Chemical Attenuation of <i>Plasmodium</i> in the Liver Modulates Severe Malaria Disease Progression

Lewis, Matthew D.; Behrends, Jochen; Cunha, Claudia Sa E; Mendes, António M.; Lasitschka, Felix; Sattler, Julia M.; Heiß, Kirsten; Kooij, Taco W. A.; Prudêncio, Miguel; Bringmann, Gerhard; Frischknecht, Friedrich; Mueller, Ann‐Kristin

doi:10.4049/jimmunol.1400863

Cited by 18 publications

(19 citation statements)

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“…Very few studies have addressed the potential of an early inflammatory response upon sporozoite infection in modulating downstream effector responses and consequently disease outcome during the erythrocytic stage. Previous studies have shown that preerythrocytic or early immune responses may modulate downstream host immune responses and reduce ECM development or clinical symptoms, respectively, in mice and in humans (52)(53)(54)(55) or exacerbate symptoms in clinical malaria (9). Our study contributes to a better understanding of the key role of γδ-T cells in promoting the critical IFN-γ response upon sporozoite infection, which impacts in the immunogenicity of liver-derived parasites, blood-stage inflammation, and, ultimately, the development of ECM.…”

Section: Discussionmentioning

confidence: 99%

γδ-T cells promote IFN-γ–dependentPlasmodiumpathogenesis upon liver-stage infection

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Neres

Zuzarte‐Luís

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Cerebral malaria (CM) is a major cause of death due to Plasmodium infection. Both parasite and host factors contribute to the onset of CM, but the precise cellular and molecular mechanisms that contribute to its pathogenesis remain poorly characterized. Unlike conventional αβ-T cells, previous studies on murine γδ-T cells failed to identify a nonredundant role for this T cell subset in experimental cerebral malaria (ECM). Here we show that mice lacking γδ-T cells are resistant to ECM when infected with Plasmodium berghei ANKA sporozoites, the liver-infective form of the parasite and the natural route of infection, in contrast with their susceptible phenotype if challenged with P. berghei ANKA-infected red blood cells that bypass the liver stage of infection. Strikingly, the presence of γδ-T cells enhanced the expression of Plasmodium immunogenic factors and exacerbated subsequent systemic and brain-infiltrating inflammatory αβ-T cell responses. These phenomena were dependent on the proinflammatory cytokine IFN-γ, which was required during liver stage for modulation of the parasite transcriptome, as well as for downstream immune-mediated pathology. Our work reveals an unanticipated critical role of γδ-T cells in the development of ECM upon Plasmodium liver-stage infection.cerebral malaria | gamma-delta T cells | Plasmodium | liver stage | interferon-gamma

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Section: Discussionmentioning

confidence: 99%

γδ-T cells promote IFN-γ–dependentPlasmodiumpathogenesis upon liver-stage infection

Ribot

Neres

Zuzarte‐Luís

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Cerebral vascular leakage was investigated using Evans Blue72. Histological examinations of mouse brain sections was performed as described73. Briefly, Mice were killed and perfused with 10 ml PBS and 10 ml 4% paraformaldehyde before brains were carefully removed and incubated in 4% paraformaldehyde for 24 h at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes

et al. 2016

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Plasmodium falciparum infections can cause severe malaria, but not every infected person develops life-threatening complications. In particular, carriers of the structural haemoglobinopathies S and C and infants are protected from severe disease. Protection is associated with impaired parasite-induced host actin reorganization, required for vesicular trafficking of parasite-encoded adhesins, and reduced cytoadherence of parasitized erythrocytes in the microvasculature. Here we show that aberrant host actin remodelling and the ensuing reduced cytoadherence result from a redox imbalance inherent to haemoglobinopathic and fetal erythrocytes. We further show that a transient oxidative insult to wild-type erythrocytes before infection with P. falciparum induces the phenotypic features associated with the protective trait of haemoglobinopathic and fetal erythrocytes. Moreover, pretreatment of mice with the pro-oxidative nutritional supplement menadione mitigate the development of experimental cerebral malaria. Our results identify redox imbalance as a causative principle of protection from severe malaria, which might inspire host-directed intervention strategies.

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“…This regimen induced an earlier than normal proinflammatory immune response, with activation of CD4 ϩ and CD8 ϩ T cells in the liver and of CD8 ϩ T cells in the spleen, as well as increased production of IFN-␥, TNF-␣, and IL-2, which was protective against ECM (34). However, immunized mice eventually succumbed to infection due to hyperparasitemia-associated anemia (34).…”

Section: In Vivo Chemical Attenuation Following Inoculation Of Sporozmentioning

confidence: 99%

“…Immunized mice had a delay in blood-stage parasite patency compared to control mice and did not suffer from experimental cerebral malaria (ECM) (34), an outcome which is usually associated with this model. This regimen induced an earlier than normal proinflammatory immune response, with activation of CD4 ϩ and CD8 ϩ T cells in the liver and of CD8 ϩ T cells in the spleen, as well as increased production of IFN-␥, TNF-␣, and IL-2, which was protective against ECM (34). However, immunized mice eventually succumbed to infection due to hyperparasitemia-associated anemia (34).…”

Section: In Vivo Chemical Attenuation Following Inoculation Of Sporozmentioning

confidence: 99%

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Chemical Attenuation in the Development of a Whole-Organism Malaria Vaccine

2017

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Malaria vaccine development has been dominated by the subunit approach; however, many subunit vaccine candidates have had limited efficacy in settings of malaria endemicity. As our search for an efficacious malaria vaccine continues, the development of a whole-organism vaccine is now receiving much scrutiny. One strategy currently being explored in the development of a whole-organism vaccine involves chemical attenuation of the malaria parasite. In vivo and in vitro chemical attenuation of both liver-stage and blood-stage Plasmodium parasites has been investigated. Here, we discuss both approaches of chemical attenuation in the development of a whole-organism vaccine against malaria.KEYWORDS chemical attenuation, malaria, whole-organism vaccine C urrent methods in malaria control, such as the use of indoor residual spraying, insecticide-treated nets, and drug therapies, have led to reductions in malaria cases and malaria-related deaths (1). However, malaria still remains a leading cause of morbidity and mortality, with 3.3 billion people at risk of becoming infected with Plasmodium parasites (1). In 2015 alone, there were 212 million clinical cases and approximately 429,000 deaths due to malaria (2); therefore, the need for an efficacious malaria vaccine remains prominent. However, despite concerted efforts over many years, an effective malaria vaccine remains elusive. There have been continued concerns with the efficacy of the subunit vaccine approach (3-6), leading to a renewed interest in the use of the whole-organism vaccine approach for malaria.Whole-organism vaccines have been used successfully to protect individuals and populations from infectious diseases (reviewed in reference 7). This approach maximizes the number of antigens presented to the immune system and thus may limit the impact of antigenic diversity on vaccine efficacy. There are different types of wholeorganism vaccines, including killed and live attenuated vaccines, that can be produced using heat, genetic manipulation, radiation, or chemicals. Some of the earliest vaccines utilized formalin to chemically treat the infectious organism (reviewed in reference 8). These vaccines are often referred to as "inactivated" vaccines and include vaccines against polio, hepatitis A, and cholera (9-11). More recently, chemicals have been used as attenuating agents in the development of a malaria vaccine, with promising results. CHEMICAL ATTENUATION OF MALARIA PARASITES IN VIVOSome of the earliest evidence that protection could be induced by infection and drug cure in malaria was provided by antimalaria drug evaluation studies in monkeys (12) and studies using malaria therapy in patients with neurosyphilis (13,14). Although not the primary aim of these studies, they demonstrated that drug cure given after a patent primary infection induced protection against a subsequent secondary infection, (12)(13)(14). Since these initial studies were conducted, numerous studies (in animals and humans) have focused on the protection and immunity induced by a ...

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Chemical Attenuation of Plasmodium in the Liver Modulates Severe Malaria Disease Progression

Cited by 18 publications

References 65 publications

γδ-T cells promote IFN-γ–dependentPlasmodiumpathogenesis upon liver-stage infection

γδ-T cells promote IFN-γ–dependentPlasmodiumpathogenesis upon liver-stage infection

Oxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes

Chemical Attenuation in the Development of a Whole-Organism Malaria Vaccine

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