Clinical Protection from Falciparum Malaria Correlates with Neutrophil Respiratory Bursts Induced by Merozoites Opsonized with Human Serum Antibodies

Abstract

BackgroundEffective vaccines to combat malaria are urgently needed, but have proved elusive in the absence of validated correlates of natural immunity. Repeated blood stage infections induce antibodies considered to be the main arbiters of protection from pathology, but their essential functions have remained speculative.Methodology/Principal FindingsThis study evaluated antibody dependent respiratory burst (ADRB) activity in polymorphonuclear neutrophils (PMN) induced by Plasmodium falciparum merozoites and antibodies in the sera of two different African endemic populations, and investigated its association with naturally acquired clinical protection. Respiratory bursts by freshly isolated PMN were quantified by chemiluminescence readout in the presence of isoluminol, which preferentially detects extra-cellular reactive oxygen species (ROS). Using a standardized, high throughput protocol, 230 sera were analyzed from individuals of all age groups living in meso- (Ndiop) or holo-endemic (Dielmo) Senegalese villages, and enrolled in a cross-sectional prospective study with intensive follow-up. Statistical significance was determined using non-parametric tests and Poisson regression models. The most important finding was that PMN ADRB activity was correlated with acquired clinical protection from malaria in both high and low transmission areas (P = 0.006 and 0.036 respectively). Strikingly, individuals in Dielmo with dichotomized high ADRB indexes were seventeen fold less susceptible to malaria attacks (P = 0.006). Complementary results showed that ADRB activity was (i) dependent on intact merozoites and IgG opsonins, but not parasitized erythrocytes, or complement, (ii) correlated with merozoite specific cytophilic IgG1 and IgG3 antibody titers (P<0.001 for both), and (iii) stronger in antisera from a holo-endemic compared to a meso-endemic site (P = 0.002), and reduced in asymptomatic carriers (P<0.001).Conclusions/SignificanceThis work presents the first clearly demonstrated functional antibody immune correlate of clinical protection from Plasmodium falciparum malaria, and begs the question regarding the importance of ADRB by PMN for immune protection against malaria in vivo.

Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact

“…The respiratory syncytial virus receptor, CX3CR1 (48,49), is found on intestinal macrophages, whereas CD81, an entry factor for hepatitis C virus, is also found on macrophages (50,51). Finally, it is evident from previous studies that Fc-FcγR-mediated cellular immunity plays a major role in mounting an effective protective response toward bacterial pathogens (52,53). Even in those circumstances, it is possible that a molecular bridge between the pathogen and the effector cell may enhance cell-mediated immunity.…”

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

“…been associated with protection against blood-stage infection in humans (16), possibly through the induction of Ab-dependent cellular inhibition (23,60) or Ab-dependent respiratory burst (22) mechanisms via interaction with FcgRs on innate effector immune cells (61). Although little is known about how rhesus IgG1-4 isotype function corresponds to their human counterparts, this study has highlighted the need for the development of rhesusspecific reagents to assess these.…”

“…Studies of naturally acquired immunity and experimental immunization in humans and animal models have painted a complex picture (14), with protection associated with Abs against merozoite Ags (15), specific IgG isotypes (16), T cells against blood-stage parasites (17)(18)(19)(20), innate effector cell types (21)(22)(23), serum cytokines (21,24), and regulatory T cells (25). Numerous other studies described the immunomodulatory effects of parasite exposure on T and B lymphocyte populations (26)(27)(28).…”

Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

“…Although protective blood-stage immunity has been widely associated with Ab responses, a growing body of evidence in both animal and human studies supports a contributing role for cellular immunity (15,16). Although infected erythrocytes lack MHC molecules with which to present parasite-derived peptides, it is thought that effector CD4 + T cells can enhance clearance of opsonized parasitized RBCs by macrophages in the spleen, orchestrate the induction of parasiticidal proinflammatory serum cytokine responses, and/or provide polarizing help for B cells leading to the induction of protective cytophilic IgG subclasses that may better interact with innate cellular effectors such as monocytes or neutrophils (17,18). CD8 + T cells have been shown to be protective in the Plasmodium yoelii mouse model at both the liver stage (19,20) and blood stage of malaria infection (21).…”