James Kazura - Profile on Academia.edu (original) (raw)

Papers by James Kazura

JCI insight, Sep 21, 2017

BACKGROUND. Inflammation and monocytes are thought to be important to human malaria pathogenesis.... more BACKGROUND. Inflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood. METHODS. We evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1-to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community. RESULTS. Acute malaria was marked by elevated levels of proinflammatory and regulatory cytokines and expansion of the inflammatory "intermediate" monocyte subset that returned to levels of healthy asymptomatic children 6 weeks later. Monocytes displayed activated phenotypes during acute malaria, with changes in surface expression of markers important to innate and adaptive immunity. Functionally, acute malaria monocytes and monocytes from asymptomatic infected children had impaired phagocytosis of P. falciparum-infected erythrocytes relative to asymptomatic children with no blood-stage infection. Monocytes from both acute malaria and recovery time points displayed strong and equivalent cytokine responsiveness to innate immune agonists that were independent of infection status. Monocyte transcriptional profiles revealed regulated and balanced proinflammatory and antiinflammatory and altered phagocytosis gene expression patterns distinct from malaria-naive monocytes. CONCLUSION. These observations provide insights into monocyte functions and the innate immune response during uncomplicated malaria and suggest that asymptomatic parasitemia in children is not clinically benign. FUNDING. Support for this work was provided by NIH/National Institute of Allergy and Infectious Diseases (R01AI095192-05), the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene, and the Rainbow Babies & Children's Foundation.

Malaria Induces Anemia through CD8+T Cell-Dependent Parasite Clearance and Erythrocyte Removal in the Spleen

mBio, 2015

Severe malarial anemia (SMA) in semi-immune individuals eliminates both infected and uninfected e... more Severe malarial anemia (SMA) in semi-immune individuals eliminates both infected and uninfected erythrocytes and is a frequent fatal complication. It is proportional not to circulating parasitemia but total parasite mass (sequestered) in the organs. Thus, immune responses that clear parasites in organs may trigger changes leading to anemia. Here, we use an outbred-rat model where increasing parasite removal in the spleen escalated uninfected-erythrocyte removal. Splenic parasite clearance was associated with activated CD8+T cells, immunodepletion of which prevented parasite clearance. CD8+T cell repletion and concomitant reduction of the parasite load was associated with exacerbated (40 to 60%) hemoglobin loss and changes in properties of uninfected erythrocytes. Together, these data suggest that CD8+T cell-dependent parasite clearance causes erythrocyte removal in the spleen and thus anemia. In children infected with the human malaria parasite Plasmodium falciparum, elevation of pa...

Additional file 1: of A novel approach to identifying patterns of human invasion-inhibitory antibodies guides the design of malaria vaccines incorporating polymorphic antigens

Detailed methods and additional analysis of antibody data. (DOCX 1576 kb)

Additional file 1: of Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children

Supplementary figures: Supporting data. (DOCX 1232Â kb)

The American Journal of Tropical Medicine and Hygiene, 2003

To better understand risk factors for hydrocele as a consequence of Wuchereria bancrofti infectio... more To better understand risk factors for hydrocele as a consequence of Wuchereria bancrofti infection, 342 men more than 15 years of age in an endemic area in Papua New Guinea were evaluated. Thirty-four subjects (9.9%) had hydrocele by physical examination. Ultrasound examination detected hydroceles in 57 men (16.7%). Compared with ultrasonography, the sensitivity of physical examination was 44.3%, the specificity was 98.2%, and the positive predictive value was 73.5%. Hydrocele was independently associated with age (odds ratio [OR] ‫ס‬ 3.3, P < 0.01) and intensity of infection as determined by filarial antigenemia (OR ‫ס‬ 2.3, P ‫ס‬ 0.07). Dilation of spermatic cord lymphatics detectable by ultrasound did not correlate with hydrocele, but was associated with the presence of infection. These observations suggest that filarial pathology of the male genitalia is under-reported when evaluated by physical examination alone and that duration and intensity of infection are risk factors for hydrocele.

The American Journal of Tropical Medicine and Hygiene, 2005

High levels of antibodies to multiple antigens may be more strongly associated with protection fr... more High levels of antibodies to multiple antigens may be more strongly associated with protection from infection than antibodies to a single antigen. Antibody-associated protection against Plasmodium falciparum infection was assessed in a cohort of 68 adults living in an area of holoendemic malaria in Kenya. Antibodies to the preerythrocytic antigens circumsporozoite protein (CSP), liver-stage antigen-1 (LSA-1), thrombospondin-related adhesive protein (TRAP), and blood-stage antigens apical membrane antigen-1 (AMA-1), erythrocyte binding antigen-175 (EBA-175), and merozoite surface protein 1 (MSP-1) were tested. Peptides were used for CSP (NANP repeat) and LSA-1 (central repeat), and recombinant antigens were used for TRAP (aa D 48-K 394), AMA-1 (ectodomain, nonglycosylated), EBA-175 (non-glycosylated), and MSP-1 (MSP-1 19). Weekly microscopy testing for P. falciparum infection was performed over a 12-week period after drug-mediated clearance of P. falciparum parasitemia. Individuals with high levels of IgG antibodies (> 2 arbitrary units) to CSP, LSA-1, and TRAP had a 57% decrease in the risk of infection (95% confidence interval ‫ס‬ 20-77%, P ‫ס‬ 0.016). This decreased risk remained significant after adjustment for age, prior parasitemia, bed net use, sickle cell trait, and village of residence. In contrast, protection against infection did not correlate with high levels of IgG antibodies to blood-stage antigens or IgM antibodies to pre-erythrocytic or blood-stage antigens. High levels of IgG antibodies to CSP, LSA-1, and TRAP may be useful immune correlates of protection against P. falciparum infection in malaria-endemic populations.

European journal of immunology, Dec 20, 2017

Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically... more Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically-modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force-of-infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. Howe...

BMC Medicine, 2016

A novel approach to identifying patterns of human invasion-inhibitory antibodies guides the desig... more A novel approach to identifying patterns of human invasion-inhibitory antibodies guides the design of malaria vaccines incorporating polymorphic antigens

Results of bivariate analysis to determine significant relative odds of high RVF disease severity according to demographic data, clinical signs, symptoms, and exposure factors

Typical peri-domestic landscape in the Sangailu area of Kenya

<p>Shown are traditional wicker and grass-mat domed houses and outbuildings, surrounded by ... more <p>Shown are traditional wicker and grass-mat domed houses and outbuildings, surrounded by a planted compound perimeter and local dense brush vegetation.</p

Clinical and Vaccine Immunology, 2015

IgG antibodies to Plasmodium falciparum are transferred from the maternal to fetal circulation du... more IgG antibodies to Plasmodium falciparum are transferred from the maternal to fetal circulation during pregnancy, wane after birth, and are subsequently acquired in response to natural infection. We examined the dynamics of malaria antibody responses of 84 Kenyan infants from birth to 36 months of age by (i) serology, (ii) variant surface antigen (VSA) assay, (iii) growth inhibitory activity (GIA), and (iv) invasion inhibition assays (IIA) specific for merozoite surface protein 1 (MSP1) and sialic acid-dependent invasion pathway. Maternal antibodies in each of these four categories were detected in cord blood and decreased to their lowest level by approximately 6 months of age. Serologic antibodies to 3 preerythrocytic and 10 blood-stage antigens subsequently increased, reaching peak prevalence by 36 months. In contrast, antibodies measured by VSA, GIA, and IIA remained low even up to 36 months. Infants sensitized to P. falciparum in utero , defined by cord blood lymphocyte recall re...

Kasehagen AJTMH 2006 FigS1

Kasehagen AJTNH 2006 TableS1

Exposure Factors and Disease Symptoms of Human Rift Valley Fever in Sangailu, Kenya

Background: Rift Valley fever virus (RVFV) causes an acute, mosquito-borne viral disease in lives... more Background: Rift Valley fever virus (RVFV) causes an acute, mosquito-borne viral disease in livestock and humans. To determine the exposure factors and range of disease symptoms associated with human RVF, we performed a household cluster survey in six villages in Northeastern Kenya in 2011. Methods: We performed a household cluster survey in six villages in Northeastern Kenya in 2011. 1081 participants were tested via anti-RVFV IgG ELISA. Results: 1081 participants were tested via anti-RVFV IgG ELISA, yielding 16% seroprevalence (95% C.I. 0.1-0.2). No significant differences were found among villages. 31% (154/498) of adults were seropositive vs. 3% of children (≤15 years; 17/583). With each additional year of age, participants were 5% more likely to be seropositive (95% C.I. 1.0-1.1). Documentation of a 3y/o seropositive boy confirmed interepidemic transmission. Males were 2.6 times more likely to be seropositive (p<0.001; 95% C.I. 1.7-3.8); herders were 1.7 times more likely (p...

Malaria Journal, 2012

Background: The 19 kDa C-terminal region of Plasmodium falciparum Merozoite Surface Protein-1 is ... more Background: The 19 kDa C-terminal region of Plasmodium falciparum Merozoite Surface Protein-1 is a known target of naturally acquired humoral immunity and a malaria vaccine candidate. MSP-1 19 has four predominant haplotypes resulting in amino acid changes labelled EKNG, QKNG, QTSR and ETSR. IgG antibodies directed against all four variants have been detected, but it is not known if these variant specific antibodies are associated with haplotype-specific protection from infection. Methods: Blood samples from 201 healthy Kenyan adults and children who participated in a 12-week treatment time-to-infection study were evaluated. Venous blood drawn at baseline (week 0) was examined for functional and serologic antibodies to MSP-1 19 and MSP-1 42 variants. MSP-1 19 haplotypes were detected by a multiplex PCR assay at baseline and weekly throughout the study. Generalized linear models controlling for age, baseline MSP-1 19 haplotype and parasite density were used to determine the relationship between infecting P. falciparum MSP-1 19 haplotype and variant-specific antibodies. Results: A total of 964 infections resulting in 1,533 MSP-1 19 haplotypes detected were examined. The most common haplotypes were EKNG and QKNG, followed by ETSR and QTSR. Children had higher parasite densities, greater complexity of infection (>1 haplotype), and more frequent changes in haplotypes over time compared to adults. Infecting MSP-1 19 haplotype at baseline (week 0) had no influence on haplotypes detected over the subsequent 11 weeks among children or adults. Children but not adults with MSP-1 19 and some MSP-1 42 variant antibodies detected by serology at baseline had delayed time-to-infection. There was no significant association of variant-specific serology or functional antibodies at baseline with infecting haplotype at baseline or during 11 weeks of follow up among children or adults. Conclusions: Variant transcending IgG antibodies to MSP-1 19 are associated with protection from infection in children, but not adults. These data suggest that inclusion of more than one MSP-1 19 variant may not be required in a malaria blood stage vaccine.

Acta tropica, 2015

Cytophilic immunoglobulin (IgG) subclass responses (IgG1 and IgG3) to Plasmodium falciparum antig... more Cytophilic immunoglobulin (IgG) subclass responses (IgG1 and IgG3) to Plasmodium falciparum antigens have been associated with protection from malaria, yet the relative importance of transmission intensity and age in generation of subclass responses to pre-erythrocytic and blood-stage antigens have not been clearly defined. We analyzed IgG subclass responses to the pre-erythrocytic antigens CSP, LSA-1, and TRAP and the blood-stage antigens AMA-1, EBA-175, and MSP-1 in asymptomatic residents age 2 years or older in stable (n=116) and unstable (n=96) transmission areas in Western Kenya. In the area of stable malaria transmission, a high prevalence of cytophilic (IgG1 and IgG3) antibodies to each antigen was seen in all age groups. Prevalence and levels of cytophilic antibodies to pre-erythrocytic and blood-stage P. falciparum antigens increased with age in the unstable transmission area, yet IgG1 and IgG3 responses to most antigens for all ages in the unstable transmission area were l...

BMC Medicine, 2015

Background: The identification of protective immune responses to P. falciparum infection is an im... more Background: The identification of protective immune responses to P. falciparum infection is an important goal for the development of a vaccine for malaria. This requires the identification of susceptible and resistant individuals, so that their immune responses may be studied. Time-to-infection studies are one method for identifying putative susceptible individuals (infected early) versus resistant individuals (infected late). However, the timing of infection is dependent on random factors, such as whether the subject was bitten by an infected mosquito, as well as individual factors, such as their level of immunity. It is important to understand how much of the observed variation in infection is simply due to chance. Methods: We analyse previously published data from a treatment-time-to-infection study of 201 individuals aged 0.5 to 78 years living in Western Kenya. We use a mathematical modelling approach to investigate the role of immunity versus random factors in determining time-to-infection in this cohort. We extend this analysis using a modelling approach to understand what factors might increase or decrease the utility of these studies for identifying susceptible and resistant individuals. Results: We find that, under most circumstances, the observed distribution of time-to-infection is consistent with this simply being a random process. We find that age, method for detection of infection (PCR versus microscopy), and underlying force of infection are all factors in determining whether time-to-infection is a useful correlate of immunity. Conclusions: Many epidemiological studies of P. falciparum infection assume that the observed variation in infection outcomes, such as time-to-infection or presence or absence of infection, is determined by host resistance or susceptibility. However, under most circumstances, this distribution appears largely due to the random timing of infection, particularly in children. More direct measurements, such as parasite growth rate, may be more useful than time-to-infection in segregating patients based on their level of immunity.

Lymphatic filariasis in Papua New Guinea: interdisciplinary research on a national health problem

Trends in Parasitology, 2003

Bancroftian filariasis is a major public health problem in Papua New Guinea, where the level of t... more Bancroftian filariasis is a major public health problem in Papua New Guinea, where the level of transmission by the mosquito vector, human infection rates and clinical morbidity are among the highest in the world. Coordinated research efforts within the country, involving the disciplines of epidemiology, vector biology, immunology and genetics, have led to new insights into the ecology and pathogenesis of human lymphatic filariasis. Recent work using this knowledge base should be helpful in assessing local and global strategies aimed at eliminating Wuchereria bancrofti and in guiding research that will facilitate achievement of this goal.

Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998

New England Journal of Medicine, 2013

Background Global efforts to eliminate lymphatic filariasis are based on the annual mass administ... more Background Global efforts to eliminate lymphatic filariasis are based on the annual mass administration of antifilarial drugs to reduce the microfilaria reservoir available to the mosquito vector. Insecticide-treated bed nets are being widely used in areas in which filariasis and malaria are coendemic. Methods We studied five villages in which five annual mass administrations of antifilarial drugs, which were completed in 1998, reduced the transmission of Wuchereria bancrofti, one of the nematodes that cause lymphatic filariasis. A total of 21,899 anopheles mosquitoes were collected for 26 months before and 11 to 36 months after bed nets treated with long-lasting insecticide were distributed in 2009. We evaluated the status of filarial infection and the presence of W. bancrofti DNA in anopheline mosquitoes before and after the introduction of insecticide-treated bed nets. We then used a model of population dynamics to estimate the probabilities of transmission cessation. Results Village-specific rates of bites from anopheline mosquitoes ranged from 6.4 to 61.3 bites per person per day before the bed-net distribution and from 1.1 to 9.4 bites for 11 months after distribution (P<0.001). During the same period, the rate of detection of W. bancrofti in anopheline mosquitoes decreased from 1.8% to 0.4% (P = 0.005), and the rate of detection of filarial DNA decreased from 19.4% to 14.9% (P = 0.13). The annual transmission potential was 5 to 325 infective larvae inoculated per person per year before the bed-net distribution and 0 after the distribution. Among all five villages with a prevalence of microfilariae of 2 to 38%, the probability of transmission cessation increased from less than 1.0% before the bed-net distribution to a range of 4.9 to 95% in the 11 months after distribution. Conclusions Vector control with insecticide-treated bed nets is a valuable tool for W. bancrofti elimination in areas in which anopheline mosquitoes transmit the parasite.