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    • Previous family based studies did

    2018-11-09

    Previous family-based studies did not take into account e but the overall evidence suggested that shared environment between twins did not contribute to MDD () in line with Zeng et al. that did not identify any effect of shared environment between siblings or family members. On the other hand, individual-specific environmental factors were found to affect significantly MDD (63%, 95% CI=58–67% ()) but this association could not be investigated by Zeng et al. because these data were lacking.
    Understanding mechanisms of immunity that protect from malaria is essential for the development of highly effective vaccines. The merozoite form of the parasite, which invades red blood cells, is an important target of protective immunity (). Biryukov et al. bring to our attention the potential ability of complement factors to enhance . merozoite invasion (). They proposed that i) complement activation at the merozoite surface enhanced the ability of merozoites to bind and invaded RBCs and ii) that purchase congo red to merozoite surface protein 1 (MSP1) C-terminal region further enhanced this process. These findings were primarily demonstrated with a murine monoclonal antibody (mAb) to MSP1-19, and some assays were performed with samples from a MSP1-42 phase I vaccine trial in malaria-naïve adults. We wish to add further discussion to the potential relevance of these findings, and how they differ from previously published studies to further understand anti-malarial immunity and pathogenesis. We previously reported that there is no difference in merozoite invasion efficiency in normal, complement active sera compared to heat inactivated, complement inactive human sera in the absence of immune antibodies, even at 80% serum concentrations (). Further, we reported that complement active serum significantly increases the inhibitory capacity of naturally acquired and vaccine-induced human and rabbit antibodies targeting the merozoite (). We showed that many antibodies required complement factors for invasion inhibitory activity, and we demonstrated the importance of this mechanism for naturally acquired and vaccine induced human and rabbit antibodies against specific merozoite proteins including the abundant merozoite surface proteins, MSP1 and MSP2 (). Recent results from a mouse model of malaria supports this role for complement-dependent invasion inhibition and reported that antibody-mediated protection from . infection malaria after immunization with a genetically attenuated parasite vaccine was partly mediated by antibody interactions with complement (). Consistent with these findings are previous studies in . models that demonstrate that C1q-deficient animals were significantly more susceptible to secondary challenge with the same parasite stain, highlighting the central role of C1q and classical complement activation in acquired immune responses (). We disagree with the suggestion of Biryukov et al. that the discrepancy between their and our findings is due to heighted sensitivity of isolated merozoites to complement activation. As we have previously shown, isolated merozoites are structurally intact, invade at similar efficiencies to standard routine culture, and do not require serum factors to invade nor show enhanced invasion in serum (). Since publication, numerous other studies have used this method for isolating viable merozoites, and increased sensitivity/decreased viability has not been reported. It is possible that the impact of complement on invasion is different in standard growth assays as used by Biryukov et al. compared to , or depending on parasite strains used. However, we and others have previously included normal sera in growth assays using a number of different parasite lines; reduced or comparable growth has been consistently reported, but not enhanced invasion compared to heat inactivated sera (() and unpublished data Boyle, Beeson et al.). It seems more likely that the major difference between the findings is the type of antibodies used; naturally acquired and vaccine induce human and rabbit polyclonal antibodies against different merozoite antigens by Boyle et al. compared to murine mAb or vaccine induced human antibodies to the C terminal of MSP1 in the case of Biryukov et al.