Publicação
Host-parasite interactions mediated by toll-like receptors in malaria liver infection
| Resumo: | Malaria is one of the most severe human infectious diseases, affecting 5 to 10% of the world's population every year. Although malaria eradication has emerged as a desirable if audacious goal, it is consensual that the development of novel intervention strategies is limited by our current understanding of the biology of Plasmodium, the causative agent of malaria, and of the complex relationships that the parasite maintains with its hosts. Plasmodium has a complex life cycle that oscillates between a mosquito vector and a vertebrate host. Upon infection of its mammalian host, each Plasmodium sporozoite establishes itself in liver hepatocytes where it replicates into thousands of new parasites (merozoites) that are subsequently released into the bloodstream, infecting red blood cells and causing malaria. Liver infection by Plasmodium is an ideal target for the development of anti-malaria strategies, as it is the first step of infection and it is clinically silent. Indeed, Plasmodium liver stage is the epitome of a perfect malaria vaccine or drug target since complete protection from infection of the treated human host abrogates clinical manifestation and, importantly, transmission of the disease. Thus, understanding the key events during liver infection will certainly facilitate our progress towards novel intervention strategies against malaria. The prime challenge for any invaded host is to detect the pathogen and orchestrate a rapid defensive response. A set of essential surface and endosomal molecules that comprise the Toll or Toll-like family of receptors perform this role in invertebrate and vertebrate organisms, reflecting a remarkable conservation of function. Functional analysis of mammalian Toll-like receptors (TLRs) has revealed that they recognize specific evolutionarily conserved microbial molecules or molecular families that are present among pathogens and are usually critical to the pathogen's function. These molecules are not found in mammals except in cell stress and inflammation, making them crucial targets for immune intervention. The members of the TLR family recognize lipids, proteins, lipoproteins, carbohydrates, peptides, lipopeptides and nucleic acid structures that are broadly expressed by specific groups of pathogens, providing the basis for innate immunity and ensuring multiple mechanisms of the adaptive immune response against parasites. Although it is clear that pathogen detection involves members of the TLR family and that hepatocytes express the majority of all known TLRs, our current understanding about their function in the innate response to Plasmodium liver infection remains elusive. The work presented in this thesis aimed to determine the role of some of these innate receptors and their adaptor molecule, MyD88, not only in the establishment of Plasmodium in the liver but also during an immunization process with attenuated forms of Plasmodium sporozoites. Liver stage infection by Plasmodium is strongly affected by manipulation of TLR4 and TLR9. While TLR2-deficient mice are infected as wild-type control mice, TLR4 and TLR9-deficient mice show increased susceptibility and resistance to liver stage infection, respectively. While TLR4 absence dampens the inflammatory response, increasing the parasite load in the liver, the lack of TLR9 seems to be detrimental for the parasite. On the other hand, administration of LPS and CpG (TLR4 and TLR9 ligands, respectively), at the time of sporozoite injection, strongly reduces the levels of Plasmodium liver load. In humans, immunization with large numbers of radiation-attenuated sporozoites (RAS) remains the only protocol that leads to the induction of sterile immunity. MyD88 is a mediator of protective immunity induced by P. berghei RAS, despite the fact that when injected with viable sporozoites, MyD88-deficient mice are infected as normal wild-type control mice. Altogether, the findings presented herewith suggest that TLRs not only mediate major events in the establishment of Plasmodium liver stage infection but are also key players during the establishment of sterile immunity. |
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| Autores principais: | França, Ana Rita Serra da Costa, 1979- |
| Assunto: | Malária Plasmodium Fígado Hepatopatias parasitárias Imunidade inata Receptores toll-like Interacções hospedeiro-parasita Teses de doutoramento - 2011 |
| Ano: | 2011 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Malaria is one of the most severe human infectious diseases, affecting 5 to 10% of the world's population every year. Although malaria eradication has emerged as a desirable if audacious goal, it is consensual that the development of novel intervention strategies is limited by our current understanding of the biology of Plasmodium, the causative agent of malaria, and of the complex relationships that the parasite maintains with its hosts. Plasmodium has a complex life cycle that oscillates between a mosquito vector and a vertebrate host. Upon infection of its mammalian host, each Plasmodium sporozoite establishes itself in liver hepatocytes where it replicates into thousands of new parasites (merozoites) that are subsequently released into the bloodstream, infecting red blood cells and causing malaria. Liver infection by Plasmodium is an ideal target for the development of anti-malaria strategies, as it is the first step of infection and it is clinically silent. Indeed, Plasmodium liver stage is the epitome of a perfect malaria vaccine or drug target since complete protection from infection of the treated human host abrogates clinical manifestation and, importantly, transmission of the disease. Thus, understanding the key events during liver infection will certainly facilitate our progress towards novel intervention strategies against malaria. The prime challenge for any invaded host is to detect the pathogen and orchestrate a rapid defensive response. A set of essential surface and endosomal molecules that comprise the Toll or Toll-like family of receptors perform this role in invertebrate and vertebrate organisms, reflecting a remarkable conservation of function. Functional analysis of mammalian Toll-like receptors (TLRs) has revealed that they recognize specific evolutionarily conserved microbial molecules or molecular families that are present among pathogens and are usually critical to the pathogen's function. These molecules are not found in mammals except in cell stress and inflammation, making them crucial targets for immune intervention. The members of the TLR family recognize lipids, proteins, lipoproteins, carbohydrates, peptides, lipopeptides and nucleic acid structures that are broadly expressed by specific groups of pathogens, providing the basis for innate immunity and ensuring multiple mechanisms of the adaptive immune response against parasites. Although it is clear that pathogen detection involves members of the TLR family and that hepatocytes express the majority of all known TLRs, our current understanding about their function in the innate response to Plasmodium liver infection remains elusive. The work presented in this thesis aimed to determine the role of some of these innate receptors and their adaptor molecule, MyD88, not only in the establishment of Plasmodium in the liver but also during an immunization process with attenuated forms of Plasmodium sporozoites. Liver stage infection by Plasmodium is strongly affected by manipulation of TLR4 and TLR9. While TLR2-deficient mice are infected as wild-type control mice, TLR4 and TLR9-deficient mice show increased susceptibility and resistance to liver stage infection, respectively. While TLR4 absence dampens the inflammatory response, increasing the parasite load in the liver, the lack of TLR9 seems to be detrimental for the parasite. On the other hand, administration of LPS and CpG (TLR4 and TLR9 ligands, respectively), at the time of sporozoite injection, strongly reduces the levels of Plasmodium liver load. In humans, immunization with large numbers of radiation-attenuated sporozoites (RAS) remains the only protocol that leads to the induction of sterile immunity. MyD88 is a mediator of protective immunity induced by P. berghei RAS, despite the fact that when injected with viable sporozoites, MyD88-deficient mice are infected as normal wild-type control mice. Altogether, the findings presented herewith suggest that TLRs not only mediate major events in the establishment of Plasmodium liver stage infection but are also key players during the establishment of sterile immunity. |
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