Bio

Bio


* Senior Research Scientist, Microbiology & Immunology, and Infectious Diseases Stanford School of Medicine (2011-present)
* Research Associate. Microbiology & Immunology, Stanford School of Medicine (2005-2011)
* Postdoctoral Fellow, Microbiology & Immunology, Stanford School of Medicine (2001-2005)
* Research Fellow, Harvard School of Public Health (1999-2000)

Education & Certifications


  • ScD, Harvard School of Public Health
  • B.A., Swarthmore College

Professional

Professional Interests


* Epidemiology of infectious disease
* Inter-individual variation in gene expression in states of health and disease
* Systems biology of the response to infection and vaccination
* Nucleic-acid based diagnostics

Professional Affiliations and Activities


  • Associate Fellow, Center for Innovation in Global Health, Stanford University (2017 - Present)
  • Member, American Society of Tropical Medicine & Hygiene (2005 - Present)
  • Board Member, Sustainable Sciences Institute, San Francisco, CA (2001 - Present)
  • Member, American Society of Microbiology (2001 - Present)

Publications

All Publications


  • Early transcriptional responses after dengue vaccination mirror the response to natural infection and predict neutralizing antibody titers. The Journal of infectious diseases Popper, S. J., Strouts, F. R., Lindow, J. C., Cheng, H. K., Montoya, M., Balmaseda, A., Durbin, A. P., Whitehead, S. S., Harris, E., Kirkpatrick, B. D., Relman, D. A. 2018

    Abstract

    Background: Several promising live attenuated virus (LAV) dengue vaccines are in development, but information about innate immune responses and early correlates of protection are lacking.Methods: We characterized human genome-wide transcripts in whole blood from 10 volunteers at 11 time-points after immunization with the dengue virus type 3 (DENV-3) component of the NIH dengue vaccine candidate TV003 and from 30 hospitalized children with acute primary DENV-3 infection. We compared day-specific gene expression patterns with subsequent neutralizing antibody (NAb) titers.Results: The transcriptional response to vaccination was largely confined to days 5-20 and was dominated by an interferon-associated signature and a cell cycle signature that peaked on days 8 and 14, respectively. Changes in transcript abundance were much greater in magnitude and scope in symptomatic natural infection than following vaccination (maximum fold-change >200 versus 21 post-vaccination; 3,210 versus 286 transcripts with significant fold-change), but shared gene modules were induced in the same sequence. The abundance of 131 transcripts on days 8 and 9 post-vaccination was strongly correlated with NAb titers measured 6 weeks post-vaccination.Conclusions: LAV dengue vaccination elicits early transcriptional responses that mirror those found in symptomatic natural infection and provide candidate early markers of protection against DENV infection. Clinical Trial Registration Number: NCT00831012 (available at clinicaltrials.gov).

    View details for PubMedID 30010906

  • Cathelicidin Insufficiency in Patients with Fatal Leptospirosis. PLoS pathogens Lindow, J. C., Wunder, E. A., Popper, S. J., Min, J., Mannam, P., Srivastava, A., Yao, Y., Hacker, K. P., Raddassi, K., Lee, P. J., Montgomery, R. R., Shaw, A. C., Hagan, J. E., Araújo, G. C., Nery, N., Relman, D. A., Kim, C. C., Reis, M. G., Ko, A. I. 2016; 12 (11)

    Abstract

    Leptospirosis causes significant morbidity and mortality worldwide; however, the role of the host immune response in disease progression and high case fatality (>10-50%) is poorly understood. We conducted a multi-parameter investigation of patients with acute leptospirosis to identify mechanisms associated with case fatality. Whole blood transcriptional profiling of 16 hospitalized Brazilian patients with acute leptospirosis (13 survivors, 3 deceased) revealed fatal cases had lower expression of the antimicrobial peptide, cathelicidin, and chemokines, but more abundant pro-inflammatory cytokine receptors. In contrast, survivors generated strong adaptive immune signatures, including transcripts relevant to antigen presentation and immunoglobulin production. In an independent cohort (23 survivors, 22 deceased), fatal cases had higher bacterial loads (P = 0.0004) and lower anti-Leptospira antibody titers (P = 0.02) at the time of hospitalization, independent of the duration of illness. Low serum cathelicidin and RANTES levels during acute illness were independent risk factors for higher bacterial loads (P = 0.005) and death (P = 0.04), respectively. To investigate the mechanism of cathelicidin in patients surviving acute disease, we administered LL-37, the active peptide of cathelicidin, in a hamster model of lethal leptospirosis and found it significantly decreased bacterial loads and increased survival. Our findings indicate that the host immune response plays a central role in severe leptospirosis disease progression. While drawn from a limited study size, significant conclusions include that poor clinical outcomes are associated with high systemic bacterial loads, and a decreased antibody response. Furthermore, our data identified a key role for the antimicrobial peptide, cathelicidin, in mounting an effective bactericidal response against the pathogen, which represents a valuable new therapeutic approach for leptospirosis.

    View details for DOI 10.1371/journal.ppat.1005943

    View details for PubMedID 27812211

  • Early Transcriptional Signatures of the Immune Response to a Live Attenuated Tetravalent Dengue Vaccine Candidate in Non-human Primates PLOS NEGLECTED TROPICAL DISEASES Strouts, F. R., Popper, S. J., Partidos, C. D., Stinchcomb, D. T., Osorio, J. E., Relman, D. A. 2016; 10 (5)

    Abstract

    The development of a vaccine against dengue faces unique challenges, including the complexity of the immune responses to the four antigenically distinct serotypes. Genome-wide transcriptional profiling provides insight into the pathways and molecular features that underlie responses to immune system stimulation, and may facilitate predictions of immune protection.In this study, we measured early transcriptional responses in the peripheral blood of cynomolgus macaques following vaccination with a live, attenuated tetravalent dengue vaccine candidate, TDV, which is based on a DENV-2 backbone. Different doses and routes of vaccine administration were used, and viral load and neutralizing antibody titers were measured at different time-points following vaccination. All 30 vaccinated animals developed a neutralizing antibody response to each of the four dengue serotypes, and only 3 of these animals had detectable serum viral RNA after challenge with wild-type dengue virus (DENV), suggesting protection of vaccinated animals to DENV infection. The vaccine induced statistically significant changes in 595 gene transcripts on days 1, 3, 5 and 7 as compared with baseline and placebo-treated animals. Genes involved in the type I interferon (IFN) response, including IFI44, DDX58, MX1 and OASL, exhibited the highest fold-change in transcript abundance, and this response was strongest following double dose and subcutaneous (versus intradermal) vaccine administration. In addition, modules of genes involved in antigen presentation, dendritic cell activation, and T cell activation and signaling were enriched following vaccination. Increased abundance of gene transcripts related to T cell activation on day 5, and the type I IFN response on day 7, were significantly correlated with the development of high neutralizing antibody titers on day 30.These results suggest that early transcriptional responses may be predictive of development of adaptive immunity to TDV vaccination in cynomolgus macaques, and will inform studies of human responses to dengue vaccines.

    View details for DOI 10.1371/journal.pntd.0004731

    View details for Web of Science ID 000377769300067

    View details for PubMedID 27214236

    View details for PubMedCentralID PMC4877054

  • Type I Interferon Suppresses Type II Interferon-Triggered Human Anti-Mycobacterial Responses SCIENCE Teles, R. M., Graeber, T. G., Krutzik, S. R., Montoya, D., Schenk, M., Lee, D. J., Komisopoulou, E., Kelly-Scumpia, K., Chun, R., Iyer, S. S., Sarno, E. N., Rea, T. H., Hewison, M., Adams, J. S., Popper, S. J., Relman, D. A., Stenger, S., Bloom, B. R., Cheng, G., Modlin, R. L. 2013; 339 (6126): 1448-1453

    Abstract

    Type I interferons (IFN-α and IFN-β) are important for protection against many viral infections, whereas type II interferon (IFN-γ) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-β and IFN-γ gene expression programs. IFN-γ and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-β and its downstream genes, including interleukin-10 (IL-10), were induced in monocytes by M. leprae in vitro and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-γ-induced macrophage vitamin D-dependent antimicrobial peptide response was inhibited by IFN-β and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections.

    View details for DOI 10.1126/science.1233665

    View details for Web of Science ID 000316740700047

    View details for PubMedID 23449998

    View details for PubMedCentralID PMC3653587

  • Temporal Dynamics of the Transcriptional Response to Dengue Virus Infection in Nicaraguan Children PLOS NEGLECTED TROPICAL DISEASES Popper, S. J., Gordon, A., Liu, M., Balmaseda, A., Harris, E., Relman, D. A. 2012; 6 (12)

    Abstract

    Dengue is the most prevalent mosquito-borne human illness worldwide. The ability to predict disease severity during the earliest days of the illness is a long-sought, but unachieved goal.We examined human genome-wide transcript abundance patterns in daily peripheral blood mononuclear cell (PBMC) samples from 41 children hospitalized with dengue virus (DENV) infection in Nicaragua, as well as 8 healthy control subjects. Nine patients had primary dengue fever (DF1), 11 had dengue fever with serologic evidence of prior DENV infection, i.e., secondary dengue fever (DF2), 12 had dengue hemorrhagic fever (DHF), and 9 had dengue shock syndrome (DSS). We identified 2,092 genes for which transcript abundance differed significantly between patients on days 3-6 of fever and healthy subjects (FDR<1%). Prior DENV infection explained the greatest amount of variation in gene expression among patients. The number of differentially expressed genes was greatest on fever day 3 in patients with DF1, while the number in patients with DF2 or DHF/DSS was greatest on day 5. Genes associated with the mitotic cell cycle and B cell differentiation were expressed at higher levels, and genes associated with signal transduction and cell adhesion were expressed at lower levels, in patients versus healthy controls. On fever day 3, a set of interferon-stimulated gene transcripts was less abundant in patients who subsequently developed DSS than in other patient groups (p<0.05, ranksum). Patients who later developed DSS also had higher levels of transcripts on day 3 associated with mitochondrial function (p<0.01, ranksum). These day 3 transcript abundance findings were not evident on subsequent fever days.In conclusion, we identified differences in the timing and magnitude of human gene transcript abundance changes in DENV patients that were associated with serologic evidence of prior infection and with disease severity. Some of these differential features may predict the outcome of DENV infection.

    View details for DOI 10.1371/journal.pntd.0001966

    View details for Web of Science ID 000312910200031

    View details for PubMedID 23285306

    View details for PubMedCentralID PMC3527342

  • Transforming growth factor-beta signaling pathway in patients with Kawasaki disease. Circulation. Cardiovascular genetics Shimizu, C., Jain, S., Davila, S., Hibberd, M. L., Lin, K. O., Molkara, D., Frazer, J. R., Sun, S., Baker, A. L., Newburger, J. W., Rowley, A. H., Shulman, S. T., Burgner, D., Breunis, W. B., Kuijpers, T. W., Wright, V. J., Levin, M., Eleftherohorinou, H., Coin, L., Popper, S. J., Relman, D. A., Fury, W., Lin, C., Mellis, S., Tremoulet, A. H., Burns, J. C. 2011; 4 (1): 16-25

    Abstract

    Transforming growth factor (TGF)-β is a multifunctional peptide that is important in T-cell activation and cardiovascular remodeling, both of which are important features of Kawasaki disease (KD). We postulated that variation in TGF-β signaling might be important in KD susceptibility and disease outcome.We investigated genetic variation in 15 genes belonging to the TGF-β pathway in a total of 771 KD subjects of mainly European descent from the United States, the United Kingdom, Australia, and the Netherlands. We analyzed transcript abundance patterns using microarray and reverse transcriptase-polymerase chain reaction for these same genes, and measured TGF-β2 protein levels in plasma. Genetic variants in TGFB2, TGFBR2, and SMAD3 and their haplotypes were consistently and reproducibly associated with KD susceptibility, coronary artery aneurysm formation, aortic root dilatation, and intravenous immunoglobulin treatment response in different cohorts. A SMAD3 haplotype associated with KD susceptibility replicated in 2 independent cohorts and an intronic single nucleotide polymorphism in a separate haplotype block was also strongly associated (A/G, rs4776338) (P=0.000022; odds ratio, 1.50; 95% confidence interval, 1.25 to 1.81). Pathway analysis using all 15 genes further confirmed the importance of the TGF-β pathway in KD pathogenesis. Whole-blood transcript abundance for these genes and TGF-β2 plasma protein levels changed dynamically over the course of the illness.These studies suggest that genetic variation in the TGF-β pathway influences KD susceptibility, disease outcome, and response to therapy, and that aortic root and coronary artery Z scores can be used for phenotype/genotype analyses. Analysis of transcript abundance and protein levels further support the importance of this pathway in KD pathogenesis.

    View details for DOI 10.1161/CIRCGENETICS.110.940858

    View details for PubMedID 21127203

    View details for PubMedCentralID PMC3073847

  • Dissecting Interferon-Induced Transcriptional Programs in Human Peripheral Blood Cells PLOS ONE Waddell, S. J., Popper, S. J., Rubins, K. H., Griffiths, M. J., Brown, P. O., Levin, M., Relman, D. A. 2010; 5 (3)

    Abstract

    Interferons are key modulators of the immune system, and are central to the control of many diseases. The response of immune cells to stimuli in complex populations is the product of direct and indirect effects, and of homotypic and heterotypic cell interactions. Dissecting the global transcriptional profiles of immune cell populations may provide insights into this regulatory interplay. The host transcriptional response may also be useful in discriminating between disease states, and in understanding pathophysiology. The transcriptional programs of cell populations in health therefore provide a paradigm for deconvoluting disease-associated gene expression profiles.We used human cDNA microarrays to (1) compare the gene expression programs in human peripheral blood mononuclear cells (PBMCs) elicited by 6 major mediators of the immune response: interferons alpha, beta, omega and gamma, IL12 and TNFalpha; and (2) characterize the transcriptional responses of purified immune cell populations (CD4+ and CD8+ T cells, B cells, NK cells and monocytes) to IFNgamma stimulation. We defined a highly stereotyped response to type I interferons, while responses to IFNgamma and IL12 were largely restricted to a subset of type I interferon-inducible genes. TNFalpha stimulation resulted in a distinct pattern of gene expression. Cell type-specific transcriptional programs were identified, highlighting the pronounced response of monocytes to IFNgamma, and emergent properties associated with IFN-mediated activation of mixed cell populations. This information provides a detailed view of cellular activation by immune mediators, and contributes an interpretive framework for the definition of host immune responses in a variety of disease settings.

    View details for DOI 10.1371/journal.pone.0009753

    View details for Web of Science ID 000275894300006

    View details for PubMedID 20339534

    View details for PubMedCentralID PMC2842296

  • Transcriptional response in the peripheral blood of patients infected with Salmonella enterica serovar Typhi PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Thompson, L. J., Dunstan, S. J., Dolecek, C., Perkins, T., House, D., Dougan, G., Nguyen Thi Hue, T. H., Tran Thi Phi La, T. P., Du, D. C., Le Thi Phuong, T. P., Nguyen Thi Dung, T. D., Tran Tinh Hien, T. H., Farrar, J. J., Monack, D., Lynn, D. J., Popper, S. J., Falkow, S. 2009; 106 (52): 22433-22438

    Abstract

    We used microarrays and transcriptional profiling of peripheral blood to investigate the host response of 29 individuals who contracted typhoid fever in the Mekong Delta region of Vietnam. Samples were taken over a nine month period encompassing acute disease, convalescence, and recovery. We found that typhoid fever induced a distinct and highly reproducible signature in the peripheral blood that changed during treatment and convalescence, returning in the majority of cases to the "normal" profile as measured in healthy uninfected controls. Unexpectedly, there was a strong, distinct signature of convalescence present at day 9 after infection that remained virtually unchanged one month after acute infection and in some cases persisted as long as nine months despite a complete clinical recovery in all patients. Patients who retain the convalescent signature may be genetically or temporarily incapable of developing an effective immune response and may be more susceptible to reinfection, relapse, or the establishment of a carrier state.

    View details for DOI 10.1073/pnas.0912386106

    View details for Web of Science ID 000273178700071

    View details for PubMedID 20018727

    View details for PubMedCentralID PMC2792164

  • Streptococcus pneumoniae nasopharyngeal colonization induces type I interferons and interferon-induced gene expression BMC GENOMICS Joyce, E. A., Popper, S. J., Falkow, S. 2009; 10

    Abstract

    We employed DNA microarray technology to investigate the host response to Streptococcus pneumoniae in a mouse model of asymptomatic carriage. Over a period of six weeks, we profiled transcript abundance and complexity in the Nasal Associated Lymphoid Tissue (NALT) to identify genes whose expression differed between pneumococcal-colonized and uncolonized states.Colonization with S. pneumoniae altered the expression of hundreds of genes over the course of the study, demonstrating that carriage is a dynamic process characterized by increased expression of a set of early inflammatory responses, including induction of a Type I Interferon response, and the production of several antimicrobial factors. Subsequent to this initial inflammatory response, we observed increases in transcripts associated with T cell development and activation, as well as wounding, basement membrane remodeling, and cell proliferation. Our analysis suggests that microbial colonization induced expression of genes encoding components critical for controlling JAK/STAT signaling, including stat1, stat2, socs3, and mapk1, as well as induction of several Type I Interferon-inducible genes and other antimicrobial factors at the earliest stages of colonization.Examining multiple time points over six weeks of colonization demonstrated that asymptomatic carriage stimulates a dynamic host response characterized by temporal waves with distinct biological programs. Our data suggest that the usual response to the presence of the pneumocccus is an initial controlled inflammatory response followed by activation of host physiological processes such as response to wounding, basement membrane remodeling, and increasing cellular numbers that ultimately allow the host to maintain an intact epithelium and eventually mount a preventive adaptive immune response.

    View details for DOI 10.1186/1471-2164-10-404

    View details for Web of Science ID 000270394200002

    View details for PubMedID 19712482

    View details for PubMedCentralID PMC2743716

  • Gene Transcript Abundance Profiles Distinguish Kawasaki Disease from Adenovirus Infection Joint Meeting of the Pediatric-Academic-Societies/Asian-Society-for-Pediatric-Research Popper, S. J., Watson, V. E., Shimizu, C., Kanegaye, J. T., Burns, J. C., Relman, D. A. OXFORD UNIV PRESS INC. 2009: 657–66

    Abstract

    Acute Kawasaki disease (KD) is difficult to distinguish from other illnesses that involve acute rash or fever, in part because the etiologic agent(s) and pathophysiology remain poorly characterized. As a result, diagnosis and critical therapies may be delayed.We used DNA microarrays to identify possible diagnostic features of KD. We compared gene expression patterns in the blood of 23 children with acute KD and 18 age-matched febrile children with 3 illnesses that resemble KD.Genes associated with platelet and neutrophil activation were expressed at higher levels in patients with KD than in patients with acute adenovirus infections or systemic adverse drug reactions, but levels in patients with KD were not higher than those in patients with scarlet fever. Genes associated with B cell activation were also expressed at higher levels in patients with KD than in control subjects. A striking absence of interferon-stimulated gene expression in patients with KD was confirmed in an independent cohort of patients with KD. Using a set of 38 gene transcripts, we successfully predicted the diagnosis for 21 of 23 patients with KD and 7 of 8 patients with adenovirus infection.These findings provide insight into the molecular features that distinguish KD from other febrile illnesses and support the feasibility of developing novel diagnostic reagents for KD based on the host response.

    View details for DOI 10.1086/603538

    View details for Web of Science ID 000268009700024

    View details for PubMedID 19583510

    View details for PubMedCentralID PMC2878183

  • Patterns of host genome-wide gene transcript abundance in the peripheral blood of patients with acute dengue hemorrhagic fever JOURNAL OF INFECTIOUS DISEASES Simmons, C. P., Popper, S., Dolocek, C., Chau, T. N., Griffiths, M., Dung, N. T., Long, T. H., Hoang, D. M., Chau, N. V., Thao, L. T., Hien, T. T., Relman, D. A., Farrar, J. 2007; 195 (8): 1097-1107

    Abstract

    Responses by peripheral blood leukocytes may contribute to the pathogenesis of dengue hemorrhagic fever (DHF). We used DNA microarrays to reveal transcriptional patterns in the blood of 14 adults with DHF. Acute DHF was defined by an abundance of transcripts from cell cycle- and endoplasmic reticulum (ER)-related genes, suggesting a proliferative response accompanied by ER stress. Transcript-abundance levels for immunoresponse-associated genes, including cell surface markers, immunoglobulin, and innate response elements, were also elevated. Twenty-four genes were identified for which transcript abundance distinguished patients with dengue shock syndrome (DSS) from those without DSS. All the gene transcripts associated with DSS, many of which are induced by type I interferons, were less abundant in patients with DSS than in those without DSS. To our knowledge, these data provide the first snapshot of gene-expression patterns in peripheral blood during acute dengue and suggest that DSS is associated with attenuation of selected aspects of the innate host response.

    View details for DOI 10.1086/512162

    View details for Web of Science ID 000245405100005

    View details for PubMedID 17357045

  • Gene-expression patterns reveal underlying biological processes in Kawasaki disease GENOME BIOLOGY Popper, S. J., Shimizu, C., Shike, H., Kanegaye, J. T., Newburger, J. W., Sundel, R. P., Brown, P. O., Burns, J. C., Relman, D. A. 2007; 8 (12)

    Abstract

    Kawasaki disease (KD) is an acute self-limited vasculitis and the leading cause of acquired heart disease in children in developed countries. No etiologic agent(s) has been identified, and the processes that mediate formation of coronary artery aneurysms and abatement of fever following treatment with intravenous immunoglobulin (IVIG) remain poorly understood.In an initial survey, we used DNA microarrays to examine patterns of gene expression in peripheral whole blood from 20 children with KD; each was sampled during the acute, subacute, and convalescent phases of the illness. Acute KD was characterized by increased relative abundance of gene transcripts associated with innate immune and proinflammatory responses and decreased abundance of transcripts associated with natural killer cells and CD8+ lymphocytes. There was significant temporal variation in transcript levels during the acute disease phase and stabilization thereafter. We confirmed these temporal patterns in a second cohort of 64 patients, and identified additional inter-individual differences in transcript abundance. Notably, higher levels of transcripts of the gene for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) were associated with an increased percentage of unsegmented neutrophils, fewer days of illness, higher levels of C-reactive protein, and subsequent non-response to IVIG; this last association was confirmed by quantitative reverse transcription PCR in a third cohort of 33 patients, and was independent of day of illness.Acute KD is characterized by dynamic and variable gene-expression programs that highlight the importance of neutrophil activation state and apoptosis in KD pathogenesis. Our findings also support the feasibility of extracting biomarkers associated with clinical prognosis from gene-expression profiles of individuals with systemic inflammatory illnesses.

    View details for DOI 10.1186/gb-2007-8-12-r261

    View details for Web of Science ID 000253451800009

    View details for PubMedID 18067656

    View details for PubMedCentralID PMC2246263

  • The absence of anti-Tat antibodies is associated with risk of disease progression in HIV-2 infection JOURNAL OF INFECTIOUS DISEASES Rodriguez, S. K., Sarr, A. D., Olorunnipa, O., Popper, S. J., Gueye-Ndiaye, A., Traore, I., Dia, M. C., Mboup, S., Kanki, P. J. 2006; 194 (6): 760-763

    Abstract

    The Tat protein of human immunodeficiency virus (HIV) is essential for viral replication and has extracellular pathogenic activity. We sought to determine whether the anti-Tat antibody response was predictive of disease progression in 144 HIV type 2 (HIV-2)-infected subjects observed longitudinally between 1985 and 2003. Sixty-eight percent of the subjects tested positive for anti-Tat antibodies, with reactivity notably established early after seroconversion and stably maintained over the course of infection. The risk and rate of progression to advanced HIV-2 AIDS was significantly higher in anti-Tat-negative subjects than in anti-Tat-positive subjects, extending the importance of this prognostic marker for HIV-2 AIDS.

    View details for Web of Science ID 000240316600006

    View details for PubMedID 16941341

  • Early days: genomics and human responses to infection CURRENT OPINION IN MICROBIOLOGY Liu, M., Popper, S. J., Rubins, K. H., Relman, D. A. 2006; 9 (3): 312-319

    Abstract

    DNA microarray-based gene transcript-profiling of the responses of primates to infection has begun to yield new insights into host-pathogen interactions; this approach, however, remains plagued by challenges and complexities that have yet to be adequately addressed. The rapidly changing nature over time of acute infectious diseases in a host, and the genetic diversity of microbial pathogens present unique problems for the design and interpretation of functional-genomic studies in this field. In addition, there are the more common problems related to heterogeneity within clinical samples, the complex, non-standardized confounding variables associated with human subjects and the complexities posed by the analysis and validation of highly parallel data. Whereas various approaches have been developed to address each of these issues, there are significant limitations that remain to be overcome. The resolution of these problems should lead to a better understanding of the dialogue between the host and pathogen.

    View details for DOI 10.1016/j.mib.2006.04.006

    View details for Web of Science ID 000238795100013

    View details for PubMedID 16679048

  • Genomewide analysis of the host response to malaria in Kenyan children JOURNAL OF INFECTIOUS DISEASES Griffiths, M. J., Shafi, M. J., Popper, S. J., Hemingway, C. A., Kortok, M. M., Wathen, A., Rockett, K. A., Mott, R., Levin, M., Newton, C. R., Marsh, K., Relman, D. A., Kwiatkowski, D. P. 2005; 191 (10): 1599-1611

    Abstract

    Malaria is a global problem, and there is a critical need for further understanding of the disease process. When malarial parasites invade and develop within the bloodstream, they stimulate a profound host response whose main clinical sign is fever. To explore this response, we measured host gene expression in whole blood from Kenyan children hospitalized with either acute malaria or other febrile illnesses. Genomewide analysis of expression identified 2 principal gene-expression profiles related to neutrophil and erythroid activity. In addition to these general acute responses, a third gene-expression profile was associated with host parasitemia; mediators of erythrophagocytosis and cellular stress were notable components of this response. The delineation of subjects on the basis of patterns of gene expression provides a molecular perspective of the host response to malaria and further functional insight into the underlying processes of pathogenesis.

    View details for Web of Science ID 000228465000005

    View details for PubMedID 15838786

  • Highly active Antiretroviral therapy and viral response in HIV type 2 infection CLINICAL INFECTIOUS DISEASES Mullins, C., Eisen, G., Popper, S., Sarr, A. D., Sankale, J. L., Berger, J. J., Wright, S. B., Chang, H. R., Coste, G., Cooley, T. P., Rice, P., Skolnik, P. R., Sullivan, M., Kanki, P. J. 2004; 38 (12): 1771-1779

    Abstract

    Human immunodeficiency virus type 2 (HIV-2), the second human retrovirus known to cause AIDS, is endemic to West Africa but is infrequently found outside this region. We present a case series of 10 HIV-2--infected individuals treated in the United States. Physicians applied the principles of highly active antiretroviral therapy (HAART), normally used in treating HIV type 1, with modifications considered appropriate for treating HIV-2. CD4+ cell count, HIV-2 virus load, and clinical status were found to correlate well, providing evidence that HIV-2 virus load is useful in managing treatment of patients with HIV-2 who are receiving therapy. However, HAART regimens with predicted efficacy for treatment of HIV type 1 infection are not as efficacious for treatment of HIV-2. Controlled clinical trials of HIV-2-infected patients receiving various HAART regimens are needed to provide therapeutic guidance to the medical community.

    View details for Web of Science ID 000222087500021

    View details for PubMedID 15227626

  • Individuality and variation in gene expression patterns in human blood PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Whitney, A. R., Diehn, M., Popper, S. J., Alizadeh, A. A., Boldrick, J. C., Relman, D. A., Brown, P. O. 2003; 100 (4): 1896-1901

    Abstract

    The nature and extent of interindividual and temporal variation in gene expression patterns in specific cells and tissues is an important and relatively unexplored issue in human biology. We surveyed variation in gene expression patterns in peripheral blood from 75 healthy volunteers by using cDNA microarrays. Characterization of the variation in gene expression in healthy tissue is an essential foundation for the recognition and interpretation of the changes in these patterns associated with infections and other diseases, and peripheral blood was selected because it is a uniquely accessible tissue in which to examine this variation in patients or healthy volunteers in a clinical setting. Specific features of interindividual variation in gene expression patterns in peripheral blood could be traced to variation in the relative proportions of specific blood cell subsets; other features were correlated with gender, age, and the time of day at which the sample was taken. An analysis of multiple sequential samples from the same individuals allowed us to discern donor-specific patterns of gene expression. These data help to define human individuality and provide a database with which disease-associated gene expression patterns can be compared.

    View details for DOI 10.1073/pnas.252784499

    View details for Web of Science ID 000181073000082

    View details for PubMedID 12578971

    View details for PubMedCentralID PMC149930

  • Associations between MHC class I and susceptibility to HIV-2 disease progression JOURNAL OF HUMAN VIROLOGY Diouf, K., Sarr, A. D., Eisen, G., Popper, S., Mboup, S., Kanki, P. 2002; 5 (1): 1-7

    Abstract

    Human immunodeficiency virus type 2 (HIV-2) progression to disease is significantly slower than that of human immunodeficiency virus type 1 (HIV-1). Genetic determinants for susceptibility to disease progression were hypothesized to play a more significant role in this infection compared with HIV-1. We sought to identify common human lymphocyte antigen (HLA) alleles in the Senegalese population and to compare HLA profiles between HIV-2-infected individuals with low and high risk for disease progression.We conducted a case-control study investigating possible associations between MHC class I genes and the risk of disease progression in HIV-2-infected individuals. The MHC class I genotype was molecularly defined using polymerase chain reaction with sequence specific primers (PCR-SSP) in 62 female sex workers from the Dakar, Senegal cohort. Lack of antibodies to the HIV-2 antigen p26 has been previously shown to predict disease progression and was used in this study as a surrogate marker. Twenty-one cases were identified lacking antibodies to p26, therefore at a higher risk of disease progression, and were compared with 41 p26 antibody-positive, randomly selected controls.Statistical analysis showed that HLA B35 was significantly associated with lack of p26 antibodies, and higher risk of disease progression ( < 0.05). The same association was found for the self-defined class I haplotypes B35-Cw4 and A23-Cw 7 ( < 0.05). The HLA B 53 allele was associated with slower disease progression; however, this association was not statistically significant. We observed a trend whereby heterozygotes were at lower risk for HIV-2 disease progression, as previously reported in HIV-1 disease.In this West African population, a distinct profile of HLA class I alleles was observed, and many of these appear to influence disease progression in HIV-2 infection.

    View details for DOI 10.1097/01.QHV.0000021465.39141.02

    View details for Web of Science ID 000177956300001

    View details for PubMedID 12352262

  • Immunologic and virologic response after tetanus toxoid booster among HIV-1-and HIV-2-infected Senegalese individuals VACCINE Dieye, T. N., Sow, P. S., Simonart, T., Gueye-Ndiaye, A., Popper, S. J., Delforge, M. L., Dieye, A., Sarr, A. D., Crusiaux, A., Van Vooren, J. P., Devleeschouwer, M., Kanki, P., Mboup, S., Diakhate, L., Farber, C. M. 2001; 20 (5-6): 905-913

    Abstract

    Twelve HIV-1-infected, nine HIV-2-infected patients and eight HIV-negative subjects were given a 40IU booster dose of tetanus toxoid (TT). Blood was collected on days 0, 7 and 30 after immunization. Changes in HIV-1 or HIV-2 RNA load were evaluated by nested PCR. TT-IgG antibody levels were quantified by ELISA. CD4 cell counts as well as activation, memory and maturation markers of T lymphocyte subsets were determined by flow cytometry. The induction of apoptosis was investigated using 7-aminoactinomycin D (AAD) and propidium iodide (PI) staining. Proliferative responses to TT and pokeweed mitogen (PWM) were determined by the level of [(3)H] thymidine incorporation. Seven and 30 days after immunization, there was no detectable increase in HIV-1 or HIV-2 plasma load. There were also no changes in CD4 cell counts, CD69, HLA-DR and memory CD45RO or naive CD45RA antigens. Immunization did not increase the spontaneous apoptosis of peripheral blood mononuclear cells (PBMCs), CD4+ and CD8+ T cells subsets neither in controls nor in HIV-infected patients. Similarly, apoptosis induced in vitro by PWM or by the specific TT recall antigen did not vary during the study period. The proliferative response to PWM and to the TT recall antigen was decreased both in HIV-1- and HIV-2-infected patients compared to HIV-negative controls. Immunization significantly increased the TT-IgG levels in healthy controls and in HIV-infected patients. However, the anti-TT-IgG response, as measured by the fold-increase index between days 0 and 30, was significantly higher in healthy controls than in HIV-1- (P=0.036) and HIV-2-infected patients (P=0.003). In conclusion, we found no deleterious immunologic or virologic effect was detected in healthy HIV-1- and HIV-2-infected individuals after antigenic challenge with a TT booster. However, the response to TT vaccination was lower in HIV-1- and in HIV-2-infected individuals than in healthy HIV-negative controls.

    View details for Web of Science ID 000172871700031

    View details for PubMedID 11738756

  • Robust HIV type 2 cellular immune response measured by a modified anthrax toxin-based enzyme-linked immunospot assay AIDS RESEARCH AND HUMAN RETROVIRUSES Sarr, A. D., Lu, Y. C., Sankale, J. L., Eisen, G., Popper, S., Mboup, S., Kanki, P. J., Cao, H. Y. 2001; 17 (13): 1257-1264

    Abstract

    Evaluation of immune mechanisms responsible for control of viral replication is critical to understanding HIV-2 attenuated biological characteristics in pathogenesis and transmission. Evaluation of the cellular immune response is often based on labor-intensive techniques that limit the scope of most studies performed. A simple and rapid anthrax toxin-based ELISPOT method to assess HIV-2 cellular immune response was developed. The modified anthrax toxin-based antigen presentation process performed better than a recombinant vaccinia system and the ELISPOT method significantly enhanced the ease and simplicity of the assay. Using this method, a robust HIV-2 cellular immune response directed toward the p26 core protein was exhibited in 21 of 24 (87.5%) infected women, and all 8 seronegative subjects were negative in both assays. Cellular immune responses were associated with low HIV-2 viral load. This simple and rapid modified anthrax toxin-based ELISPOT method allowed us to demonstrate, strong cellular immune responses that may be critical determinants in the HIV-2 attenuated phenotype.

    View details for Web of Science ID 000170923900005

    View details for PubMedID 11559425

  • Low plasma human immunodeficiency virus type 2 viral load is independent of proviral load: Low virus production in vivo JOURNAL OF VIROLOGY Popper, S. J., Sarr, A. D., Gueye-Ndiaye, A., Mboup, S., Essex, M. E., Kanki, P. J. 2000; 74 (3): 1554-1557

    Abstract

    Levels of virus in the plasma are closely related to the pathogenicity of human immunodeficiency virus type 1 (HIV-1). HIV-2 is much less pathogenic than HIV-1, and infection with HIV-2 leads to significantly lower plasma viral load. To identify the source of this difference, we measured both viral RNA and proviral DNA in matched samples from 34 HIV-2-infected individuals. Nearly half had undetectable viral RNA loads (<100 copies/ml), but levels of proviral DNA were relatively high and confirmed that quantities of provirus in HIV-1 and HIV-2 infection were similar. Overall, HIV-2 proviral DNA load did not correlate with viral RNA load, and higher viral RNA load was associated with increased production of plasma virus from the proviral template. These results suggest that low viral load in HIV-2 infection is due to decreased rates of viral production, rather than differences in target cell infectivity.

    View details for Web of Science ID 000084738100055

    View details for PubMedID 10627569

    View details for PubMedCentralID PMC111493

  • Lower human immunodeficiency virus (HIV) type 2 viral load reflects the difference in pathogenicity of HIV-1 and HIV-2 JOURNAL OF INFECTIOUS DISEASES Popper, S. J., Sarr, A. D., Travers, K. U., Gueye-Ndiaye, A., Mboup, S., Essex, M. E., Kanki, P. J. 1999; 180 (4): 1116-1121

    Abstract

    Human immunodeficiency virus type 2 (HIV-2) is less pathogenic than HIV type 1 (HIV-1), but the mechanisms underlying this difference have not been defined. We developed an internally controlled quantitative reverse transcriptase-polymerase chain reaction to measure HIV-2 viral load and determined levels of plasma virus in a cohort of registered commercial sex workers in Dakar, Senegal. The assay has a lower limit of detection of 100 copies/mL and is linear over 4 logs. HIV-2 viral RNA was detectable in 56% of all samples tested; the median load was 141 copies/mL. Levels of viral RNA in the plasma were inversely related to CD4+ cell counts. HIV-2 and HIV-1 viral loads were compared among the seroincident women in the cohort; the median viral load was 30x lower in the HIV-2-infected women (P<.001, Wilcoxon rank sum test), irrespective of the length of time infected. This suggests that plasma viremia is linked to the differences in the pathogenicity of the 2 viruses.

    View details for Web of Science ID 000083019500024

    View details for PubMedID 10479138

  • Relation between HIV-2 proviral load and CD4(+) lymphocyte count differs in monotypic and dual HIV infections JOURNAL OF HUMAN VIROLOGY Sarr, A. D., Popper, S., Thior, I., Hamel, D. J., Sankale, J. L., Siby, T., Marlink, R., Essex, M., Mboup, S., Kanki, P. 1999; 2 (1): 45-51

    Abstract

    To explore and compare the relations between proviral DNA load and CD4+ lymphocyte counts in both HIV-2 monotypic and HIV dual infection.In Dakar, Senegal, where the HIV-1 and HIV-2 epidemics overlap, serum and peripheral blood mononuclear cell (PBMC) DNA samples were collected from registered female sex workers and hospitalized patients. Sera were evaluated for reactivity to antigens of HIV-1 and HIV-2 by immunoblot; dual reactivity was confirmed with recombinant envelope peptides for HIV-1 and HIV-2. These samples were then subjected to HIV-1 and HIV-2 proviral DNA polymerase chain reaction (PCR). To evaluate the HIV-2 cellular proviral DNA loads, a quantitative competitive PCR (QC-PCR) was developed using nested primers to amplify the gag region of HIV-2. This assay used an internal competitor generated by inserting 25 bp in the first-round PCR target sequence. T-lymphocyte subset counts were estimated by flow cytometry for both HIV-2 monotypic and dually infected persons.35 HIV-2-infected and 33 dually seroreactive samples were evaluated in this study. The CD4+ lymphocyte counts were similar in both groups, with mean values of 449 +/- 390 cells/mm3 for the HIV-2 monotypic infected persons and 476 +/- 308 cells/mm3 among the dually infected persons. However, the median proviral loads differed significantly, with those in the HIV-2 group ranging from 63.2 to 669.8 copies/10(5) CD4+ cells and demonstrating an inverse correlation with CD4+ lymphocyte count. The HIV dually infected persons showed less variation in viral load, ranging from 9.9 to 43.3 copies/10(5) CD4+ cells. Among the HIV dually infected persons, low HIV-2 proviral load was correlated with low CD4+ lymphocyte counts.The HIV-2 proviral loads in HIV dually infected persons were significantly lower than those in HIV-2 monotypically infected individuals (P < .0001), despite comparable CD4+ lymphocyte counts. These results suggest that different HIV-2 proviral dynamics prevail in HIV dual infection.

    View details for Web of Science ID 000083084900007

    View details for PubMedID 10200599

  • Antibodies to the HIV type 2 core protein p26 and Vpx: Association with disease progression AIDS RESEARCH AND HUMAN RETROVIRUSES Popper, S. J., Sankale, J. L., Thior, I., Siby, T., Marlink, R. G., Mboup, S., Essex, M., Kanki, P. J. 1998; 14 (13): 1157-1162

    Abstract

    A longitudinal cohort study was conducted to define the prevalence and temporal pattern of antibody response to the HIV-2 virion-associated proteins p26gag and Vpx. One hundred and forty-one asymptomatic HIV-2-infected women were enrolled, and followed for up to 11 years. Eighty-one percent of the subjects had antibodies to p26, and 51% to Vpx; response to these two antigens was not correlated. The response to both proteins was determined early in infection, and remained stable over time. The absence of antibodies to p26 was a highly significant predictor of CDC category IV HIV-related disease (p < 0.01) in both univariate and multivariate analysis. Antibody response to Vpx alone was not associated with disease progression. However, those individuals lacking anti-p26 antibodies, and with anti-Vpx antibodies, were six times more likely to be classified as CDC category IV by the end of the study (p < 0.01). This represents the first identification of virus-specific serological markers for HIV-2-related disease progression.

    View details for Web of Science ID 000075685400006

    View details for PubMedID 9737587

  • AMPLIFICATION OF KINETOPLAST DNA AS A TOOL IN THE DETECTION AND DIAGNOSIS OF LEISHMANIA EXPERIMENTAL PARASITOLOGY Rodgers, M. R., Popper, S. J., Wirth, D. F. 1990; 71 (3): 267-275

    Abstract

    This paper demonstrates how the polymerase chain reaction can be used to increase the sensitivity of detection of Leishmania parasites by DNA hybridization methods through the amplification of the minicircle target sequence. The oligonucleotide primers used are able to direct the amplification of all Leishmania strains tested. In addition, the PCR products from L. mexicana and L. braziliensis strains can be distinguished by hybridization with kDNA probes. The method is sensitive enough to detect the kDNA from a single organism and this sensitivity allows the use of nonradioactive hybridization methods. This method can be used to detect Leishmania from human biopsy material.

    View details for Web of Science ID A1990EC57700003

    View details for PubMedID 2170165