AN IMMUNOPATHOLOGICAL ASSESSMENT OF HOST REPONSE TO PLASMODIUM BURGEI YOELII INFECTION

Abstract

In spite of the spectacular advances in the last three decades in the world wide effort to control malaria, the disease still remains a global problem. This situation is due partly to the emergence of insecticide-resistant strains of the mosquito vector and to the ability of the parasite itself to adapt to its environment. Sero-epidemiological studies have been of tremendous importance in the assessment of malaria endemicity but there is clear evidence that individuals in whose sera high tittered antibody may be demonstrated are nevertheless susceptible to infection. Furthermore, the discovery of cyclic antigenic modulations in the course of the parasite’s life cycle indicates that specific antibody may not be completely effective. These findings have highlighted the need for a thorough understanding of the biology of the parasite and elucidation of finer details of host parasite relationships so that new strategies may be formulated for intervention. A mouse model has therefore been set up to define the effects of defects of B- and T-lymphocytes on the course of malaria infection and on tissue response to the parasite, and to assess the effect of parasitization on the lectin- mediated agglutination of erythrocytes.

In addition, in an effort to determine the role of non¬lymphoid elements of the peripheral leucocyte pool in malaria-induced immuno-suppression, human peripheral granulocytes were examined during acute malaria infections to assess their response to chemotactic stimulation and also their phagocytic and intracellular killing capacities. Parasitological and histopathological studies were conducted to determine the effect of specific immunological deficiencies on the response of CBA mice to infection by Plasmodium berghei yoelii. A spectrum of susceptibility was discovered which extends from normal, immunocompetent CBA/Ca and CBA/T6T6 mice which were resistant to P. yoelii and recovered spontaneously within 23-27 days from a mild infection (3.5±0.66% parasitaemia), through B cell deficient (CBA/N) mice of intermediate susceptibility which also recovered from severe infections of long duration (54-60 days, 40±3.6% parasitaemia), to T-cell deprived (CBA/nunu) which did not recover (survival time 34-44 days and 21-35 days respectively). Histologically, hyperplasia of lynphoreticular tissue and evidence of extramedullary haematopoiosis were observed, as well as intrasplenic and intrahepatic accumulation of activated debris - laden macrophagos. All of these reactions were strong in normal animals but were blunted or absent in immunodeficient ones, particularly in those lacking T-lynphocytes. Pathological changes such as cloudy swelling and vacuolar degeneration, necrosis and morphological disturbances were seen in tissues from fatally infected animals. These results indicate that although B-lyuphocytcs may augment immunological response to malaria infection, T- lymphocytes seen to be the essential effector cells in the elicitation of effective resistance. Haematologically, it was observed that while normal mice were able to amount a neutrophilic response (30% in uninfected animals, 48% in infected ones), congenitally athymic mice were unable to do so (69% and 70%). Lymphocyte levels were depressed in all infected animals. There was severe anaemia in all animals as evidenced by a marked reticulocytosis and a drop in the packed cell volume. Of special interest was the monocytosis which accompanied the rise in parasitaemia. the .nonocyte level rose from about 3-4% in uninfected animals to 12-20% in infected ones. The monocytes appeared atypical and were christened "monocytoid cells". It seems as if these monocytoid cells are indicative of a crisis during a malaria infection. Previous experience indicate that individuals presenting with malaria exhibit a predisposition to superinfections. The apparent depression of immunity was thought to be due to an over commitment of immuno¬competent cells to malaria processing. Studies with human peripheral granulocytes indicated that this cell population, unlike the lymphoid elements, were not affected by malaria. Granulocytes were found to be effectively mobilised and were not deactivated in vitro by complement derived chemotactic factors Furthermore, granulocyte phagocytic capacity as assessed by Staphylococcus aureus ingestion and the intracellular killing ability as measured by the nitroblue tetrazolium test were both normal. These findings provide evidence that malarial immunosuppression is restricted only to some specific T- and B-lymphocyte related functions, possibly via lymphocyte polyclonal activation, but that non-specific immunological reactions remain normal. Current thought suggests that erythrocytes possess membrane-bound ligands which influence the attachment and penetration of malaria parasites and also affect the intravascular behaviour of the cells. Many of these ligands are composed of or associated with saccharide residues which may serve as receptors for a variety of lectins. The attraction between a lectin and the erythrocyte may induce erythrocyte agglutination, the amount of lectin required for optical agglutination depending on the number of distribution of the specific receptor on the cell surface. Studies reported here have shown that P. yoelii infected arythrocytes are more readily agglutinated than uninfected cells. With Phaseolus linensis lectin fro example, complete agglutination of uninfected cells was achieved with a concentration of 0.25 mg/rnl whereas only 0.016 ng/nl was required for infected cells, representing a 16-fold difference in terms of lectin concentration. Further investigations employing 125I -label led Arachis hyno^enc and t hascolns limensis showed that infected cells hound up to 36* less lectin than uninfected cells. This implies a one-third cocrcase in the amount of lectin-specific ligand present on the erythrocyte surface following parasitization. While no lectins were found which bound to cither cell population to the complete exclusion of the other, it is apparent that parasite internalization has some effect on the lectin binding ability of erythrocytes. Possible reasons for tho observed changes include a real loss of surface material (with probable association of lost ligand(s) with parasite receptor site), a substitution of now specificities and/or a change of membrane fluidity leading to a lectin-induced clustering of receptors.