The contribution of Plasmodium chabaudi to our understanding of malaria

Stephens, Robin; Culleton, Richard; Lamb, Tracey J.

doi:10.1016/j.pt.2011.10.006

Cited by 163 publications

(166 citation statements)

References 105 publications

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“…Tolerance almost certainly occurs in patients from holoendemic areas of malaria that do not exhibit the signs and symptoms of the disease despite the presence of blood parasites (41,42). Likewise, body temperature and weight are normalized after the control of acute parasitemia in PcAS-infected mice (5). In agreement with the concept that stimulatory and regulatory molecular pathways coexist during PcAS malaria, CD4…”

Section: Discussionsupporting

confidence: 60%

“…Among them, Plasmodium chabaudi infection is a feasible model to study strain-specific and strain-transcending immunity because of the variety of well-characterized parasite clones and the similarities to the human disease caused by Plasmodium falciparum (5). Reinfection with homologous P. falciparum parasites in humans or P. chabaudi in mice results in significant parasite control, whereas limited protection to heterologous secondary infections has been observed in both cases (3,(6)(7)(8).…”

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confidence: 99%

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IFN-γ–Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria

Silva

Salles

Panatieri

et al. 2013

The Journal of Immunology

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The mechanism by which protective immunity to Plasmodium is lost in the absence of continued exposure to this parasite has yet to be fully elucidated. It has been recently shown that IFN-γ produced during human and murine acute malaria primes the immune response to TLR agonists. In this study, we investigated whether IFN-γ–induced priming is important to maintain long-term protective immunity against Plasmodium chabaudi AS malaria. On day 60 postinfection, C57BL/6 mice still had chronic parasitemia and efficiently controlled homologous and heterologous (AJ strain) challenge. The spleens of chronic mice showed augmented numbers of effector/effector memory (TEM) CD4+ cells, which is associated with increased levels of IFN-γ–induced priming (i.e., high expression of IFN-inducible genes and TLR hyperresponsiveness). After parasite elimination, IFN-γ–induced priming was no longer detected and protective immunity to heterologous challenge was mostly lost with >70% mortality. Spontaneously cured mice had high serum levels of parasite-specific IgG, but effector T/TEM cell numbers, parasite-driven CD4+ T cell proliferation, and IFN-γ production were similar to noninfected controls. Remarkably, the priming of cured mice with low doses of IFN-γ rescued TLR hyperresponsiveness and the capacity to control heterologous challenge, increasing the TEM cell population and restoring the CD4+ T cell responses to parasites. Contribution of TLR signaling to the CD4+ T cell responses in chronic mice was supported by data obtained in mice lacking the MyD88 adaptor. These results indicate that IFN-γ–induced priming is required to maintain protective immunity against P. chabaudi and aid in establishing the molecular basis of strain-transcending immunity in human malaria.

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Section: Discussionsupporting

confidence: 60%

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confidence: 99%

IFN-γ–Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria

Silva

Salles

Panatieri

et al. 2013

The Journal of Immunology

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“…At least in our experiments, the most severe anemia following treatment occurred when resistant parasites were at frequencies of 0.01% or lower when treatment began (Figure 4). Of course P. falciparum in people and P. chabaudi in laboratory mice are not the same, 16,33 not least because the mice in these experiments were naïve to malaria infections, perhaps giving the relapsing resistant clone an advantage it would not have in a semi-immune host. Nevertheless, it is intriguing that the relapses we saw occurred 7-10 days posttreatment, which, scaling the 24-hour life cycle of P. chabaudi to the 48-hour life cycle of P. falciparum, is suggestively similar to the 14-42 days seen in relapsing P. falciparum infections.…”

Section: Discussionmentioning

confidence: 98%

Relevance of Undetectably Rare Resistant Malaria Parasites in Treatment Failure: Experimental Evidence from Plasmodium chabaudi

Huijben

Chan

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2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Resistant malaria parasites are frequently found in mixed infections with drug-sensitive parasites. Particularly early in the evolutionary process, the frequency of these resistant mutants can be extremely low and below the level of molecular detection. We tested whether the rarity of resistance in infections impacted the health outcomes of treatment failure and the potential for onward transmission of resistance. Mixed infections of different ratios of resistant and susceptible Plasmodium chabaudi parasites were inoculated in laboratory mice and dynamics tracked during the course of infection using highly sensitive genotype-specific quantitative polymerase chain reaction (qPCR). Frequencies of resistant parasites ranged from 10% to 0.003% at the onset of treatment. We found that the rarer the resistant parasites were, the lower the likelihood of their onward transmission, but the worse the treatment failure was in terms of parasite numbers and disease severity. Strikingly, drug resistant parasites had the biggest impact on health outcomes when they were too rare to be detected by any molecular methods currently available for field samples. Indeed, in the field, these treatment failures would not even have been attributed to resistance.

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“…is a natural rodent pathogen that allows for the study of the blood stage of malaria in C57BL/6 mice (29). Previous studies using the P. chabaudi model of malaria infection in mice demonstrate that Ab responses to a secondary unrelated Ag (e.g., of NP-chicken gamma globulin [CGG]) are of a lower avidity when injection occurred at the same time as infection and that P. chabaudi infection had no effect on an already established humoral memory response to the secondary Ag (30,31).…”

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Acute Plasmodium chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen but Enhances Responses to a Secondary T-Independent Antigen

Wilmore

Maue

Lefebvre

et al. 2013

The Journal of Immunology

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High rates of coinfection occur in malaria endemic regions, leading to more severe disease outcomes. Understanding how coinfecting pathogens influence the immune system is important in the development of treatment strategies that reduce morbidity and mortality. Using the Plasmodium chabaudi mouse model of malaria and immunization with model Ags that are either T-dependent (4-hydroxy-3-nitrophenyl [NP]-OVA) or T-independent (NP-Ficoll), we analyzed the effects of acute malaria on the development of humoral immunity to secondary Ags. Total Ig and IgG1 NP–specific Ab responses to NP-OVA were significantly decreased in the P. chabaudi–infected group compared with the uninfected group, whereas NP-specific IgG2c Ab was significantly increased in the P. chabaudi–infected group. In contrast, following injection with T-independent NP-Ficoll, the P. chabaudi–infected group had significantly increased NP-specific total Ig, IgM, and IgG2c Ab titers compared with controls. Treatment with anti–IFN-γ led to an abrogation of the NP-specific IgG2c Ab induced by P. chabaudi infection but did not affect other NP-specific Ab isotypes or titers. IFN-γ depletion also increased the percentage of plasma cells in both P. chabaudi–infected and uninfected groups but decreased the percentage of B cells with a germinal center (GC) phenotype. Using immunofluorescent microscopy, we were able to detect NP+ GCs in the spleens of noninfected mice, but there were no detectible NP+ GCs in mice infected with P. chabaudi. These data suggest that during P. chabaudi infection, there is a shift toward an extrafollicular Ab response that could be responsible for decreased Ab responses to secondary T-dependent Ags.

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The contribution of Plasmodium chabaudi to our understanding of malaria

Cited by 163 publications

References 105 publications

IFN-γ–Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria

IFN-γ–Induced Priming Maintains Long-Term Strain-Transcending Immunity against Blood-Stage Plasmodium chabaudi Malaria

Relevance of Undetectably Rare Resistant Malaria Parasites in Treatment Failure: Experimental Evidence from Plasmodium chabaudi

Acute Plasmodium chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen but Enhances Responses to a Secondary T-Independent Antigen

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