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Biomedical subjects

P A Zimmerman

Publications and source records attributed to P A Zimmerman.

At least 19 recordsLinked to original sources
PubMed2005

Dynamic regulation of single- and mixed-species malaria infection: insights to specific and non-specific mechanisms of control.

Our increasing appreciation of the high prevalence of mixed-species Plasmodium infection in malaria-endemic regions has resulted in controversy regarding the likely mechanism(s) of regulation for mixed parasite burden within an individual human host. In the present study, we examined dynamic models of Plasmodium spp. regulation by fever and by non-specific (NS) and species-specific (SS) immunity (including the influence of their variable time-delays, duration, and efficacy) in order to assess the likely role of these factors in regulating detectable parasitemia and clinical disease. Our models suggest that in order to observe the irregular waves of fever and parasitemia that are often found in multiply infected subjects, there must be a differential SS immune effect (beyond the regulatory effects of the species-transcendent density-dependent factors previously posited to control mixed-species parasitemia), and time-dependent variation in immunity to the dominant species. By implementation of individual SS immune controls of non-permanent duration, the resulting multi-dimensional model can be viewed as multiple single-species oscillators coupled via a NS species-transcendent controller. This extended model exhibits the essential patterns of long-term mixed infections. Although this 'circuit-immunity' model gives only a qualitative estimate of the complex web of participating agents and reaction pathways, it provides a starting point for future studies of the specific and NS within-host mechanisms that regulate mixed-species malaria infection.

Animals↗
PubMed2005

Expression of Duffy antigen receptor for chemokines during reticulocyte maturation: using a CD71 flow cytometric technique to identify reticulocytes.

Flow cytometric methods commonly used to identify reticulocytes are of limited usefulness in malarious areas, since RNA staining also detects plasmodia. An important antigen expressed on reticulocytes is Duffy antigen receptor for chemokines (DARC, also known as Fy), the receptor for Plasmodium vivax. An early marker for reticulocytes is CD71 (transferrin receptor). We have been interested in CD71 as an alternative marker for reticulocytes in the context of Fy expression. Flow cytometry was used to determine the expression of Fy on CD71-positive and -negative reticulocytes and to correlate serology and genotype. A reduction of 13 percent was seen in Fy6 expression between CD71-positive reticulocytes and RNA-positive reticulocytes. CD71 disappears early during reticulocyte maturation, while Fy6 expression is relatively preserved. CD71 is an alternative to staining for RNA for reticulocyte assays relating to Fy6 expression.

Antigens, CD↗
PubMed2003

CR1 Knops blood group alleles are not associated with severe malaria in the Gambia.

The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value <0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels.

Amino Acid Sequence↗
PubMed2003

Polymorphisms of innate immunity genes and susceptibility to lymphatic filariasis.

We examined 906 residents of an area of Papua New Guinea where bancroftian filariasis is endemic for genetic polymorphisms in three innate immunity genes suspected of contributing to susceptibility to infection and lymphatic pathology. Active infection was confirmed by the presence of blood-borne microfilariae and circulating filarial antigen in plasma. Disease was ascertained by physical examination for the presence of overt lymphedema (severe swelling of an arm or leg) or hydrocele. There was no association of infection status, lymphedema of an extremity, or hydrocele with chitotriosidase genotype (CHIT1). Polymorphisms of toll-like receptor-2 and toll-like receptor-4 genes (TLR4 A896G; TLR2 T2178A, G2258A) were not detected (N=200-625 individuals genotyped) except for two individuals heterozygous for a TLR2 mutation (C2029 T). These results indicate that a CHIT1 genotype associated previously with susceptibility to filariasis in residents of southern India and TLR2 and TLR4 polymorphisms do not correlate with infection status or disease phenotype in this Melanesian population.

Animals↗
PubMed2002

Expansion of the Knops blood group system and subdivision of Sl(a).

BACKGROUND: Complement receptor type 1 (CR1), which bears the Knops (Kn [KN]) blood group antigens, is involved in the rosetting of Plasmodium falciparum- infected RBCs with uninfected cells. As a first step in understanding this interaction, the molecular basis for the blood group antigens encoded by CR1 was investigated. STUDY DESIGN AND METHODS: An antibody from a white donor who exhibited an apparent anti-Sl(a) was used for population studies of several racial groups. The donor's genomic DNA was sequenced to identify the Sl(a) mutation and other mutations. RESULTS: The donor with anti-Sl(a) typed as Sl(a+) with some sera and had the CR1 genotype AA at bp 4828 (R1601). However, she was homozygous for a new mutation (GG) at bp 4855 changing amino acid 1610 from S1610 to T1610 (S1610T). This mutation occurred in heterozygous form in eight white and one Asian donor. The site is only nine amino acids from the previously described Sl(a) polymorphism and appears to produce a new conformational epitope. CONCLUSION: The antigen formerly known as Sl(a) can now be subdivided. A new terminology is proposed that recognizes both linear and conformational epitopes on the CR1 protein. At amino acid 1601, Sl 1 (Sl(a)) is represented by R, Sl 2 (Vil) is represented by glycine, and Sl 3 requires both R1601 and S1610. Sl 4 and Sl 5 are hypothetical epitopes represented by S1610 and T1610, respectively.

Amino Acid Sequence↗
PubMed2001

The association of the glycophorin C exon 3 deletion with ovalocytosis and malaria susceptibility in the Wosera, Papua New Guinea.

Erythrocyte polymorphisms, including ovalocytosis, have been associated with protection against malaria. This study in the Wosera, a malaria holoendemic region of Papua New Guinea, examined the genetic basis of ovalocytosis and its influence on susceptibility to malaria infection. Whereas previous studies showed significant associations between Southeast Asian ovalocytosis (caused by a 27- base pair deletion in the anion exchanger 1 protein gene) and protection from cerebral malaria, this mutation was observed in only 1 of 1019 individuals in the Wosera. Polymerase chain reaction strategies were developed to genotype individuals for the glycophorin C exon 3 deletion associated with Melanesian Gerbich negativity (GPCDeltaex3). This polymorphism was commonly observed in the study population (GPCDeltaex3 frequency = 0.465, n = 742). Although GPCDeltaex3 was significantly associated with increased ovalocytosis, it was not associated with differences in either Plasmodium falciparum or P vivax infection measured over the 7-month study period. Future case-control studies will determine if GPCDeltaex3 reduces susceptibility to malaria morbidity.

Erythrocytes, Abnormal↗
PubMed2001

Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America.

The mechanistic basis for chloroquine resistance (CQR) in Plasmodium falciparum recently has been linked to the polymorphic gene pfcrt. Alleles associated with CQR in natural parasite isolates harbor threonine (T), as opposed to lysine (K) at amino acid 76. P. falciparum CQR strains of African and Southeast Asian origin carry pfcrt alleles encoding an amino acid haplotype of CVIET (residues 72-76), whereas most South American CQR strains studied carry an allele encoding an SVMNT haplotype; chloroquine-sensitive strains from malarious regions around the world carry a CVMNK haplotype. Upon investigating the origin of pfcrt alleles in Papua New Guinean (PNG) P. falciparum we found either the chloroquine-sensitive-associated CVMNK or CQR-associated SVMNT haplotypes previously seen in Brazilian isolates. Remarkably we did not find the CVIET haplotype observed in CQR strains from Southeast Asian regions more proximal to PNG. Further we found a previously undescribed CQR phenotype to be associated with the SVMNT haplotype from PNG and South America. This CQR phenotype is significantly less responsive to verapamil chemosensitization compared with the effect associated with the CVIET haplotype. Consistent with this, we observed that verapamil treatment of P. falciparum isolates carrying pfcrt SVMNT is associated with an attenuated increase in digestive vacuole pH relative to CVIET pfcrt-carrying isolates. These data suggest a key role for pH-dependent changes in hematin receptor concentration in the P. falciparum CQR mechanism. Our findings also suggest that P. falciparum CQR has arisen through multiple evolutionary pathways associated with pfcrt K76T.

ATP-Binding Cassette Transporters↗
PubMed2001

Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1.

Complement receptor 1 (CR1) has been implicated in rosetting of uninfected red blood cells to Plasmodium falciparum-infected cells, and rosette formation is associated with severe malaria. The Knops blood group (KN) is located on CR1 and some of these antigens, ie, McCoy (McC) and Swain-Langley (Sl(a)), show marked frequency differences between Caucasians and Africans. Thus, defining the molecular basis of these antigens may provide new insight into the mechanisms of P falciparum malaria. Monoclonal antibody epitope mapping and serologic inhibition studies using CR1 deletion constructs localized McC and Sl(a) to long homologous repeat D of CR1. Direct DNA sequencing of selected donors identified several single nucleotide polymorphisms in exon 29 coding for complement control protein modules 24 and 25. Two of these appeared to be blood group specific: McC associated with K1590E and Sl(a) with R1601G. These associations were confirmed by inhibition studies using allele-specific mutants. A sequence-specific oligonucleotide probe hybridization assay was developed to genotype several African populations and perform family inheritance studies. Concordance between the 1590 mutation and McC was 94%; that between Sl(a) and 1601 was 88%. All but 2 samples exhibiting discrepancies between the genotype and phenotype were found to be due to low red cell CR1 copy numbers, low or absent expression of some alleles, or heterozygosity combined with low normal levels of CR1. These data further explain the variability observed in previous serologic studies of CR1 and show that DNA and protein-based genetic studies will be needed to clarify the role of the KN antigens in malaria.

Animals↗
PubMed2001

Duffy-null promoter heterozygosity reduces DARC expression and abrogates adhesion of the P. vivax ligand required for blood-stage infection.

The Duffy blood group antigen is an essential receptor for Plasmodium vivax entry into erythrocytes in a process mediated by the parasite ligand, the Duffy binding protein (DBP). Recently, individuals living in a malaria endemic region of Papua New Guinea were identified as heterozygous for a new allele conferring Duffy negativity, which results in 50% less Duffy antigen on their erythrocytes. We demonstrate that DBP adherence to erythrocytes is significantly reduced for erythrocytes from heterozygous individuals who carry one Duffy antigen negativity allele. These data provide evidence that emergence of this new allelic form of Duffy negativity is correlated with resistance against vivax malaria.

Alleles↗
PubMed2001

Genetic polymorphisms in molecules of innate immunity and susceptibility to infection with Wuchereria bancrofti in South India.

A pilot study was conducted to determine if host genetic factors influence susceptibility and outcomes in human filariasis. Using the candidate gene approach, a well-characterized population in South India was studied using common polymorphisms in six genes (CHIT1, MPO, NRAMP, CYBA, NCF2, and MBL2). A total of 216 individuals from South India were genotyped; 67 normal (N), 63 asymptomatic microfilaria positive (MF+), 50 with chronic lymphatic dysfunction/elephantiasis (CP), and 36 tropical pulmonary eosinophilia (TPE). An association was observed between the HH variant CHIT1 genotype, which correlates with decreased activity and levels of chitotriosidase and susceptibility to filarial infection (MF+ and CP; P = 0.013). The heterozygosity of CHIT1 gene was over-represented in the normal individuals (P = 0.034). The XX genotype of the promoter region in MBL2 was associated with susceptibility to filariasis (P = 0.0093). Since analysis for MBL-sufficient vs insufficient haplotypes was not informative, it is possible the MBL2 promoter association results from linkage disequilibrium with neighboring loci. We have identified two polymorphisms, CHIT1 and MBL2 that are associated with susceptibility to human filarial infection, findings that merit further follow-up in a larger study.

Animals↗
PubMed2000

Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the Multicenter AIDS Cohort Study.

OBJECTIVE: To examine whether polymorphism in the RANTES gene is associated with HIV disease outcome. DESIGN: RANTES, a ligand of the major HIV co-receptor, CCR5, is known to block HIV-CCR5 interactions. Recently, two single nucleotide polymorphisms in the RANTES gene promoter region, designated -403G/A and -28C/G, have been described. Both polymorphisms can affect in-vitro promoter activity, and the RANTES -403A, -28G haplotype has been associated with a slower CD4 cell count decline rate in a Japanese cohort. METHODS: We compared RANTES compound genotype frequencies between HIV-positive and exposed-uninfected participants of the Multicenter AIDS Cohort Study (MACS) and rates of progression to AIDS for MACS seroconverters. RESULTS: We found that the two most common RANTES promoter compound genotypes, G1 (-403G/G, -28C/C) found in 67% of Caucasians, and G4 (-403G/A, -28C/C) found in 23% of Caucasians, were associated with altered risk of HIV transmission and progression, particularly in individuals who lacked the protective CCR5 mutation, CCR5delta32. In this study, individuals with a G4 compound genotype were more likely to acquire HIV than individuals with a G1 compound genotype (OR 1.72, P = 0.016) and the risk increased when individuals possessing CCR5delta32 were omitted from consideration (OR 2.13, P = 0.005). Among seroconverters lacking CCR5delta32, those who had the G4 compound genotype progressed significantly slower to AIDS-1993 than those with the G1 compound genotype (median time to AIDS 7.6 versus 5.4 years; RH 0.65; P = 0.007). CONCLUSIONS: These data implicate the RANTES-403A allele as a risk factor for HIV transmission and as a protective factor for HIV progression.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Differential expression of the duffy antigen receptor for chemokines according to RBC age and FY genotype.

BACKGROUND: The Duffy (Fy) blood group (also known as Duffy antigen receptor for chemokines, or DARC) may be involved in regulation of the level of circulating proinflammatory chemokines, and it is an obligatory receptor on RBCs for the human malaria parasite Plasmodium vivax. STUDY DESIGN AND METHODS: Because quantification of Fy expression by using RBCs of various ages will not detect acute changes associated with inflammatory states, and because P. vivax exclusively invades reticulocytes, a flow cytometric method was developed to measure the level of surface expression of Fy. Reticulocytes and mature RBCs from persons with different genotypes (GATA-1 T-->C promoter mutation at nt -46; FY*A and FY*B in the ORF) were used. RESULTS: Expression of the Fy6 epitope, which is required for P. vivax invasion, was 49 +/- 19 percent higher on reticulocytes than on mature RBCs, regardless of donor genotype (p<0.0001). Fy6 levels were approximately 50 percent lower in persons who were heterozygous for the GATA-1 promoter mutation and were significantly lower on reticulocytes and mature RBCs of the FY*B/FY*B genotype than on those of the FY*A/FY*A or FY*A/FY*B genotype. CONCLUSION: Fy has greater expression on reticulocytes than on mature RBCs in flow cytometry. This method may be useful in further studies of this antigen, such as characterization of reticulocytes and RBC phenotypes across populations, in response to chemokine regulation, and in the context of susceptibility to P. vivax and other parasites.

Alleles↗
PubMed2000

Resistance to replication of human immunodeficiency virus challenge in SCID-Hu mice engrafted with peripheral blood mononuclear cells of nonprogressors is mediated by CD8(+) T cells and associated with a proliferative response to p24 antigen.

High levels of resistance to challenge with human immunodeficiency virus type 1 SF162 were observed in animals engrafted with peripheral blood mononuclear cells of four long-term nonprogressors (LTNPs). Resistance was abrogated by depletion of CD8(+) T cells in vivo and was observed only in LTNPs with proliferative responses to p24. In a subgroup of nonprogressors, CD8(+) T cells mediated restriction of challenge viruses, and this response was associated with strong proliferative responses to p24 antigen.

Animals↗
PubMed2000

Random distribution of mixed species malaria infections in Papua New Guinea.

Plasmodium falciparum (Pf), P. vivax (Pv), P. malariae (Pm), and P. ovale (Po) infections are endemic in coastal areas of Papua New Guinea. Here 2,162 individuals living near Dreikikir, East Sepik Province, have been analyzed for complexity of malaria infection by blood smear and polymerase chain reaction (PCR) diagnoses. According to blood smear, the overall prevalence of Plasmodium infection was 0.320. Most individuals (0.283) were infected with a single species only. The prevalence of mixed species infections was low (0.037). Further analysis of a 173-sample subset by nested PCR of small subunit ribosomal DNA resulted in an overall 3.0-fold increase in prevalence of infection, with a 17.5-fold increase in the frequency of mixed species infections. Among mixed species infections detected by PCR, the frequency of double species was 0.364, and that of triple species was 0.237. Nine individuals (0.052) were infected with all 4 species. To determine if infection status (uninfected, single, and multiple infections) deviates from an independent random distribution (null hypothesis), observed versus expected frequencies of all combinations of Plasmodium species infections, or assemblages (Pf-, Pv-, Pm-, Po-, to Pf+, Pv+, Pm+, Po+), were compared using a multiple-kind lottery model. All 4 species were randomly distributed whether diagnosed by blood smear or PCR in the overall population and when divided into age group categories. These findings suggest that mixed species malaria infections are common, and that Plasmodium species appear to establish infection independent of one another.

Animals↗
PubMed2000

Application of a polymerase chain reaction-ELISA to detect Wuchereria bancrofti in pools of wild-caught Anopheles punctulatus in a filariasis control area in Papua New Guinea.

Chemotherapy-based eradication programs are aimed at stopping transmission of Wuchereria bancrofti by its obligatory mosquito vector. This study compares one year post-treatment W. bancrofti infection rates of Anopheles punctulatus, the main vector of lymphatic filariasis in Papua New Guinea, using traditional dissection techniques and a polymerase chain reaction (PCR)-based ELISA of a parasite-specific Ssp I repeat. A total of 633 mosquitoes in 35 batches were dissected. Six batches contained W. bancrofti-infected mosquitoes, giving a minimum infection rate of 0.9%. This value was not different than the actual infection rate, which was 9 (1.4%) of 633 mosquitoes (P = 0.48). The DNA was extracted from 47 pools containing a mean of 13.2 mosquitoes per pool. A total of 621 mosquitoes were processed for the PCR-ELISA, including 486 caught by human bait and 135 by light trap, which included both dead and live mosquitoes. Of 23 pools of alcohol-preserved human-bait mosquitoes, seven were positive by the PCR-ELISA, giving an infection rate identical to that obtained by dissection of individual mosquitoes (1.4%). The minimum infection rates for pools of light-trap mosquitoes found dead and alive were 2.7% (2 of 74) and 4.9% (3 of 61), respectively. These values did not differ from each other (P = 0.84), but the overall infection rate of light-trap mosquitoes was greater than that of mosquitoes captured by human bait (3.7% versus 1.4%; P = 0.09). These data indicate that the PCR-ELISA of a W. bancrofti Ssp I repeat using pools of mosquitoes is comparable to traditional dissection techniques for monitoring transmission intensity following introduction of mass chemotherapy. This approach may also be useful for rapid and cost-effective assessment of transmission in endemic areas where the frequency of overt lymphatic pathology is low.

Animals↗
PubMed1999

Emergence of FY*A(null) in a Plasmodium vivax-endemic region of Papua New Guinea.

In Papua New Guinea (PNG), numerous blood group polymorphisms and hemoglobinopathies characterize the human population. Human genetic polymorphisms of this nature are common in malarious regions, and all four human malaria parasites are holoendemic below 1500 meters in PNG. At this elevation, a prominent condition characterizing Melanesians is alpha(+)-thalassemia. Interestingly, recent epidemiological surveys have demonstrated that alpha(+)-thalassemia is associated with increased susceptibility to uncomplicated malaria among young children. It is further proposed that alpha(+)-thalassemia may facilitate so-called "benign" Plasmodium vivax infection to act later in life as a "natural vaccine" against severe Plasmodium falciparum malaria. Here, in a P. vivax-endemic region of PNG where the resident Abelam-speaking population is characterized by a frequency of alpha(+)-thalassemia >/=0.98, we have discovered the mutation responsible for erythrocyte Duffy antigen-negativity (Fy[a-b-]) on the FY*A allele. In this study population there were 23 heterozygous and no homozygous individuals bearing this new allele (allele frequency, 23/1062 = 0.022). Flow cytometric analysis illustrated a 2-fold difference in erythroid-specific Fy-antigen expression between heterozygous (FY*A/FY*A(null)) and homozygous (FY*A/FY*A) individuals, suggesting a gene-dosage effect. In further comparisons, we observed a higher prevalence of P. vivax infection in FY*A/FY*A (83/508 = 0.163) compared with FY*A/FY*A(null) (2/23 = 0.087) individuals (odds ratio = 2.05, 95% confidence interval = 0.47-8.91). Emergence of FY*A(null) in this population suggests that P. vivax is involved in selection of this erythroid polymorphism. This mutation would ultimately compromise alpha(+)-thalassemia/P. vivax-mediated protection against severe P. falciparum malaria.

Animals↗