Monoclonal Antibodies Binding to Malarial Merozoite Surface Protein 1 Protect <i>in vivo</i> Against <i>Plasmodium yoelii</i> Infection

The malarial merozoite invades the erythrocyte and develops within the host cell. One of the most important and well studied parasite surface proteins at this stage of the life cycle is merozoite surface protein-1 (MSP-1). Plasmodium falciparum MSP-1 undergoes proteolytic processing into several fragments, of which only the carboxyl-terminal 19 kDa fragment (MSP-119) remains on the merozoite surface during invasion of a new erythrocyte. To study the importance of antibodies to the 19 kDa fragment of Plasmodium yoelii MSP-1 in providing protective immunity against infection, MSP-1-specific monoclonal antibodies were produced and characterised. Six antibodies were studied in detail. When naïve mice were passively immunised with these antibodies and then challenged with P. yoelii YM; which is a virulent and lethal parasite line, four of the antibodies showed a protective effect, reducing the level of parasitacmia and increasing host survival. There was some correlation between antibody subclass and protection. The epitopes for the antibodies were located on MSP-1, two antibodies bound to a recombinant protein comprised of the whole of MSP-119, and two others bound to a smaller sub-domain of it. These antibodies also recognised a similar recombinant protein from P. yoelii 265 BY ; this cross-reaction occurred despite quite extensive sequence differences between the two polypeptides. Two other MSP-1 specific antibodies did not recognise recombinant MSP-119, one bound to an epitope in the protein sequence adjacent to MSP-119 and the second recognised a larger structure that included MSP-119. This panel of biologically active antibodies enables the mechanisms of antibody inhibition of erythrocyte invasion to be studied in detail

Suppressive and additive effects in protection mediated by combinations of monoclonal antibodies specific for merozoite surface protein 1 of Plasmodium yoelii

<p>Abstract</p> <p>Background</p> <p>The merozoite surface protein (MSP)-1 is a target antigen of protective immunity and a malaria vaccine candidate. The nature of this protective immune response warrants further investigation: although specific antibody is thought to play a major role, the mechanisms of protection are still unclear. Monoclonal antibodies (mAbs) specific for the C-terminus of MSP-1 from <it>Plasmodium yoelii </it>have been shown previously to provide protection against challenge infection when administered by passive immunization to mice. Three protective mAbs were re-examined and, in particular, the effect of combinations of antibodies on the protection provided was studied. It was found that a combination of two antibodies can either provide additive protective effects or result in a suppression of protection. In this report the importance of antibody subclass and epitope specificity in the outcome of these passive immunization experiments are discussed.</p> <p>Methods</p> <p>The minimum protective dose (MPD) for each mAb was determined, and then combinations of antibody at their MPD were investigated for their ability to control parasitaemia and promote survival in groups of mice. Mice were inoculated over three days with the MPD and challenged with a blood stage infection of the virulent <it>P. yoelii </it>17 XL. The resultant parasitaemia was assessed daily on Giemsa-stained blood films. Following the infection the presence of MSP-1 specific antibodies in the sera was monitored, and the proliferative responses of cells in the spleen of protected mice were measured.</p> <p>Results</p> <p>Combining antibodies resulted in either an additive effect on protection, with reduced peak parasitaemia and better survival, or resulted in a suppression of protection over that achieved by a single antibody alone. An additive effect was observed when B6 and F5 that have the same isotype and similar fine specificity, were combined. However, a combination of mAb D3, an IgG2a, with either B6 or F5 (both IgG3) suppressed protection, an effect that may have been due to the combination of different isotypes or to the different fine specificity of the antibodies.</p> <p>Conclusions</p> <p>These results suggest that a combination of protective antibodies with either the same or different isotypes can produce either an additive or a suppressive effect in passive immunization. This phenomenon may be important in better understanding immunity in this experimental mouse model of malaria.</p

Bone Fractures With and Without Sickle Cell Disease in the Pediatric Population

Background: Individuals with sickle cell disease are restricted from certain physical activities due to the increased risk of complications including fractures secondary to osteopenia. However the exact incidence and outcomes of fractures amongst these patients is unknown. Objectives: (1) describe the incidence, epidemiology, and outcomes of fractures in patients with SCD. (2) to compare fracture patterns and outcomes in patients with and without SCD. Methods: This is a retrospective, cohort study of patients aged 0-25 years old with HbSS, HbSC, or HbS-β-thalassemia with a fracture evaluated at a pediatric emergency department from April 2009-April 2022. Eligible patients were identified using a combination of ICD billing codes and a preexisting hematology clinic database. Patients were age/gender matched with non-SCD patients with fractures. Data on demographics, number and types of fractures and outcomes were collected. Results: 753 patients with SCD were identified during the study period. SCD patients with fractures were more likely to have multiple comorbidities, lower mean vitamin D levels and were less likely to be on vitamin D supplementation compared to those without fractures. The most common etiology was fall and carpal bones were most commonly fractured. Non-SCD patients with fractures were more likely to be obese and require surgical repair compared to their SCD peers. Conclusions: Fracture incidence among SCD patients is low. Male gender, multiple comorbidities, and lack of vitamin D supplementation are associated with increased risk of fracture. SCD patients with a fracture were less likely to require surgical treatment compared to their non-SCD counterparts

Embodiment and the origin of interval timing: kinematic and electromyographic data

Recent evidence suggests that interval timing (the judgment of durations lasting from approximately 500 ms. to a few minutes) is closely coupled to the action control system. We used surface electromyography (EMG) and motion capture technology to explore the emergence of this coupling in 4-, 6-, and 8-month-olds. We engaged infants in an active and socially relevant arm-raising task with 7 cycles and response period. In one condition cycles were slow (every 4 seconds) in another they were fast (every 2 seconds). In the slow condition, we found evidence of time locked sub-threshold EMG activity even in the absence of any observed overt motor responses at all 3 ages. This study shows that EMGs can be a more sensitive measure of interval timing in early development than overt behavior

Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals

During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres: less than 1:50 in 33% and below 1:1,000 in 79%, while only 1% showed titres above 1:5,000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC₅₀ values) as low as single digit nanograms per millitre. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective

Duffy blood group gene polymorphisms among malaria vivax patients in four areas of the Brazilian Amazon region

<p>Abstract</p> <p>Background</p> <p>Duffy blood group polymorphisms are important in areas where <it>Plasmodium vivax </it>predominates, because this molecule acts as a receptor for this protozoan. In the present study, Duffy blood group genotyping in <it>P. vivax </it>malaria patients from four different Brazilian endemic areas is reported, exploring significant associations between blood group variants and susceptibility or resistance to malaria.</p> <p>Methods</p> <p>The <it>P. vivax </it>identification was determined by non-genotypic and genotypic screening tests. The Duffy blood group was genotyped by PCR/RFLP in 330 blood donors and 312 malaria patients from four Brazilian Amazon areas. In order to assess the variables significance and to obtain independence among the proportions, the Fisher's exact test was used.</p> <p>Results</p> <p>The data show a high frequency of the <it>FYA/FYB </it>genotype, followed by <it>FYB/FYB, FYA/FYA</it>, <it>FYA/FYB-33 </it>and <it>FYB/FYB-33</it>. Low frequencies were detected for the <it>FYA/FY</it>^<it>X</it>, <it>FYB/FY</it>^<it>X</it>, <it>FYX/FY</it>^{<it>X </it>}and <it>FYB-33/FYB-33 </it>genotypes. Negative Duffy genotype (<it>FYB-33/FYB-33</it>) was found in both groups: individuals infected and non-infected (blood donors). No individual carried the <it>FY</it>^<it>X</it><it>/FYB-33 </it>genotype. Some of the Duffy genotypes frequencies showed significant differences between donors and malaria patients.</p> <p>Conclusion</p> <p>The obtained data suggest that individuals with the <it>FYA/FYB </it>genotype have higher susceptibility to malaria. The presence of the <it>FYB-33 </it>allele may be a selective advantage in the population, reducing the rate of infection by <it>P. vivax </it>in this region. Additional efforts may contribute to better elucidate the physiopathologic differences in this parasite/host relationship in regions endemic for <it>P. vivax </it>malaria, in particular the Brazilian Amazon region.</p