5 – Bioquímica de Schistosoma mansoni Franklin David Rumjanek, Iramaya Rodrigues Caldas e Giovanni Gazzinelli

Atkinson & Atkinson (1980) relataram a existência de um polipeptídeo de 66 kDa, sintetizado por machos e transferido para as fêmeas. Entretanto, esse achado não foi confirmado em outros estudos. Por exemplo, Popiel & Bash (1984a), utilizando parasitos marcados com Leucina 14C, in vivo e in vitro, constataram que, embora fêmeas dos vermes tenham captado pequena quantidade de produtos metabólicos derivados de machos, não foi observada a transferência de um polipeptídeo específico de 66 kDa em quantidades significativas.

Shaw (1977) observou que fêmeas obtidas de infecções unissexuais foram estimuladas por extratos de vermes machos, solúveis em éter e acetona. Este resultado, entretanto, parece ocorrer somente em uma linhagem particular de S. mansoni (fêmeas de Cardiff), cujas células vitelinas das fêmeas são capazes de se desenvolver na ausência de machos. Popiel (1986) e Kunz et al. (1995) sugeriram que a proliferação das células vitelinas maduras seria induzida por um sinal agindo como mitógeno, isto é, estimulando a proliferação das células tronco-vitelinas. Segundo os autores, uma série de moléculas participariam na transdução de sinal em S. mansoni, mediando o processo de proliferação de células vitelinas. Para demonstrar a transferência de colesterol, machos e fêmeas adultos de Schistosoma mansoni foram incubados 24 h em meio contendo [ 3H]colesterol. Os vermes marcados foram acasalados com um par não marcado, in vitro ou in vivo, por implantação cirúrgica em hamsters. Durante o período de acasalamento os vermes marcados perderam até 65% de seu [ 3H]colesterol, captado pelo seu par não marcado. Em ambos, machos e fêmeas, não marcados, acasalados com vermes marcados, os níveis de [3H]colesterol foram mais altos que controles não acasalados. Isto sugere que a transferência de colesterol entre pares de vermes é bidirecional e é facilitada pelo contato físico mediante justaposição das membranas. A troca de colesterol em pares de vermes de Schistosoma seria, provavelmente, uma conseqüência parcial ou total da renovação da molécula no tegumento (Popiel, 1986).

O estímulo táctil, que ocorre no contato macho-fêmea, também parece ser importante na maturação sexual das fêmeas (Popiel & Erasmus, 1982; Robinson, 1960). A importância do estímulo táctil foi mostrada num interessante experimento executado por Popiel & Basch (1984b). Machos e fêmeas de S. mansoni foram cortados em segmentos, pareados em diferentes arranjos e combinações e transferidos para as veias mesentéricas de hamsters ou cultivados in vitro. O acasalamento ocorreu entre vermes íntegros ou entre segmentos de machos com as fêmeas íntegras, tanto no hospedeiro como in vitro. Na maioria das fêmeas acasaladas com os segmentos ocorreu algum desenvolvimento do sistema reprodutivo, avaliado por diferenciação de glândulas vitelinas. O desenvolvimento das glândulas foi restrito à porção de contato com os fragmentos do macho, que continuaram a exibir contrações normais do corpo e integridade morfológica durante os 24 dias de manutenção in vitro. Daí os autores concluíram que:

na ausência de intestino funcional, segmentos de vermes podem sobreviver, durante períodos prolongados, com nutrientes absorvidos através do tegumento;

o desenvolvimento da fêmea é independente de controle do sistema nervoso;

o fator estimulador dos machos não tem localização centralizada;

a diferenciação das glândulas vitelinas na fêmea requer estímulo localizado, e não se propaga através do verme.

Formação do Ovo Analise histoquímica de fêmeas mostram que as células vitelinas, além de armazenarem nutrientes para desenvolvimento do embrião, apresentam também glóbulos contendo material precursor da parede do ovo (Smyth & Clegg, 1959; Wells & Cordingley, 1991). O processo de formação da parede do ovo parece envolver oxidação de resíduos de tirosina para formação de quinonas sob a ação do sistema enzimático fenol-oxidase. Quinonas são moléculas altamente instáveis, podendo reagir com grupos amino e sulfidrila de proteínas adjacentes, levando à formação de uma parede rígida ou uma cápsula protetora (Cordingly, 1987; Eshete & LoVerde, 1993).

Detalhes da ultra-estrutura do ovo de S. mansoni podem ser encontradas em Neill et al. (1988). A composição química da casca do ovo de S. mansoni e S. japonicum mostrou abundância dos aminoácidos glicina (37% para S. mansoni e 45% para S. japonicum), ácido aspártico, lisina e serina. A casca do ovo contém de 7, 5% a 10% de carboidratos, sendo glicosamina o constituinte principal (Byram & Senft, 1979).

Desenvolvimento do Macho

Aparentemente, embora o desenvolvimento do verme macho ocorra normalmente na presença ou na ausência da fêmea (Erasmus, 1987), algumas alterações fisiológicas e antigênicas já foram descritas entre machos de infecções uni e bissexuais: maior utilização de ácido aspártico em machos não acasalados (Cornford, 1985); diferenças qualitativas na resposta humoral, em infecções uni e bissexuais, à glicoproteínas de machos (Aronstein & Strand, 1984); e uma maior atividade nos machos de infecção unissexual (Shaw, 1977). Entretanto, os machos de S. japonicum de infecções unissexuais apresentam um crescimento menor e mais lento do que os acasalados (Severinghaus, 1928; Lee, 1932). Postulou-se que nestes casos particulares o desenvolvimento do macho pode ser controlado pelo menos em parte pela fêmea (Armstrong, 1965). Mais recentemente, Khalil & Mansour (Khalil & Mansour, 1995) descreveram uma redução significativa no peso do corpo de machos de S. mansoni e S. haematobium de infecções unissexuais, com relação a bissexuais. Este aspecto da biologia de Schistosoma merece reconsideração em vista dos novos resultados obtidos.

Aspectos Moleculares da Interação Macho-fêmea

A fim de esclarecer os mecanismos moleculares resultantes da interação macho-fêmea que levam ao desenvolvimento reprodutivo da fêmea, procurou-se, inicialmente, identificar genes ativos apenas no estádio reprodutivo das fêmeas. Os genes melhor caracterizados e que são expressos durante o desenvolvimento da fêmea de S. mansoni são os precursores das proteínas p14 e p48 da casca do ovo (LoVerde et al., 2004). Os mensageiros respectivos (mRNAs) são encontrados apenas nas fêmeas sexualmente maduras e não são encontrados nem nos machos, nem nos ovos. Nas infecções bissexuais experimentais, esses mRNA’s são transcritos 28 dias após o acasalamento, atingindo o nível máximo de transcrição em 45 dias. Por conseguinte, a ativação desses genes são marcadores do acasalamento. Experimentos de hibridização in situ demonstram que estímulos do macho são necessários para a síntese e tradução dos mRNA's p14 e p48. Esses produtos dos genes estão associados aos grânulos proteináceos das células vitelinas que contêm os precursores da casca do ovo (Chen, Rekosh & LoVerde, 1992). Existem na literatura evidências da presença de vias de transdução de sinais envolvidas no desenvolvimento reprodutivo das fêmeas. Por exemplo, a expressão de Ras (que codifica um grupo de proteínas da superfamília da GTPases que estão envolvidas na regulação da proliferação celular em vários sistemas) está regulada em machos e fêmeas do parasito, variando a concentração de seus componentes (Ras, MAP-kinase e GAP) de acordo com o sexo e estádio de desenvolvimento (Schussler, Grevelding & Kunz, 1997). TGFβ (fator de crescimento) e fatores relacionados, como por exemplo a activina, sinalizam por intermédio de uma família de proteínas transmembranosas identificadas como serina/treonina quinases. Existem dois tipos de receptores que atuam em conjunção com serina/treonina quinases, que são os tipos I e II. A expressão do receptor tipo I, identificada em S. mansoni, está aumentada após a infecção do hospedeiro (Davies, Shoemaker & Pearce, 1998). RI ativado transduz o sinal para uma família de proteínas denominadas Smads, que atuam como efetores da família de TGFβ. Através desses efetores o sinal é transferido para o núcleo, regulando a transcrição de genes específicos, em resposta à ativação de receptores. Três diferentes membros da família Smads já foram isolados em S. mansoni. Dois deles, SmSmads-2 e SmSmads-4 foram encontrados nas células vitelinas através de imunolocalização e hibridização in situ (Osman, Niles & Loverde, 2001).

Vários outros receptores que ativam quinases envolvidas na sinalização já foram identificados em S. mansoni e certamente influenciam o desenvolvimento e maturação do parasito (para detalhes adicionais ver a revisão de LoVerde et al. 2004).

Deve-se, ainda, mencionar que o desenvolvimento do parasito e, em especial, a sua fecundidade são também influenciados por citocinas do hospedeiro. Este aspecto, todavia, será abordado em detalhes no capítulo sobre imunologia.

 

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