Biomedical subjects
A Saul
Publications and source records attributed to A Saul.
The role of variant surface antigens on malaria-infected red blood cells.
It has been proposed that the primary role of variant antigens appearing on the surface of red blood cells infected with malaria parasites is to mediate cytoadherence, and that the antigenic variation they display is an adaptation to avoid immune attack. Here, Allan Saul proposes that their role is the opposite: that their primary purpose is to generate an immune response, which regulates their growth and thereby establishes a chronic infection, and that the role of cytoadherence is to ensure that parasites failing to express this flag to the immune system are destroyed by the spleen.
Anaemia of acute malaria infections in non-immune patients primarily results from destruction of uninfected erythrocytes.
While anaemia has long been recognized as a consequence of acute infections with malaria, the relative contributions of direct erythrocyte destruction by parasites, destruction of uninfected erythrocytes and changes in erythropoiesis have been unclear. Fitting of parasitaemia and anaemia data from neurosyphilis patients undergoing malaria therapy to a mathematical model shows that in these patients, an average of 8.5 erythrocytes were destroyed in addition to each erythrocyte observed to become parasitized. The model also showed that dyserythropoiesis plays an insignificant role in the resulting anaemia. The anaemia occurs before a substantial antibody response to parasites or erythrocytes could be generated. We postulate that uninfected erythrocyte destruction occurs through phagocytosis of erythrocytes bound to merozoites killed as a result of the accompanying malaria paroxysms.
DNA sequence analysis of the ribosomal DNA ITS2 region for the Anopheles punctulatus group of mosquitoes.
The internal transcribed spacer 2 (ITS2) from the ribosomal DNA was sequenced and characterized for ten cryptic species in the Anopheles punctulatus group, the members of which are major vectors of malaria and filariasis in the south-west Pacific. The length of the ITS2 ranged from 549 bp to 565 bp and displayed levels of sequence variation ranging from 2.3% to 24.3% due mainly to indels of simple sequences. The GC content varied from 61.3% to 70.9%. These values were higher than those found in other cryptic species of mosquitoes and comparable only to members of the An. dirus complex suggesting a possible link between this group of Asian mosquitoes and the An. punctulatus group. Optimal and suboptimal secondary structures were investigated and revealed structures where the 5' region folded independently of the 3' region. Due to the large level of sequence variation between species, the ITS2 region proved unsuitable for phylogenetic analysis.
A single point mutation at a splice site generates a silent RH50 gene in a composite heterozygous RHnull blood donor.
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stevor and rif are Plasmodium falciparum multicopy gene families which potentially encode variant antigens.
Several multicopy gene families have been described in Plasmodium falciparum, including the var genes that code for the variant surface antigen PfEMP1, the stevor family of subtelomeric open reading frames and the rif interspersed repetitive elements. This report documents the chromosomal location of stevor genes, their transcription and characteristics of the deduced protein. On 14 chromosomes, 34 stevor copies were identified from the Dd2 parasite line. Most are in subtelomeric regions within 50 kb of the telomere. stevor genes are located close to var genes and rij. All stevor genes sequenced had two exons: a short exon 1 encoding a start codon and a transmembrane domain; exon 2 encoding for the remainder of the approximately 30 kDa protein and including two more transmembrane segments. A similar structure was found for copies of rif and its predicted protein. In both STEVOR and RIF proteins, a highly polymorphic region is predicted to be a loop on the outer side of the membrane. We propose that stevor and rif are members of a larger superfamily. The number of copies of stevor and rif, their location close to the var genes, their extreme polymorphism and the predicted structure of the proteins suggest that stevor and rif code for variant surface antigens.
The RhD- trait in a white patient with the RhCCee phenotype attributed to a four-nucleotide deletion in the RHD gene.
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The circumsporozoite protein of Plasmodium chabaudi contains a large, pre-region I repeat domain.
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Aboriginality as a variable in epidemiology.
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A novel single missense mutation identified along the RH50 gene in a composite heterozygous Rhnull blood donor of the regulator type.
Rare individuals who lack all of the Rh blood group antigens are called Rhnull and may be classified as "regulator" or "amorph" types. The suppression of Rh antigen expression for regulator types may be attributed to mutations of the RH50 gene, which is independent of the RH locus. The RH50 gene encodes a glycoprotein that interacts with the Rh proteins to form a functional complex within the red blood cell membrane. This report describes an RH50 gene mutation for a previously unclassified Rhnull donor. Sequencing cDNA clones from Rh50 mRNA revealed a single base change (G836A) yielding a missense and nonconservative mutation (Gly279Glu) within a predicted hydrophobic domain for this membrane protein. Genomic DNA studies using polymerase chain reaction (PCR) restriction analysis and sequencing showed that the Rhnull propositus was a composite heterozygote for this mutation, carrying two alleles with the A and G at nucleotide 836, respectively. In contrast, cDNA studies showed that only the A836 sequence was present, suggesting that the second allele with G836 was apparently silent (no transcript detected). Family studies showed that the mutant RH50 allele (836A) was inherited maternally, whereas the silent RH50 allele (836G) was from paternal transmission. These findings provide further evidence that rare but diverse genetic alterations may occur along the RH50 gene where the Rhnull syndrome of the regulator type occurs. The single amino acid change (Gly to Glu) provides insight into the critical value of these residues for assembly of the Rh antigen complex within the membrane.
Evolution and systematics of Anopheles: insights from a molecular phylogeny of Australasian mosquitoes.
Relationships among the genus Anopheles and its many sibling species-groups are obscure despite the importance of anophelines as the vectors of human malaria. For the first time, the interrelationships and the origin of Australasian members of the subgenus Cellia are investigated by a cladistic analysis of sequence variation within the mitochondrial cytochrome oxidase subunit II gene. Estimated divergence times between many Australasian and Oriental taxa predate the mid Miocene collision of Australasia and Southeast Asia. Phylogenetic analysis suggests that two-way exchanges with Oriental mosquitoes rather than only immigration may have been a characteristic of anopheline paleobiogeography in Australasia. The Australasian fauna is mostly included in a large clade. The medically important Punctulatus Group is monophyletic and appears derived from Oriental stock. Populations within this group from as far apart as Australia and Vanuatu were in contact in the recent past (i.e., 0.35-2.44 mya), supporting dispersal rather than vicariance explanations. Some support for the monophyly of the Myzomyia, Neomyzomyia, and Pyretophorus Series was found. However, the subgenera Anopheles and Cellia and the Neocellia Series are paraphyletic, but branch support at these taxonomic levels was poor. The COII gene shows promise for questions concerning alpha taxonomy but appears to be of limited use for resolving deeper relationships within the Anopheles.
Malaria mortality: the pacific enigma-reply.
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Models for the in-host dynamics of malaria revisited: errors in some basic models lead to large over-estimates of growth rates.
The mathematical model of the in-host dynamics for malaria parasites of Anderson, R. M., May, R. M. & Gupta, S. (1989), Parasitology 99 (Suppl.) S59-S79, and subsequently used by other authors, contains an error. This leads to very substantial over-estimates in parasite growth rates. A corrected form of the model is presented in this paper.
Definition of T cell epitopes within the 19 kDa carboxylterminal fragment of Plasmodium yoelii merozoite surface protein 1 (MSP1(19)) and their role in immunity to malaria.
MSP1(19) is one of the leading malaria vaccine candidates. However, the mechanism of protection is not clear. To determine whether MSP1(19)-specific effector T cells can control parasitaemia, we analysed the specificity of T cells induced following immunization with recombinant forms of P. yoelii MSP1(19) and asked whether they could protect mice. There was no evidence that effector T cells were capable of protecting since: (1) immunization of mice with yMSP1(19), but not defined epitopes, was able to induce protection; and (2) long term MSP1(19)-specific CD4+ T cell lines were incapable of adoptively transferring protection. In contrast, priming mice with the T cell epitopes resulted in a rapid anamnestic antibody response to MSP1(19) after either challenge with MSP1(19) or parasite. Thus, MSP1(19) contains multiple T cell epitopes but such epitopes are the targets of helper T cells for antibody response but not of identified effector T cells capable of controlling parasitaemia.
Autoantibodies to autologous skin in guttate and plaque forms of psoriasis and cross-reaction of skin antigens with streptococcal antigens.
BACKGROUND: Psoriasis is a chronic disease of the skin that appears to be of autoimmune nature. It has a strong association with throat streptococcal infections, as well as with stressful events. Although many groups consider psoriasis to be a T-cell-mediated autoimmune disease, autoantibodies could also play a role in the development of this process. METHODS: In this work, we looked for autoantibodies to psoriatic skin in 21 psoriatic patients and four healthy donors (controls). The immunoperoxidase technique was used to look for autoantibodies in autologous sera in skin sections obtained from lesions or from healthy areas of the same patient, before and after immunoadsorption with a Streptococcus pyogenes extract. The skin biopsies were also analyzed with a pool of sera from mice immunized with the streptococcal extract. RESULTS: We found that all psoriatic patients had autoantibodies to antigens present in keratinocytes, whereas healthy subjects did not. These antibodies did not recognize epitopes on healthy skin from the same psoriatic patients or controls. Immunoadsorption of autologous sera removed the reactivity to antigens in skin lesions in all cases. Mouse anti-streptococcal sera recognized epidermal antigens present in lesional psoriatic skin, but not in healthy skin from psoriatic patients or controls. Deposits of immunoglobulin G (IgG) were not detected in the lesions. CONCLUSIONS: It seems that autoantibodies, although they do not appear to participate in the pathogenesis of psoriasis, are an important feature, and that skin antigens, which appear in lesional immature keratinocytes, cross-react with S. pyogenes and contribute to the autoimmune process in psoriasis.
IgG antibody subclasses, tumor necrosis factor and IFN-gamma levels in patients with type II lepra reaction on thalidomide treatment.
A group of 9 Mexican lepromatous leprosy patients was studied at the beginning of a type II reaction (erythema nodosum leprosum, ENL) and after 1 or 2 months of thalidomide treatment. ENL patients at the onset of the reaction had slightly higher amounts of anti-Mycobacterium leprae IgG1 and IgG2 antibodies, compared to similar lepromatous patients that did not develop ENL. Neither these antibody levels nor IgM and the other IgG subclasses were importantly modified after thalidomide treatment. Serum TNF was significantly higher in the patients that developed ENL compared to those that did not develop the reaction. TNF levels were slightly decreased after 1 month of thalidomide treatment and significantly decreased after 2 months of treatment. Serum IFN-gamma was significantly lower in patients at the onset of ENL and was increased after 1 and 2 months of thalidomide treatment.
Profile of Morong, Bataan, an area of low malaria endemicity in the Philippines.
A malaria study area in the Philippines is described. It consists of the municipality of Morong, Bataan on the Island of Luzon. In January 1992, the population was 19454 in 106 villages located on a narrow coastal plain, or in valleys of streams running from the mountainous interior. This is an area of low level but persistent seasonal transmission of malaria with approximately one thousand cases reported each year, mainly from February to July. In spite of the low level of malaria, it is apparently quite stable. The study site has been used to investigate parameters leading to stable malaria. Hypotheses tested were that there was substantial under reporting of cases; that there was strain specific immunity stabilising the incidence of malaria and that malaria transmission in this area is highly localised in small regions with a high enough malaria prevalence to account for the year to year stability. The study plan included cross sectional surveys of parasite prevalence and seropositivity, longitudinal surveys, passive case detection, entomological surveys, anthropological surveys to assess knowledge of malaria and documentation of the health-seeking behaviour of the population.
Vector abundance and behaviour in an area of low malaria endemicity in Bataan, the Philippines.
The vectorial importance of known and potential vectors in Morong, Bataan, Philippines was assessed based on human and animal baited collections of adult mosquitoes and on larval collections. Anopheles flavirostris, the principal vector in the Philippines, was the most abundant among human landing catches, followed by An. maculatus sensu lato (s.l.). Both showed similar seasonal abundance with a peak during the early drier part of the year, which coincided with the peak in malaria cases. Both An. flavirostris and An. maculatus s.l. fed throughout the night with the broad peak of capture from 00:00 to 04:00 and from 22:00 to 00:00, respectively. The two species had similar parous rates (0.76 and 0.72, respectively) giving an average life span equivalent to four feeding cycles. Neither vector was abundant with average human landing rates on collectors of 0.6 and 0.4 mosquitoes per person per night, respectively over the study period. An. maculatus s.l. showed a stronger preference for outdoor feeding compared to An. flavirostris. An. maculatus s.l. was markedly zoophilic with a biting rate on water buffalo 50 times the human landing rate. An. flavirostris was less zoophilic with a corresponding ratio of 7.5. It was concluded that in this area, An. flavirostris is the principal vector. The combination of localised transmission, late night biting pattern and localised breeding sites of An. flavirostris suggest that the use of bed nets and environmental management are relevant control measures that can be implemented through community participation.