ABSTRACT
Many infections, including malaria, are associated with an increase in autoantibodies (AAbs). Prior studies have reported an association between genetic markers of susceptibility to autoimmune disease and resistance to malaria, but the underlying mechanisms are unclear. Here, we performed a longitudinal study of children and adults (n = 602) in Mali and found that high levels of plasma AAbs before the malaria season independently predicted a reduced risk of clinical malaria in children during the ensuing malaria season. Baseline AAb seroprevalence increased with age and asymptomatic Plasmodium falciparum infection. We found that AAbs purified from the plasma of protected individuals inhibit the growth of blood-stage parasites and bind P. falciparum proteins that mediate parasite invasion. Protected individuals had higher plasma immunoglobulin G (IgG) reactivity against 33 of the 123 antigens assessed in an autoantigen microarray. This study provides evidence in support of the hypothesis that a propensity toward autoimmunity offers a survival advantage against malaria.
Subject(s)
Autoantibodies , Immunoglobulin G , Malaria, Falciparum , Plasmodium falciparum , Humans , Plasmodium falciparum/immunology , Autoantibodies/immunology , Malaria, Falciparum/immunology , Malaria, Falciparum/parasitology , Child , Child, Preschool , Adult , Immunoglobulin G/immunology , Immunoglobulin G/blood , Female , Mali , Male , Adolescent , Antibodies, Protozoan/immunology , Longitudinal Studies , Infant , Antigens, Protozoan/immunology , Young Adult , Autoantigens/immunology , Seroepidemiologic Studies , Middle AgedABSTRACT
Natural killer (NK) cells lyse virus-infected cells and transformed cells through polarized delivery of lytic effector molecules into target cells. We have shown that NK cells lyse Plasmodium falciparum-infected red blood cells (iRBC) via antibody-dependent cellular cytotoxicity (ADCC). A high frequency of adaptive NK cells, with elevated intrinsic ADCC activity, in people chronically exposed to malaria transmission is associated with reduced parasitemia and resistance to disease. How NK cells bind to iRBC and the outcome of iRBC lysis by NK cells has not been investigated. We applied gene ablation in inducible erythrocyte precursors and antibody-blocking experiments with iRBC to demonstrate a central role of CD58 and ICAM-4 as ligands for adhesion by NK cells via CD2 and integrin αMß2, respectively. Adhesion was dependent on opsonization of iRBC by IgG. Live imaging and quantitative flow cytometry of NK-mediated ADCC toward iRBC revealed that damage to the iRBC plasma membrane preceded damage to P. falciparum within parasitophorous vacuoles (PV). PV were identified and tracked with a P.falciparum strain that expresses the PV membrane-associated protein EXP2 tagged with GFP. After NK-mediated ADCC, PV were either found inside iRBC ghosts or released intact and devoid of RBC plasma membrane. Electron microscopy images of ADCC cultures revealed tight NK-iRBC synapses and free vesicles similar in size to GFP+ PV isolated from iRBC lysates by cell sorting. The titer of IgG in plasma of malaria-exposed individuals that bound PV was two orders of magnitude higher than IgG that bound iRBC. This immune IgG stimulated efficient phagocytosis of PV by primary monocytes. The selective NK-mediated damage to iRBC, resulting in release of PV, and subsequent phagocytosis of PV by monocytes may combine for efficient killing and removal of intra-erythrocytic P.falciparum parasite. This mechanism may mitigate the inflammation and malaria symptoms during blood-stage P. falciparum infection.
Subject(s)
Malaria, Falciparum , Malaria , Humans , Monocytes , Ligands , Vacuoles , Malaria, Falciparum/parasitology , Erythrocytes/parasitology , Killer Cells, Natural , Plasmodium falciparum , Malaria/metabolism , Phagocytosis , Immunoglobulin G/metabolismABSTRACT
IgG antibodies play a role in malaria immunity, but whether and how IgM protects from malaria and the biology of Plasmodium falciparum (Pf)-specific IgM B cells is unclear. In a Mali cohort spanning infants to adults, we conducted longitudinal analyses of Pf- and influenza-specific B cells. We found that Pf-specific memory B cells (MBCs) are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to influenza-specific MBCs that are predominantly IgG+ from infancy to adulthood. B cell receptor analysis showed Pf-specific IgM MBCs are somatically hypermutated at levels comparable to influenza-specific IgG B cells. During acute malaria, Pf-specific IgM B cells expand and upregulate activation/costimulatory markers. Finally, plasma IgM was comparable to IgG in inhibiting Pf growth and enhancing phagocytosis of Pf by monocytes in vitro. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in children, expand and activate during malaria, and produce IgM that inhibits Pf through neutralization and opsonic phagocytosis.
Subject(s)
Antibodies, Protozoan/immunology , B-Lymphocytes/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Malaria, Falciparum/immunology , Malaria/immunology , Plasmodium falciparum/immunology , Adolescent , Adult , Antibodies, Protozoan/blood , Antigens, Protozoan/immunology , Child , Child, Preschool , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Immunologic Memory , Infant , Infant, Newborn , Longitudinal Studies , Malaria/blood , Malaria/epidemiology , Malaria/parasitology , Malaria, Falciparum/blood , Malaria, Falciparum/epidemiology , Malaria, Falciparum/parasitology , Male , Mali/epidemiology , Phagocytosis/immunology , Young AdultABSTRACT
Borrelia burgdorferi possesses a sophisticated and complex chemotaxis system, but how the organism utilizes this system in its natural enzootic life cycle is poorly understood. Of the three CheY chemotaxis response regulators in B. burgdorferi, we found that only deletion of cheY3 resulted in an altered motility and significantly reduced chemotaxis phenotype. Although ΔcheY3 maintained normal densities in unfed ticks, their numbers were significantly reduced in fed ticks compared with the parental or cheY3-complemented spirochetes. Importantly, mice fed upon by the ΔcheY3-infected ticks did not develop a persistent infection. Intravital confocal microscopy analyses discovered that the ΔcheY3 spirochetes were motile within skin, but appeared unable to reverse direction and perform the characteristic backward-forward motility displayed by the parental strain. Subsequently, the ΔcheY3 became 'trapped' in the skin matrix within days of inoculation, were cleared from the skin needle-inoculation site within 96 h post-injection and did not disseminate to distant tissues. Interestingly, although ΔcheY3 cells were cleared within 96 h post-injection, this attenuated infection elicited significant levels of B. burgdorferi-specific IgM and IgG. Taken together, these data demonstrate that cheY3-mediated chemotaxis is crucial for motility, dissemination and viability of the spirochete both within and between mice and ticks.
Subject(s)
Arachnid Vectors/microbiology , Bacterial Proteins/genetics , Borrelia burgdorferi/genetics , Chemotaxis , Ixodes/microbiology , Lyme Disease/microbiology , Methyl-Accepting Chemotaxis Proteins/genetics , Animals , Antibodies, Bacterial/biosynthesis , Bacterial Load , Bacterial Proteins/metabolism , Borrelia burgdorferi/growth & development , Borrelia burgdorferi/pathogenicity , Gene Deletion , Gene Expression , Genetic Complementation Test , Immunoglobulin G/biosynthesis , Immunoglobulin M/biosynthesis , Lyme Disease/immunology , Lyme Disease/pathology , Lyme Disease/transmission , Methyl-Accepting Chemotaxis Proteins/deficiency , Mice , Mice, Inbred C57BL , Phenotype , Skin/microbiology , Skin/pathologyABSTRACT
Borrelia burgdorferi must migrate within and between its arthropod and mammalian hosts in order to complete its natural enzootic cycle. During tick feeding, the spirochete transmits from the tick to the host dermis, eventually colonizing and persisting within multiple, distant tissues. This dissemination modality suggests that flagellar motor rotation and, by extension, motility are crucial for infection. We recently reported that a nonmotile flaB mutant that lacks periplasmic flagella is rod shaped and unable to infect mice by needle or tick bite. However, those studies could not differentiate whether motor rotation or merely the possession of the periplasmic flagella was crucial for cellular morphology and host persistence. Here, we constructed and characterized a motB mutant that is nonmotile but retains its periplasmic flagella. Even though ΔmotB bacteria assembled flagella, part of the mutant cell is rod shaped. Cryoelectron tomography revealed that the flagellar ribbons are distorted in the mutant cells, indicating that motor rotation is essential for spirochetal flat-wave morphology. The ΔmotB cells are unable to infect mice, survive in the vector, or migrate out of the tick. Coinfection studies determined that the presence of these nonmotile ΔmotB cells has no effect on the clearance of wild-type spirochetes during murine infection and vice versa. Together, our data demonstrate that while flagellar motor rotation is necessary for spirochetal morphology and motility, the periplasmic flagella display no additional properties related to immune clearance and persistence within relevant hosts.