogens such as trypanosomes and malaria use antigenic variation to evade immune responses and prolong the duration of infections. As pathogens typically express more than one antigen, even relatively rare conserved antigens might be expected to trigger cross-reactive immune responses capable of clearing the infection. We use simple mathematical models that explicitly consider the dynamic interplay between the replicating pathogen, immune responses to different antigens and immune exhaustion to explore how pathogens can escape the responses to both variable and invariant (conserved) antigens. Our results suggest two hypotheses. In the first, limited quantities of invariant antigens on each pathogen may lead to saturation in killing by cross-reactive responses. In the second, antigenic variation of the dominant antigens prolongs the duration of infection sufficiently to allow for exhaustion of the cross-reactive responses to subdominant, invariant epitopes prior to their being able to control the infection. These hypotheses make distinct predictions: the former predicts that cross-reactive responses will always be ineffective while the latter predicts that appropriately timed treatment could, by preventing exhaustion, lead to the generation of long-lasting protective cross-reactive immunity and thus act similarly to a vaccine.

show abstract

Section: Discussionmentioning

confidence: 99%

How do antigenically varying pathogens avoid cross-reactive responses to invariant antigens?

et al. 2012

View full text Add to dashboard Cite

show abstract

“…However, as parasite numbers increase, an unidentified parasite-derived signal (stumpy induction factor; SIF) stimulates growth arrest in G1 (Vassella et al, 1997). This quorum sensing (QS) mechanism induces the developmental switch to morphologically stumpy forms, which do not divide, thereby limiting the increase in parasite numbers and promoting the generation of a chronic infection (Lythgoe et al, 2007). Although stumpy forms are irreversibly committed to cell division arrest in the bloodstream, this does not represent a simple example of self-destructive cooperation, as seen in some bacterial populations (Ackermann et al, 2008;Gardner and Kummerli, 2008).…”

Section: Introductionmentioning

confidence: 99%

Developmental regulation and extracellular release of a VSG expression-site-associated gene product from Trypanosoma brucei bloodstream forms

Barnwell

Deursen

Jeacock

et al. 2010

Journal of Cell Science

View full text Add to dashboard Cite

SummaryTrypanosomes evade host immunity by exchanging variant surface glycoprotein (VSG) coats. VSG genes are transcribed from telomeric expression sites, which contain a diverse family of expression-site-associated genes (ESAGs). We have discovered that the mRNAs for one ESAG family, ESAG9, are strongly developmentally regulated, being enriched in stumpy forms, a life-cycle stage in the mammalian bloodstream that is important for the maintenance of chronic parasite infections and for tsetse transmission. ESAG9 gene sequences are highly diverse in the genome and encode proteins with weak similarity to the massively diverse MASP proteins in Trypanosoma cruzi. We demonstrate that ESAG9 proteins are modified by N-glycosylation and can be shed to the external milieu, this being dependent upon coexpression with at least one other family member. The expression profile and extracellular release of ESAG9 proteins represents a novel and unexpected aspect of the transmission biology of trypanosomes in their mammalian host. We suggest that these molecules might interact with the external environment, with possible implications for infection chronicity or parasite transmission.

show abstract

“…Various other mechanisms have been suggested in the literature [60][61][62]. A model by Recker et al [63] has shown that, e.g., transient cross-reactive immune responses are able to orchestrate realistic within-host antigenic variation.…”

Section: Growth Rate Differences Related To Variant Surface Antigen Ementioning

confidence: 99%

How selection forces dictate the variant surface antigens used by malaria parasites

Severins

Klinkenberg

Heesterbeek

2011

J. R. Soc. Interface.

View full text Add to dashboard Cite

Red blood cells infected by the malaria parasite Plasmodium falciparum express variant surface antigens (VSAs) that evade host immunity and allow the parasites to persist in the human population. There exist many different VSAs and the differential expression of these VSAs is associated with the virulence (damage to the host) of the parasites. The aim of this study is to unravel the differences in the effect key selection forces have on parasites expressing different VSAs such that we can better understand how VSAs enable the parasites to adapt to changes in their environment (like control measures) and how this may impact the virulence of the circulating parasites. To this end, we have built an individual-based model that captures the main selective forces on malaria parasites, namely parasite competition, host immunity, host death and mosquito abundance at both the within-and between-host levels. VSAs are defined by the net growth rates they infer to the parasites and the model keeps track of the expression of, and antibody build-up against, each VSA in all hosts. Our results show an ordered acquisition of VSA-specific antibodies with host age, which causes a dichotomy between the more virulent VSAs that reach high parasitaemias but are restricted to young relatively non-immune hosts, and less virulent VSAs that do not reach such high parasitaemias but can infect a wider range of hosts. The outcome of a change in the parasite's environment in terms of parasite virulence depends on the exact balance between the selection forces, which sets the limiting factor for parasite survival. Parasites will evolve towards expressing more virulent VSAs when the limiting factor for parasite survival is the within-host parasite growth and the parasites are able to minimize this limitation by expressing more virulent VSAs.

show abstract

Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

Cited by 66 publications

References 58 publications

How do antigenically varying pathogens avoid cross-reactive responses to invariant antigens?

How do antigenically varying pathogens avoid cross-reactive responses to invariant antigens?

Developmental regulation and extracellular release of a VSG expression-site-associated gene product from Trypanosoma brucei bloodstream forms

How selection forces dictate the variant surface antigens used by malaria parasites

Contact Info

Product

Resources

About