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Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor
Bernardo S Franklin1, Peggy Parroche, Marco Antonio Ataíde
1Immunopathology Laboratory, René Rachou Institute, Fundaçao Oswaldo Cruz, Avenue Augusto de Lima 1715, MG 30190, Belo Horizonte, Brazil.
Abstract:
Malaria-induced sepsis is associated with an intense proinflammatory cytokinemia for which the underlying mechanisms are poorly understood. It has been demonstrated that experimental infection of humans with Plasmodium falciparum primes Toll-like receptor (TLR)-mediated proinflammatory responses. Nevertheless, the relevance of this phenomenon during natural infection and, more importantly, the mechanisms by which malaria mediates TLR hyperresponsiveness are unclear. Here we show that TLR responses are boosted in febrile patients during natural infection with P. falciparum. Microarray analyses demonstrated that an extraordinary percentage of the up-regulated genes, including genes involving TLR signaling, had sites for IFN-inducible transcription factors. To further define the mechanism involved in malaria-mediated "priming," we infected mice with Plasmodium chabaudi. The human data were remarkably predictive of what we observed in the rodent malaria model. Malaria-induced priming of TLR responses correlated with increased expression of TLR mRNA in a TLR9-, MyD88-, and IFNgamma-dependent manner. Acutely infected WT mice were highly susceptible to LPS-induced lethality while TLR9(-/-), IL12(-/-) and to a greater extent, IFNgamma(-/-) mice were protected. Our data provide unprecedented evidence that TLR9 and MyD88 are essential to initiate IL12 and IFNgamma responses and favor host hyperresponsiveness to TLR agonists resulting in overproduction of proinflammatory cytokines and the sepsis-like symptoms of acute malaria.
Insights
Malaria infection boosts Toll-like receptor (TLR) responses, leading to hyperresponsiveness and sepsis-like symptoms. This priming is dependent on TLR9, MyD88, and IFN-gamma, highlighting key mechanisms in malaria pathogenesis.
Area of Science:
- Immunology
- Infectious Diseases
- Pathophysiology
Background:
- Malaria-induced sepsis involves intense proinflammatory cytokinemia with unclear mechanisms.
- Experimental Plasmodium falciparum infection primes Toll-like receptor (TLR)-mediated responses.
- The relevance of this priming during natural infection and its mechanisms remain poorly understood.
Purpose of the Study:
- To investigate the boosting of TLR responses during natural Plasmodium falciparum infection in humans.
- To elucidate the mechanisms underlying malaria-mediated TLR hyperresponsiveness.
- To define the role of TLR9, MyD88, and IFN-gamma in malaria-induced priming and susceptibility.
Main Methods:
- Analysis of TLR responses in febrile patients with natural P. falciparum infection.
- Microarray analysis of gene expression, focusing on TLR signaling and IFN-inducible factors.
- Infection of mice with Plasmodium chabaudi to model malaria-induced priming.
- Assessment of susceptibility to LPS-induced lethality in wild-type and knockout mice (TLR9-/-, IL12-/-, IFNgamma(-/-)).
Main Results:
- TLR responses are significantly boosted in febrile patients during natural P. falciparum infection.
- Malaria-induced priming correlates with increased TLR mRNA expression in a TLR9-, MyD88-, and IFNgamma-dependent manner.
- Acutely infected wild-type mice are highly susceptible to LPS-induced lethality, while TLR9, IL12, and especially IFNgamma knockout mice are protected.
Conclusions:
- TLR9 and MyD88 are essential for initiating IL12 and IFNgamma responses during malaria.
- Malaria infection favors host hyperresponsiveness to TLR agonists, leading to excessive proinflammatory cytokine production.
- These findings explain the sepsis-like symptoms observed in acute malaria and identify critical pathways for therapeutic targeting.
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