A salmonelose septicêmica prolongada é uma entidade clinicamente individualizada caracterizada por febre prolongada com hepatoesplenomegalia que ocorre em indivíduos esquistossomóticos coinfectados com salmonelas. Os mecanismos imunopatogênicos são vários e dependem das peculiaridades das interações entre as salmonelas e várias espécies do gênero Schistosoma. As modificações ocasionadas no sistema imunitário pela infecção parasitária são responsáveis pela evolução do quadro da doença. Nesta revisão, analisamos a evolução do conhecimento sobre a entidade e discutimos os possíveis mecanismos imunofisiopatogênicos que concorrem para seu desenvolvimento.

Chronic septicemic salmonellosis is an individualized clinical entity characterized by prolonged fever with enlargement of the liver and spleen that occurs in Schistosoma-infected individuals who are coinfected with Salmonella. Several immunopathogenic mechanisms are involved, and they depend on the peculiarities of the interactions between Salmonella and various species of the genus Schistosoma. The modifications to the immune system that are caused by parasite infection are responsible for the evolution of the disease. In this review, we analyze the evolution of the knowledge on this entity and discuss the possible immuno-physiopathogenic mechanisms that contribute towards its development.

Monócitos/macrófagos desempenham uma função crítica nos mecanismos de defesa antiplasmódio e constituem as principais células responsáveis pela eliminação das formas eritrocitárias do plasmódio da circulação sangüínea. Realizamos uma avaliação microscópica dos estágios da fagocitose in vitro de eritrócitos infectados por Plasmodium falciparum por monócitos humanos. Essas células foram obtidas de indivíduos adultos sadios por centrifugação em Percoll e incubadas com eritrócitos infectados por Plasmodium falciparum previamente incubados com um pool de soro imune contra plasmódio. Descrevemos os estágios da fagocitose, desde a aderência dos eritrócitos infectados até sua destruição nos fagolisossomas dos monócitos. Observou-se que eritrócitos infectados por todos os diferentes estágios assexuados do parasito foram ingeridos pelos monócitos e que o processo de fagocitose pode se completar em cerca de 30 minutos. Além disso, mostramos que a fagocitose pode ocorrer de uma forma contínua, de tal maneira que diferentes fases do processo foram observadas no mesmo fagócito.

Monocytes/macrophages play a critical role in the defense mechanisms against malaria parasites, and are the main cells responsible for the elimination of malaria parasites from the blood circulation. We carried out a microscope-aided evaluation of the stages of in vitro phagocytosis of Plasmodium falciparum-infected erythrocytes, by human monocytes. These cells were obtained from healthy adult individuals by means of centrifugation through a cushion of Percoll density medium and were incubated with erythrocytes infected with Plasmodium falciparum that had previously been incubated with a pool of anti-plasmodial immune serum. We described the stages of phagocytosis, starting from adherence of infected erythrocytes to the phagocyte membrane and ending with their destruction within the phagolisosomes of the monocytes. We observed that the different erythrocytic forms of the parasite were ingested by monocytes, and that the process of phagocytosis may be completed in around 30 minutes. Furthermore, we showed that phagocytosis may occur continuously, such that different phases of the process were observed in the same phagocyte.

Malaria emerges from a disequilibrium of the system 'human-plasmodium-mosquito' (HPM). If the equilibrium is maintained, malaria does not ensue and the result is asymptomatic plasmodium infection. The relationships among the components of the system involve coadaptive linkages that lead to equilibrium. A vast body of evidence supports this assumption, including the strategies involved in the relationships between plasmodium and human and mosquito immune systems, and the emergence of resistance of plasmodia to antimalarial drugs and of mosquitoes to insecticides. Coadaptive strategies for malaria control are based on the following principles: (1) the system HPM is composed of three highly complex and dynamic components, whose interplay involves coadaptive linkages that tend to maintain the equilibrium of the system; (2) human and mosquito immune systems play a central role in the coadaptive interplay with plasmodium, and hence, in the mainten-ance of the system's equilibrium; the under- or overfunction of human immune system may result in malaria and influence its severity; (3) coadaptation depends on genetic and epigenetic phenomena occurring at the interfaces of the components of the system, and may involve exchange of infectrons (genes or gene fragments) between the partners; (4) plasmodia and mosquitoes have been submitted to selective pressures, leading to adaptation, for an extremely long while and are, therefore, endowed with the capacity to circumvent both natural (immunity) and artificial (drugs, insecticides, vaccines) measures aiming at destroying them; (5) since malaria represents disequilibrium of the system HPM, its control should aim at maintaining or restoring this equilibrium; (6) the disequilibrium of integrated systems involves the disequilibrium of their components, therefore the maintenance or restoration of the system's equilibrium depend on the adoption of integrated and coordinated measures acting on all components, that means, panadaptive strategies. Coadaptive strategies for malaria control should consider that: (1) host immune response has to be induced, since without it, no coadaptation is attained; (2) the immune response has to be sustained and efficient enough to avoid plasmodium overgrowth; (3) the immune response should not destroy all parasites; (4) the immune response has to be well controlled in order to not harm the host. These conditions are mostly influenced by antimalarial drugs, and should also be taken into account for the development of coadaptive malaria vaccines.

A malária causa importantes alterações do sistema imunitário, muitas ainda mal definidas. Para permitir uma avaliação abrangente da atividade citotóxica das células natural killer em pacientes com malária, desenvolvemos um teste capaz de avaliar concomitantemente a dinâmica e a cinética do processo. Para a avaliação da cinética, células mononucleares do sangue periférico interagiram com células K562 e foram mantidas em agarose, enquanto para avaliar a dinâmica as células eram mantidas em suspensão. A cinética da atividade citotóxica das células NK foi mais rápida em pacientes com Plasmodium vivax, do que naqueles infectados com P. falciparum. Nestes, houve correlação positiva entre a atividade citotóxica das células NK e a parasitemia. O padrão da dinâmica da atividade citotóxica nos pacientes com malária foi bem diferente daquele apresentado pelos indivíduos sadios. Enquanto nestes, a atividade estava muito aumentada no início da incubação das células, sofrendo posteriormente uma redução, nos indivíduos infectados foram detectados sucessivos picos de atividade citotóxica. Nossos resultados confirmam a ocorrência de alteração funcional das células NK na malária humana e acrescentam novos dados sobre a dinâmica e a cinética da atividade citotóxica.

Malaria causes important functional alterations of the immune system, but several of them are poorly defined. To evaluate thoroughly the natural killer cell cytotoxicity in patients with malaria, we developed a technique capable to assess both the dynamics and the kinetics of the process. For the kinetics assay, human peripheral blood mononuclear cells were previously incubated with K562 cells and kept in agarose medium, while for the dynamics assay both cells were maintained in suspension. NK activity from patients with vivax malaria presented a kinetics profile faster than those with falciparum malaria. NK cytotoxicity positively correlated with parasitemia in falciparum malaria. The dynamics of NK cytotoxicity of healthy individuals was elevated at the beginning of the process and then significantly decreased. In contrast, malaria patients presented successive peaks of NK activity. Our results confirmed the occurrence of alteration in NK cell function during malaria, and added new data about the NK cytotoxicity process.

A Amazônia é conhecida pela elevada prevalência de infecção pelo vírus da hepatite B, contribui também com mais de 90% dos casos de malária do país. É proposto que a ocorrência de co-infecções seja importante e que na associação ocorram alterações na história natural dessas enfermidades. O estudo avalia 545 pacientes com malária, em Coari, AM: 333 (61,1%) pelo Plasmodium vivax, 193 (35,4%) pelo Plasmodium falciparum e 19 (3,5%) com infecção mista. A prevalência do AgHBs foi 4,2% e a do anti-HBc total 49,7%. Os pacientes sororreativos para o VHB, não apresentaram diferenças clínicas dos outros pacientes com malária, nem associação a sinais clássicos de comprometimento hepático. Apesar de não ter sido detectada associação estatisticamente significativa, os indivíduos AgHBs reativos apresentaram baixas parasitemias e índices de reatividade de anticorpos mais elevados, sugerindo a possibilidade da resposta imune em um indivíduo co-infectado ser diferenciada e favorecer variações em relação à parasitemia e produção de anticorpos.

The Amazon region is known for a high prevalence of hepatitis B infection, and accounts for more than 90% of malaria cases in Brazil. It has been suggested that the occurrence of coinfections may be important, and may influence the natural history of both diseases. This study evaluated 545 patients with acute malaria, in Coari, Western Brazilian Amazon. 333 (61.1%) presented Plasmodium vivax malaria, 193 (35.4%) Plasmodium falciparumand 19 (3.5%) mixed infections. The HBsAg prevalence was 4.2% and total anti-HBc 49.7%. Patients with HBV serological markers presented no clinical differences than those with malaria only, nor showed any association with classic signs of hepatic disorder. Although showing no statistical significance, HBsAg reactive subjects presented lower parasitic load and higher antibody titers, suggesting the possibility that the immune response in a coinfected individual is differentiated and leads to a variation in the parasite load and antibody production.

A Amazônia é conhecida pela elevada ocorrência de hepatite B e suas seqüelas. Contribui também com mais de 98% dos casos de malária do país. Apesar de controvérsias, é proposto que quando associadas ocorram alterações na história natural das duas patologias. Este estudo estima a prevalência de prováveis coinfecções em população geral de área endêmica de ambas infecções na Amazônia Brasileira. A taxa de portadores do AgHBs encontrada foi de 3,3% (IC 95% 2,1% a 5,1%,), e a do anti-HBc total 49,9% (IC 95% 45,9% a 53,8%). A prevalência de anticorpos contra antígenos do Plasmodium vivax e Plasmodium falciparum foi de 51,4% (311/605) (IC 95% 47,3% a 55,4%). Em relação à presença simultânea de anticorpos contra antígenos do Plasmodium vivax e Plasmodium falciparum com marcadores do VHB, 1,8% (11/605), (IC95% 1,0% a 3,3%), apresentavam também o AgHBs, tendo estes em média 26 anos de idade (p<0,001). Este estudo aponta semelhanças na distribuição dessas enfermidades como, a ocorrência preferencialmente entre adulto jovens. Os eventos provavelmente ocorrem em momentos distintos. Mostra também diferenças como, o baixo risco de malária entre menores de quinze anos, onde o VHB circula com moderada intensidade. As taxas de coinfecções são provavelmente menores que as de portadores do AgHBs, apresentando padrão heterogêneo em relação ao espectro clínico da infecção pelo VHB.

The Amazon region is known for the high occurrence of hepatitis B virus (HBV) infection, and accounts for more than 98% of malaria cases in Brazil. Despite the controversy, it has been proposed that when associated they may lead to important effects in the natural history of both infections. This study estimates the prevalence of coinfection within general population of an endemic region of HBV and malaria in the Brazilian Amazon. The prevalence of HBsAg was 3.3% (95% CI 2.1%-5.1%,) and total anti-HBc 49.9% (95% CI 45.9%-53.8%). The prevalence of antibodies against Plasmodium vivax and Plasmodium falciparum antigens was 51.4% (311/605) (95% CI 47.3%-55.4%). Related to the simultaneous presence of malaria antibodies and HBV serological markers, in 1.8% (11/605), (95% CI 1.0%-3.3%), the presence of HBsAg was also demonstrated, mean age 26 years (p <0.001). This study points to similarities in the distribution of these diseases, such as the occurrence mainly among young adults. The events may occur in different times. Also shown differences such as the low risk of malaria in the group up to fifteen years, where HBV circulates with moderate intensity. The prevalence of HBV and malaria coinfection is in fact less than the rates of HBsAg carriage, showing a heterogeneous pattern related to the clinical spectrum of HBV infection.

It is well established that immunity to malaria is short-lived and is maintained by the continuous contact with the parasite. We now show that the stable transmission of malaria in Yanomami Amerindian communities maintains a degree of immunity in the exposed population capable to reduce prevalence and morbidity of malaria. We examined 508 Yanomami Amerindians living along Orinoco (407) and Mucajaí (101) rivers, on the Venezuelan and Brazilian Amazon region, respectively. At Orinoco villages, malaria was hyperendemic and presented stable transmission, while at Mucajaí villages it was mesoendemic and showed unstable transmission. The frequency of Plasmodium vivax and P. falciparum was roughly comparable in Venezuelan and Brazilian communities. Malaria presented different profiles at Orinoco and Mucajaí villages. In the former communities, malaria showed a lower prevalence (16% x 40.6%), particularly among those over 10 years old (5.2% x 34.8%), a higher frequency of asymptomatic cases (38.5% x 4.9%), and a lower frequency of cases of severe malaria (9.2% x 36.5%). Orinoco villagers also showed a higher reactivity of the immune system, measured by the frequency of splenomegaly (72.4% x 29.7%) and by the splenic index (71.4% over level 1 x 28.6), and higher prevalence (91.1% x 72.1%) and mean titer (1243 x 62) of antiplasmodial IgG antibodies, as well as a higher prevalence (77.4% x 24.7%) and mean titer (120 x 35) of antiplasmodial IgM antibodies. Our findings show that in isolated Yanomami communities the stability of malaria transmission, and the consequent continuous activation of the immune system of the exposed population, leads to the reduction of malaria prevalence and morbidity.

Human organism is interpenetrated by the world of microorganisms, from the conception until the death. This interpenetration involves different levels of interactions between the partners including trophic exchanges, bi-directional cell signaling and gene activation, besides genetic and epigenetic phenomena, and tends towards mutual adaptation and coevolution. Since these processes are critical for the survival of individuals and species, they rely on the existence of a complex organization of adaptive systems aiming at two apparently conflicting purposes: the maintenance of the internal coherence of each partner, and a mutually advantageous coexistence and progressive adaptation between them. Humans possess three adaptive systems: the nervous, the endocrine and the immune system, each internally organized into subsystems functionally connected by intraconnections, to maintain the internal coherence of the system. The three adaptive systems aim at the maintenance of the internal coherence of the organism and are functionally linked by interconnections, in such way that what happens to one is immediately sensed by the others. The different communities of infectious agents that live within the organism are also organized into functional networks. The members of each community are linked by intraconnections, represented by the mutual trophic, metabolic and other influences, while the different infectious communities affect each other through interconnections. Furthermore, by means of its adaptive systems, the organism influences and is influenced by the microbial communities through the existence of transconnections. It is proposed that these highly complex and dynamic networks, involving gene exchange and epigenetic phenomena, represent major coevolutionary forces for humans and microorganisms.

Em 1992 foi feita uma investigação sobre o efeito protetor do uso de mosquiteiros impregnados com deltametrina, em uma população do município de Costa Marques, Rondônia, sujeita à transmissão malárica. Os mosquiteiros impregnados se comportaram de modo semelhante aos não impregnados, sem modificar os índices de infecção na época de baixa transmissão. A análise multivariada, por idade e títulos de anticorpos, mostrou uma proteção significante para o grupo com mosquiteiros impregnados contra o risco de infecção, apenas na estação de alta transmissão, quando os mosquiteiros foram usados mais regularmente. Não houve diferença no efeito de ambos os tipos de mosquiteiros na prevenção de elevadas parasitemias. Ao fim do estudo, ocorreu diminuição da prevalência de esplenomegalia em ambos os grupos, porém houve uma aparente recuperação da taxa normal de hematócrito em menores de 15 anos de idade em uso de mosquiteiros impregnados.

In 1992 an investigation regarding the value of insecticide impregnated mosquito nets was conducted in the municipality of Costa Marques, Rondonia. Impregnated mosquito nets gave similar protection to those not impregnated, without modifying the incidence of infection during the season of low transmission. The multivariate analysis for age and antibody titre showed a significant protection of impregnated nets against the risk of infection only in the season of high transmission, when bed nets were used more correctly. There was no difference in the effect of both kinds of bed nets in the prevention of high parasitaemia. At the end of the study, there was a reduction of the prevalence of splenomegaly in both groups but hematocrit values rose to normal in the below 15 year olds using impregnated nets.

Investigamos a influência da carga bacteriana e de anticorpos específicos sobre a fagocitose na esquistossomose. Macrófagos de camundongos esquistossomóticos mostraram uma menor capacidade para aumentar a fagocitose mesmo na presença de alta carga bacteriana, devido a um reduzido envolvimento destas células na fagocitose e a uma incapacidade para aumentar o número de bactérias fagocitadas por macrófago. Camundongos normais e infectados por Salmonella typhimurium aumentaram sua capacidade fagocitária quando expostos a uma alta carga bacteriana. Anticorpos para Salmonella typhimurium significantemente aumentaram a capacidade fagocitária de macrófagos de camundongos esquistossomóticos devido ao aumento do número de bactérias ingeridas mas não causaram nenhuma modificação no número de macrófagos envolvidos na fagocitose. Nossos dados indicam que macrófagos de camundongos esquistossomóticos trabalham próximo ao seu limite funcional, desde que nenhum aumento significante na fagocitose foi observado após aumentar a carga bacteriana. Anticorpos específicos podem melhorar sua capacidade fagocitária e, portanto, poderiam auxiliar na eliminação da infecção concomitante por Salmonella.

We investigated the influence of Salmonella typhimurium load and specific antibodies on phagocytosis in schistosomiasis. Macrophages from Schistosoma mansoni-infected mice showed depressed capacity to increase the phagocytosis in the presence of a high bacterial load, due to a reduced involvement of these cells in phagocytosis and to a deficient ability to increase the number of phagocytosed bacteria. Normal and Salmonella-infected mice increased their phagocytic capacity when exposed to a high bacterial load. Antibody to Salmonella increased the phagocytic capacity of macrophages from Schistosoma-infected mice due to an increase in the number of bacteria phagocytosed but caused no modification in the number of macrophages engaged in phagocytosis. Our data indicate that macrophages from Schistosoma-infected mice work close to their functional limit, since no increase in phagocytosis was observed after increasing the bacterial load. Specific antibodies can improve their phagocytic capacity and, therefore, could help clearing concurrent infection.

A resposta de anticorpos para os antígenos O e H da Salmonella typhi foi avaliada em 24 indivíduos com esquistossomose hepatointestinal ou hepatoesplênica antes e apôs vacinação antitifoídica, e comparada com a resposta de indivíduos controles normais. Antes da vacinação, pacientes esquistossomóticos mostraram uma maior frequência de anticoipos positivos para o antígeno O e a mesma frequência de anticoipos positivos para o antígeno H quando comparada com aquela de indivíduos controles normais. Porém, aqueles com esquistossomose hepatoesplênica mostraram títulos maiores de anticoipos para o antígeno H do que aqueles com a forma hepatointestinal da doença ou os indivíduos controles normais. Pacientes esquistossomóticos, particularmente aqueles com a forma hepatointestinal, mostraram uma menor resposta após a vacinação antitifoídica. Esta menor capacidade para apresentar uma resposta imune para antígenos de salmonela pode interferir com a retirada da bactéria da corrente sanguínea e, portanto, contribuir como um dos determinantes de sua prolongada sobrevivência como obsewada em pacientes com salmonelose septicêmica prolongada associada â esquistossomose.

Antibody response to Salmonella typhi O and H antigens was evaluated in 24 individuals with either hepatointestinal or hepatosplenic schistosomiasis mansoni before and after typhoid vaccination, and compared with that of non-infected controls. Before vaccination, Schistosoma-infected patients showed a higher frequency of positive antibody to O antigen and the same frequency to H antigen when compared with that of healthy individuals. However, those with hepatosplenic schistosomiasis showed higher titres of antibody to H antigen than those with hepatointestinal disease or healthy individuals. Infected subjects, particularly those with hepatointestinal disease, showed a decreased response after typhoid vaccine. Tins diminished ability to mount an immune response towards typhoid antigens dining schistosomiasis may interfere ivith the clearance of the bacteria from blood stream and, therefore, play a role in the prolonged survival of salmonella as obsewed in some patients with chronic salmonellosis associated with schistosomiasis.

Com uma incidência de 3 a 10% dos casos e letalidade próxima a 70%, o comprometimento pulmonar constitui uma das manifestações mais graves da malária por Plasmodium falciparum. Embora sua patogênese não esteja perfeitamente esclarecida, reconhece-se que a hiperativação do sistema imune por antígenos liberados pelo Plasmodium falciparum desempenhe um importante papel no desencadeamento e agravamento das lesões. A estrutura alvo parece ser o endotélio capilar, responsável pelo fluxo de líquidos para o espaço intersticial. Essas células são ativadas por ação de citocinas, produzidas por linfócitos e macrófagos durante a resposta imune, e passam a expressar em sua membrana celular receptores e moléculas de aderência que facilitam a sequestração de eritrócitos parasitados e também a aderência de células capazes de produzir mediadores inflamatórios. A reação inflamatória e a lesão endotelial que se seguem, juntamente com as alterações hemodinâmicas induzidas pelo bloqueio capilar devido ao acúmulo local de eritrócitos e células inflamatórias causam alterações de permeabilidade vascular e, consequentemente, acúmulo de líquido nos espaços intersticiais e alvéolos. Nos casos mais graves, as manifestações clínicas assemelham-se às do quadro da Síndrome do desconforto respiratório do adulto. Comprometimento pulmonar grave pode se instalar rapidamente em qualquer estágio da evolução clínica da malária, mesmo após a cura parasitológica, desconhecendo-se os fatores desencadeantes. Hiperparasitismo, insuficiência renal e gravidez constituem fatores predisponentes. O prognóstico dependerá da rapidez com que o diagnóstico for estabelecido e o correto tratamento instituído. Além do tratamento instituído contra o parasita, especial atenção deverá ser dispensada à monitorização hemodinâmica, se possível através de cateter de Swan-Ganz, à manutenção de adequada oxigenação e balanço hídrico, e ao controle de outras complicações, frequentemente associadas ao comprometimento pulmonar. O esclarecimento da patogenia do comprometimento pulmonar associado à malária deverá concorrer para a racionalização da conduta terapêutica e, consequentemente, melhorar o prognóstico dos indivíduos acometidos por esta complicação

Pulmonary involvement occurs in 3 to 10% of the cases of Plasmodium falciparum malaria and represents the most serious complication of this infection, with a lethality of about 70%. The understanding of its pathogenesis is still very fragmentary, however it is recognized that activation of the immune system by antigens released by the parasite plays an important role in the induction and worsening of lung damage. Capillary endothelial cells, which control the flux of fluids to the interstitial space, appear to be the most involved structure. These cells are activated by cytokines, produced by lymphocytes and macrophages during the immune response, and express receptors and molecules of adhesion, allowing for sequestration of parasitized erythrocytes and adherence of cells, which will produce locally inflammatory mediators. The inflammatory reaction and lesion of endothelial cells that ensue, together with the hemodynamic alterations induced by the capillary blockade due to the sequestration of parasitized erythrocytes and leukocytes, cause alterations of the vascular permeability and transfer of liquid to intertitial space and alveoles. Severe cases are clinically expressed by a picture of Adult Respiratory Distress Syndrome. The clinical manifestations of pulmonary involvement may start suddenly at any time during the course of malaria, even after desappearance of circulating parasites. The inducing factors are unknown. Hyperparasite-mia, renal failure and pregnancy are predisposing factors. The prognosis will depend on how fast the diagnosis is established and convenient treatment initiated. If parasites are present they shall be treated with schizonticidal drugs, hemodynamic parameters continuously evaluated, preferably through a Swam-Ganz catheter. Appropriate oxygen supply and fluid balance have to be warranted. Other complications of malaria, frequently associated to the pulmonary involvement, need special attention and proper treatment. A better understanding of the pathogenesis of lung damage associated to malaria will certainly help to improve treatment and reduce morbidity and mortality